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ISSN: Print -2349-0977, Online - 2349-4387

 Table of Contents  
Year : 2018  |  Volume : 5  |  Issue : 1  |  Page : 10-25

The neurology timeline: Of demon holes, sacred pathways and great triumphs

Department of Radiodiagnosis, Pulmonary Medicine, Neurology, and Nuclear Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India

Date of Web Publication28-Jan-2019

Correspondence Address:
Pranav Ish
Department of Pulmonary Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2349-0977.250925

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The first chapter in neurology was composed in the prescience era. Chiseled with flint stones, grisly in nature, it was a narrative where men trephined human skull to treat such maladies as head injury, epilepsy, and disturbed mind. The ungodly practice survived from the late Stone Age until the renaissance. The first written reference to brain is found in the Edwin Smith surgical papyri. Written around 3000 BCE in Egypt, the papyri describe certain cognitive defects of head injuries. The first sapient exploration into the functions and diseases of brain opened in the sixth to fourth century BCE. It began with the Alexandrian anatomists and Hippocratic doctors, gathered steam in the classical era of science with Galen in the first century, and reached its peak with Vesalius during renaissance. Modern neurology, particularly the localization of brain functions, began with German physician Franz Joseph Gall's work on phrenology in the late 18th century and, over the next hundred years, was followed by the discovery of language, motor, and sensory cortical areas. The idea that the nervous system is made up of discrete nerve cells was born out of the neuroanatomical work of Camillo Golgi and a Spanish doctor, Santiago Ramón y Cajal, at the end of 19th century. Major 20th-century developments include advances in understanding of the frontal lobes, the role of visual cortex in perception, the function of hippocampus in memory, lateralization of cortical function, and the introduction of all revealing cross-sectional and functional imaging. While practitioners of medicine across the world unraveled the secrets of maladies that strike the seat of senses and intellect, other accomplished players struck sweet melodies of life by discovering potent molecules, devices, and surgical techniques which could work a remedy and cure.

Keywords: Advances, Cajal, Egas Moniz, Golgi, history, phrenology, Trepanning

How to cite this article:
Agarwal Y, Ish P, Chaudhry N, Sethi RS. The neurology timeline: Of demon holes, sacred pathways and great triumphs. Astrocyte 2018;5:10-25

How to cite this URL:
Agarwal Y, Ish P, Chaudhry N, Sethi RS. The neurology timeline: Of demon holes, sacred pathways and great triumphs. Astrocyte [serial online] 2018 [cited 2023 Dec 1];5:10-25. Available from: http://www.astrocyte.in/text.asp?2018/5/1/10/250925

  10,000 BCE Top

Shadows of demon holes

Practiced from the late Paleolithic period, perhaps the oldest known neurological procedure is trepanning or trephining, the removal of a piece of bone from the skull, using flint implements.

The motivation for trephining in nonliterate cultures is obscure but may have been related to the treatment of epilepsy, headaches, and mental disease, or for relief of symptoms thought to have been caused by demonic forces. The procedure was probably done to allow the escape of a demon.

Across geographic regions, human skulls have been found bearing evidence of these “demon holes.” Some skulls harbor several holes from repeated trepanning. Sometimes, the holes have healed edges, showing that some patients actually survived the operation [Figure 1].[1],[2]
Figure 1: Ancient Inca witch-surgeons created perfect holes in the skulls of patients using flint surgical tools.

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  4000 BCE Top

The observant Sumerians

Known for their hunting skills, the Sumerians recognized that physical trauma produced by the impact of an arrow in the back could lead to paraplegia in a lion [Figure 2].
Figure 2: Bas relief sculpture portraying a paraplegic lion {Sumerian, 4000 BCE}.

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  3000 BCE Top

Observations of a battlefield surgeon

Dating back to the land of Nile – Egypt, around 3000 BCE, the Edwin Smith Surgical papyri are thought to be a handbook for a battlefield surgeon. Interestingly, it also carries observations on signs of head injury, which may present with features of aphasia and seizures [Figure 3].[3]
Figure 3: The Edwin Smith surgical papyri carry interesting observations on head injuries, pulsations of the brain, and lateralizing signs of trauma.

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  570–500 BCE Top

Seat of cognition and sensation

Thought of as one of the most eminent medical theorists of antiquity, Alcmaeon of Croton [Figure 4], head of a medical school in southern Italy, was the first physician to advocate that brain is the seat of sensation and cognition. He wrote:
Figure 4: Alcmaeon of Croton. He was the first to recognize the significance of brain.

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The seat of sensations is in the brain. This contains the governing faculty. All the senses are connected in some way with the brain; consequently, they are incapable of action if the brain is disturbed or shifts its position, for this stops up the passages through which senses act. This power of the brain to synthesize sensations makes it also the seat of thought: the storing up of perceptions gives memory and belief, and when these are stabilized you get knowledge.[2]

Alcmaeon is reported to have been the first to use dissection as a tool for intellectual inquiry. He dissected the eye and described the optic nerves and chiasm and suggested they brought light to the brain.[4]

  ~425 BCE Top

On the sacred disease

Widely regarded as the father of medicine, ancient Greek physician Hippocrates [Figure 5], born in ca. 460 BCE, Island of Cos, Greece and died in ca. 375 BCE, Larissa, Thessaly, who lived during Greece's classical period, left behind a large corpus of scientific writings and over 60 treatises. Of them, of greatest relevance to neurology is the famed essay “On the Sacred Disease,” aka epilepsy, where the work identifies the brain as the seat of epilepsy and discounts its divine nature.[5] The treatise waxes eloquently on the general functions of the brain:
Figure 5: Hippocrates of Island of Cos. He broke out of orthodoxy and thought of epilepsy as a disease centered in the brain rather than a sacred disease.

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It ought to be generally known that the source of our pleasure, merriment, laughter and amusement, as of our grief, pain, anxiety and tears is none other than the brain. It is specially the organ which enables us to think, see, and hear and to distinguish the ugly and the beautiful, the bad and the good, pleasant and unpleasant. it is the brain too which is the seat of madness and delirium.[2]

  Second Century AD Top

Birth of experimental neurology

Galen of Pergamon (129–213) was the first physician, anatomist, and physiologist to unveil the gross anatomy and functions of the brain. Though dissection of human cadavers was taboo in the era, Galen's description of the gross anatomy of the brain was the most accurate, particularly in relation to the ventricles and cerebral circulation. His work was mostly based on oxen anatomy.[6]

Using animal models, he carried out the first systematic experiments on the functions of the nervous system. He could establish that a brain injury could impair sensory perception even when the (peripheral) sense organs were intact. Likewise, if the animal's recurrent laryngeal nerve was bisected, the animal could no longer squeal [Figure 6].[7]
Figure 6: Galen demonstrating the effect of bisecting of the recurrent laryngeal nerve in a squealing pig.

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Galen's work on cranial nerves and spinal cord was outstanding. He described seven of the cranial nerves and tried to experimentally determine their functions. He studied the effects of transections of the spinal cord at various levels and concluded that the spinal cord was an extension of the brain and the conduit of sensory signals from and motor commands to the body below the head. He stated that specific spinal nerves controlled specific muscles and held the view that mental diseases were all diseases of the brain.

  Fifth to 15th Century AD Top

The bizarre ventricular doctrine

During the Dark Ages, Europe harbored a totally flawed view of the brain function. It was thought that mental faculties were localized in the ventricles [Figure 7]. The belief was that the anterior (frontal horns of the lateral) ventricle received inputs from the sense organs and was the site of “common sense.” The sensations yielded images, and thus, fantasy and imagination were also considered to be seated in the anterior ventricle. The middle ventricle was considered the seat of cognition: reasoning, judgment, and thought. The posterior (fourth) ventricle was thought as the seat of memory.[2]
Figure 7: The flawed medieval ventricular doctrine. The belief was that inputs from the nose, tongue, eye, and ear go to the first ventricle which houses common sense, fantasy, and imagination. The second ventricle contains thought and judgment; memory is in the third ventricle.

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  1543 AD Top

Executed criminals light anatomy renaissance

Dissecting the bodies of executed criminals in Padua, and lighting the torch of evidence based knowledge, Flemish anatomist, physician, and author Andreas Vesalius published “De humani corporis fabrica libri septem” (On the Fabric of the Human Body), setting the foundation of modern human anatomy. With this watershed work, the structure of the human body became a subject to be studied systematically by dissecting human cadavers [Figure 8].
Figure 8: Through his outstanding work on human cadavers, a first, master anatomist, Andreas Vesalius, gave birth to modern anatomy.

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Vesalius disapproved of the crude medieval drawings of ventricular localization of mental function. He stated, “Such are the inventions of those who never look into our Maker's ingenuity in the building of the human body.” He was modest enough to concede that a greater understanding of brain anatomy could not pry open the lid on how the brain functioned: “How the brain performs its functions in imagination, in reasoning, in thinking and in memory. I can form no opinion whatsoever. Nor do I think that anything more will befound out by anatomy.”[2]

  1650 Ad Top

Understanding the etiology of stroke

Until the mid-1600s, nobody knew what caused stroke. It was the Swiss physician Johann Jakob Wepfer who first identified that patients who died with stroke had hemorrhage in the brain. He also recognized that stroke could also be caused by a blockage of one of the main arteries that supply blood to the brain. From postmortem studies, he provided information on the carotid and vertebral arteries that supply the brain with blood. In 1658, he published a classic treatise on strokes, titled Historiae


  1664 AD Top

Birth of neurology

The first comprehensive text on the brain, Cerebri Anatomie, authored by the English physician Thomas Willis [Figure 9]a was published in 1664. The work dealt not only with brain anatomy but also with neurophysiology, neurochemistry, and clinical neurology and introduced for the first time the term “neurology.” Cerebri Anatomie was the intellectual produce of a group of savants known as the Virtuosi, such as Robert Boyle and Christopher Wren, who later became founding members of the new Royal Society.[8]

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Willis rejected the medieval belief of ventricles being the seats of higher psychological functions. He instead associated “the critical and grey part of the cerebrum” in memory and will. He ascribed voluntary movements to the cortex but involuntary ones to the cerebellum. His ideas on brain function came from his own experiments on brain lesions in animals, from the correlation of the effects of human brain damage with post mortem pathology, and from the comparison of the brains of various animals with those of humans.

Willis defined the mesolobe (corpus callosum), corpora striata, and the optic thalami. In the cerebellum, he described the arborescent arrangement of the white and grey matter and gave an account of the internal carotids and their communication with the branches of the basilar artery.[9] The complex vascular supply of the brain was first described by him, and for that reason, the circle of arteries at the base of the brain has been named after him [Figure 9]b.

  1780 AD Top

From frog's legs to action potential

Using his frog nerve-muscle preparation, Italian physician, physicist, and biologist, Luigi Aloisio Galvani (1737–1798) [Figure 10] discovered that the muscles of dead frogs' legs twitched when struck by an electrical spark. This led to the birth of bioelectricity, a field that studies the electrical patterns and signals from tissues such as the nerves and muscles.[2]
Figure 10: Italian physician Luigi Galvani (1737–1798): known for his seminal work on bioelectricity.

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  1796 AD Top

The beginning of modern neuroscience

German anatomist and physiologist, Franz Joseph Gall's idea that different regions of the cerebral cortex possess different function was truly revolutionary for his time. Gall [Figure 11] worked with a fellow German physician JC Spurzheim (1776–1832) to create a popular phrenology wave in neurosciences, which swept across continents taking Europe and the Unites States by storm.[2]
Figure 11: German physician Franz Joseph Gall (1748–1828) gave birth to the idea of phrenology.

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The central aim of phrenology was to correlate brain structure and function. It was based on five basic assumptions [2]:

  1. The brain is an elaborately wired machine for producing behavior, thought, and emotions
  2. The cerebral cortex is a set of organs, each corresponding to an affective or intellectual function
  3. Differences in traits among people and within individuals depend on differential development of different cortical areas
  4. Development of a cortical area is reflected in its size
  5. Size of a cortical area is correlated with the overlying skull (“bumps”)

Gall and Spurzheim collected large numbers of skulls of people whose traits and abilities were known, examined the heads of distinguished savants and inhabitants of mental hospitals and prisons, and studied portraits of the high and low born on various intellectual and affective dimensions. In spite of its absurdities and excesses, phrenology became a major stimulus for the development of modern neuroscience. It generated an interest in the brain and behavior. It directed attention to the cerebral cortex. It stimulated study of both human brain damage and experimental lesions in animals. It inspired tracing pathways from sense organs and to the muscles in order to identify “organs” of the cerebral cortex. It spurred the anatomical subdivision of the cerebral cortex by way of cytoarchitectonics and myeloarchitectonics to find organs of the brain [Figure 12].[10]
Figure 12: The well-demarcated phrenological regions: a figment of ingenuity that laid the foundation of the concept that different regions of the cerebral cortex possess different functions.

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  1857 AD Top

The first antiepileptic

Until the mid-1850s, the treatment of epilepsy mostly rested on herbal and chemical substances. It was in 1857 that Sir Charles Locock Granger (1799–1875) [Figure 13] identifying the anticonvulsant and sedative properties of potassium bromide introduced it as an antiepileptic. Potassium bromide continued to be a choice treatment for patients with epileptic seizures and nervous disorders till 1912, when phenobarbital was discovered.[11],[12]
Figure 13: British neurologist Sir Charles Locock introduced potassium bromide as an antiepileptic.

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  1861 AD Top

Language and the brain

Based on the experience with two of his head injury patients who had lost the ability to speak following injury to the posterior inferior frontal gyrus of the left hemisphere of the brain, French surgeon Pierre Paul Broca [Figure 14]a identified that this area of the brain was critical for the generation of articulate speech. Since then, this region has eponymously come to be known as the Broca's area, and the deficit in language production as Broca's aphasia, also called expressive aphasia.[13]

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Over time, the Broca's area has become better defined. It is now typically defined in terms of the pars opercularis and pars triangularis of the inferior frontal gyrus, represented in Brodmann's cytoarchitectonic map as Brodmann areas 44 and 45 of the dominant hemisphere [Figure 14]b. Functional magnetic resonance imaging (MRI) has shown language processing to also involve the third part of the inferior frontal gyrus the pars orbitalis, as well as the ventral part of BA6, and these are now often included in a larger area called Broca's region.

In addition to serving a role in speech production, the Broca area also is involved in language comprehension, in motor-related activities associated with hand movements, and in sensorimotor learning and integration.

  1868 AD Top

Spatial abilities and the brain

In “Notes on the Physiology and Pathology of the Nervous System,” British neurologist John Hughlings Jackson (1835–1911) reported how the damage to the right hemisphere impairs spatial abilities.[2]

  1870 AD Top

Discovery of motor cortex

Until the 1700s, most physicians considered the cortex to be a functionally insignificant outer shell of the brain. This corresponds to its original meaning when translated from Latin, which is “bark.” By the 1800s, however, neuroscientists had begun to assign functions to the cerebral cortex.

Still, the simple truth that the cerebral cortex controls the motor functions was not known until 1870, when German physiologist Gustav Theodor Fritsch [Figure 15] and neurologist Eduard Hitzig [Figure 16] carried out a morbid experiment that was typical of the day. They restrained live dogs and, without giving them any anesthesia, cut away the dogs' skulls to expose an area of cortex. Then, they stimulated that cortex with electric current from a battery. Fritsch and Hitzig saw that stimulation of the cortex caused movement of the dogs' contralateral muscles. Furthermore, they found that the stimulation produced movement in a predictable way, as if certain areas of the body were mapped onto the cortex. This was the first widely recognized piece of experimental evidence, which helped establish the presence of what would eventually be known as the motor cortex. Hitzig and Fritsch went on to support their findings by damaging areas of the cortex in dogs and observing that the dogs then had difficulty with movement in the opposite side of the body.[2]
Figure 15: German physiologist Gustav Fritsch 1838–1927.

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Figure 16: German neurologist Eduard Hitzig (1838–1907).

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Fritsch and Hitzig had no hesitation in announcing the general significance of their discovery:

By the results of our own investigations, the premises for many conclusions about the basic properties of the brain are changed not a little... some psychological functions, and perhaps all of them... need circumscribed centers of the cerebral cortex.[2]

  1873 Ad Top

Christening of multiple sclerosis

Considered as one of the founding fathers of neurology, and celebrated for his astute clinical observations, French physician Jean-Martin Charcot first described and named multiple sclerosis in 1873.[14] Based on the previous reports and adding his own clinical and pathological observations, Charcot [Figure 17] called the disease sclérose en plaques describing the three signs of multiple sclerosis – nystagmus, intention tremor, and telegraphic speech – together known as Charcot's triad. Charcot also observed the cognition changes, describing it as “marked enfeeblement of the memory” and “conceptions that formed slowly.”[15]
Figure 17: French physician Jean-Martin Charcot (1825–1893). He was also deeply interested in the subject of hysteria.

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Charcot's contribution to neurology is a legend. He was the first to describe the Charcot joint, a degeneration of joint surfaces resulting from loss of proprioception; research the functions of different parts of the brain and the role of arteries in cerebral hemorrhage; first to describe Charcot–Marie–Tooth disease or peroneal muscular atrophy; and his studies between 1868 and 1881 were a landmark in the understanding of Parkinson's disease (PD), when he differentiated between rigidity, weakness, and bradykinesia and renamed the disease, formerly named paralysis agitans after James Parkinson.

  1873 Ad Top

Developing an understanding of epilepsy

British neurologist John Hughlings Jackson (1835–1911) [Figure 18] set the research on epilepsy on a solid scientific base. He pioneered the study of epilepsy on pathological and anatomical basis. One of the first to state that abnormal mental states may result from structural brain damage, in the year 1863, he discovered epileptic convulsions, now known as Jacksonian epilepsy, that progress through the body in a series of spasms, and in 1875, he traced them to lesions of the motor region of the cerebral cortex, or outer layer of the brain. Jackson's epilepsy studies initiated the development of modern methods of clinical localization of brain lesions and the investigation of localized brain functions. His work Study of Convulsions was the culmination of his research stressing the existence of localized lesions on cortex involved in epileptic convulsions. In 1873, Jackson gave the following definition for epilepsy: “Epilepsy is the name for occasional, sudden, excessive, rapid and local discharges of grey matter.” This definition was subsequently confirmed by electroencephalography.[11]
Figure 18: British neurologist John Hughlings Jackson, who gave a solid basis to understanding of epilepsy.

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  1873–1897 AD Top

Birth of Golgi stain and neuron doctrine

As a physician at a home for incurables in Abbiategrasso, Italy, and with only rudimentary facilities at his disposal, Italian physician and cytologist Camillo Golgi [Figure 19] devised the silver nitrate method of staining nerve tissue, an invaluable tool in subsequent nerve studies. This stain enabled him to demonstrate the existence of a kind of nerve cell (which came to be known as the Golgi cell) possessing many short, branching extensions (dendrites) and serving to connect several other nerve cells.[2]
Figure 19: Italian cytologist Camillo Golgi. He developed the Golgi stain.

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The discovery of Golgi cells led the German anatomist Wilhelm von Waldeyer-Hartz [Figure 20] to postulate, and Spanish histologist Santiago Ramón y Cajal [Figure 21] to establish in 1891, that the nerve cell is the basic structural unit of the nervous system, a critical point in the development of modern neurology.[2]
Figure 20: German cytologist Wilhelm von Waldeyer-Hartz.

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Figure 21: Spanish histologist Santiago Ramón y Cajal.

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The 1890s were also the years when the cellular lexicon of neurology was born. While the term “dendrite” was coined by Wilhelm His in 1890, “neuron” was coined by Wilhelm von Waldeyer in 1891, “axon” by Albrecht von Kolliker in 1896, and “synapse” by Charles Sherrington in 1897.[2]

For his investigations into the fine structure of the nervous system, Camillo Golgi received the 1906 Nobel Prize for Medicine, sharing it with Santiago Ramón y Cajal.

  1874 AD Top

Wernicke describes sensory aphasia

German neurologist Carl Wernicke [Figure 22] established that loss of linguistic skills, or sensory aphasia, is related to damage to the left temporal lobe. Seven years later, in 1881, he published his famous work titled Lehrbuch der Gehirnkrankheiten (Textbook of Brain Disorders). The work is a comprehensive attempt to account for cerebral localization of all neurologic diseases. It described some neurological disorders for the first time, Wernicke's encephalopathy, caused by thiamine deficiency being one of them.[2]
Figure 22: German neurologist Carl Wernicke.

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  1876 AD Top

Mapping the brain

Scottish neurologist Sir David Ferrier [Figure 23] published his first work “The Functions of the Brain” providing a map of the regions in brain which specialize in motor, sensory, and association functions. The work described his experimental results and became very influential in the succeeding years, to become one of the classics of neuroscience. In 1886, he published a new edition, considerably expanded and reviewed.[2]
Figure 23: Scottish neurologist Sir David Ferrier.

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The second book, which was published 2 years later – The Localization of Brain Disease – had as its subject the clinical applications of cortical localization. Together with his friends Hughlings Jackson and Crichton-Browne, Ferrier was one of the founders of the journal Brain in 1878, which was dedicated to the interaction between experimental and clinical neurology and is still published today.[2]

  1896 AD Top

The Babinski Sign

A chance observation of contrasting toe reflex between two female patients, one a hysteric and the other a hemiplegic, led French neurologist Joseph Jules François Félix Babinski [Figure 24] to describe the pathognomic Babinski sign in 1896. He observed that on scratching the lateral aspect of the sole, the great toe turned upward in cases where the spinal cord or brain harbored a lesion (upper motor neuron lesion). He named the phenomenon “phenomenon desorteils,” or more simply, the phenomenon of the great toe.[16]
Figure 24: French neurologist Joseph Babinski.

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  1912 AD Top

Emergence of phenobarbital

A German physician Hauptmann (1881–1948) introduced phenobarbital [Figure 25] in the therapy of epilepsy as one of the first antiepileptic drugs. Phenobarbital was brought to market by the drug company Bayer using the brand Luminal. Hauptmann administered Luminal to his epilepsy patients as a tranquilizer and discovered that their epileptic attacks were susceptible to the drug.[11]
Figure 25: Molecular structure of phenobarbital.

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  1924 Ad Top

Recording the brain waves

German physician-psychiatrist Hans Berger makes a historical breakthrough by making a recording of the electrical waves of brain on July 6, 1924. This first EEG (electroencephalogram) was taken during a neurosurgical operation on a 17-year-old boy, performed by the neurosurgeon Nikolai Guleke. Berger reported his research in 1929, using the terms alpha and beta waves.[17] In 1932, Berger [Figure 26] reported sequential postictal EEG changes after a generalized tonic–clonic seizure, and in 1933, he published the first example of interictal changes and a minor epileptic seizure with 3/s rhythmic waves in the EEG. In the next few years until 1939, Berger made important observations on patients and on healthy subjects. His work on epileptic EEG was completed by the American neurologist, Frederic Andrews Gibbs (1903–1992), and his wife Erna Leonhardt-Gibbs (1904–1987). In collaboration with W. Lennox, she established the correlation between EEG findings and epileptic convulsions. Lennox and Gibbs published in 1941 their monumental monograph  Atlas More Details of Electroencephalography, in which they included also mechanical and mathematical analysis of EEGs.[18]
Figure 26: German physician-psychiatrist Hans Berger with the electro-encephalogram of his daughter.

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The discovery of electroencephalography proved to be a major milestone in the advancement of neuroscience and of neurologic and neurosurgical practice, especially in patients with seizures.

  1927 AD Top

Birth of cerebral angiography

The art and science of cerebral angiography [Figure 27] was pioneered by António Caetano de Abreu Freire Egas Moniz, widely known as Egas Moniz [Figure 28], a Portuguese neurologist. During his experiments, Moniz injected radiopaque dyes into brain arteries and took X-rays to visualize abnormalities.[19] His epoch-making work eased the diagnosis of internal carotid occlusion, angiomatous malformations, intracranial aneurysms, and a host of intracranial tumors, offering precise information from therapeutic and surgical perspective.
Figure 27: The first cerebral angiography in a human subject was performed by Egas Moniz in 1927.

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Figure 28: Portuguese neurologist Egas Moniz featured on a 10,000 Escudos currency note of 1989 of Bank of Portugal.

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A few years later, Egas Moniz pioneered the surgical procedure of leucotomy, thus becoming a father figure in modern psychosurgery. The first leucotomy was performed in a female patient with depression, anxiety, paranoia, hallucinations, and insomnia. She experienced a dramatic recovery, becoming far more calm, less paranoid, and well oriented within 2 months. Leucotomy later gave way to lobotomy, while Moniz became the first Portuguese to receive a Nobel Prize in 1949.[20],[21]

  1938 AD Top

Launch of phenytoin as antiepileptic

Phenytoin [Figure 29] was introduced in the therapy of epilepsy. Although synthesized by Heinrich Biltz in 1908, it held no interest as an antiepileptic till 1938 since it did not have any sedative properties. Merritt (1902–1979), an eminent academic neurologist, along with Putnam (1894–1975), discovered, in 1938, the anticonvulsant properties of phenytoin and its effect on the control of epileptic seizures publishing their results in a series of papers.[22]
Figure 29: Molecular structure of phenytoin.

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Phenytoin soon became the first-line medication for the prevention of partial and tonic–clonic seizures and for acute cases of epilepsies or status epilepticus, giving an alternative therapeutic choice for patients not responding to bromides or barbiturates.

  1950 AD Top

Unlocking the secret of memory

American psychologist and behaviorist, Karl Spencer Lashley [Figure 30], experimented to unlock the secrets of learning and memory. Using rats for his experiments, he trained them to perform specific tasks, then induced carefully quantified specific brain cortex damage, either before or after the animals had received the training. The cortical lesions had definite effects on acquisition and retention of knowledge, but the location of the removed cortex had no effect on the rats' performance. This led Lashley to conclude that memory is not localized to any one part of the brain but is widely distributed throughout the cortex.
Figure 30: Karl Spencer Lashley (1890–1958) worked hard to unlock the secrets of memory.

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Lashley's work had a wide-ranging impact on the study and understanding of learning, memory, and other key brain functions.

  1949 AD Top

The discovery of limbic system

American physician and neuroscientist, Paul Donald MacLean [Figure 31], gave birth to the term “limbic system.” Composed of a complex set of structures that lie on both sides of the thalamus, just under the cerebrum, it includes the hypothalamus, the hippocampus, the amygdala, and several other neighboring cortical, subcortical, and diencephalic structures. It operates by influencing the endocrine system and the autonomic nervous system and is highly interconnected with the nucleus accumbens, which plays a role in sexual arousal and the “high” derived from certain recreational drugs. Besides being the nerve center of emotion, behavior, and motivation, it plays a key role in long-term memory and olfaction. These responses are heavily modulated by dopaminergic projections from the limbic system. Describing the limbic system in his seminal paper, Paul Maclean called it “the visceral brain.”
Figure 31: Paul MacLean was the first to describe the limbic system.

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  1950s Top

Birth of new antiepileptics

During the 1950s, many new antiepileptic drugs hit the market. Of them, carbamazepine came in 1953, primidone in 1954, ethosuximide in 1958, and sodium valproate in 1963.[23]

Carbamazepine [Figure 32] was synthesized by Schindler and Blattner at J. R. Geigy AG, Basel, Switzerland, in the course of development of another antidepressant drug imipramine. Its antiepileptic effects were reported in 1963 and 1964, and it came to be used as an anticonvulsant drug in the United Kingdom since 1965 and has been approved in the USA since 1974.[23]
Figure 32: Carbamazepine introduced as an antiepileptic in 1953.

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Ethosuximide was first introduced in clinical practice in the early 1950s for the therapy of absence “petit mal.”

Valproate, though initially synthesized in 1881 by Beverly Burton in the USA, was first released as an antiepileptic drug in France in 1967 following the publication of certain preclinical studies establishing its anticonvulsant properties. During 1970, it received the license to other European countries and was licensed in the USA in 1978.[24]

  1957 AD Top

The memory center hippocampus

A major advance in the neurology of memory came from the study of American patient Henry Gustav Molaison, widely known as HM [Figure 33]. He underwent an experimental surgery with surgeon William Scoville operating on him in 1953, wherein a bilateral medial temporal lobectomy was carried out to surgically resect the anterior two-thirds of his hippocampi, parahippocampal cortices, entorhinal cortices, piriform cortices, and amygdalae in an attempt to cure his epilepsy. Subsequent to the surgery, HM developed very severe anterograde amnesia: he appeared to be unable to store any new information for more than a few minutes, and his short-term memory never became long-term. Subsequent research indicated that only his “declarative” memory (memory for facts and events) was impaired, whereas his “procedural” memory (such as memory for motor and perceptual skills, and classical conditioning) was intact.[2]
Figure 33: American patient HM, who underwent a bilateral medial temporal lobectomy. Following surgery, he lost the ability to garner new memory for facts and events. He often wondered why he looked older than 27 years, the age at which he had undergone surgery.

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Similar dissociations between the two types of memory have been found in other patients after hippocampal damage. The hippocampus is necessary for the formation of long-term declarative memories, which appear to be stored in portions of the cerebral cortex.

  1970s Top

Newer antiepileptic drugs

Several new antiepileptic drugs were introduced during the 1970s. These included clobazam (1,5-benzodiazepine) in 1970, clonazepam (1,4-benzodiazepine) again in 1970, and piracetam, shortly after.[11]

  1972 AD Top

Birth of Computed Tomography Scan

Neuroradiology took a major leap in 1972 with the birth of a new computed tomography scanning technology. Opening a new three-dimensional window to the human body, the CT scan was invented simultaneously by two scientists working independently. British engineer Godfrey Newbold Hounsfield [Figure 34] of EMI laboratories conceived the CT scan in England, and South African born physicist Allan Cormack of Tufts University created it in the United States. The first machines were installed between 1974 and 1976 and were originally designed to scan the head. The whole-body systems came in 1976.
Figure 34: Sir Godfrey Hounsfield standing before his brainchild: a CT scan machine; with an anatomical cross-section of human brain.

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The birth of CT scan has revolutionized the diagnostic arena in the realm of neuroimaging. Over time, as the CT scanners have become more advanced, they have become faster and offer a far improved image quality. Current research in the field stands focused in providing still better image quality for greater diagnostic confidence and the use of lowest possible radiation dosage and exposure.

Sir Godfrey Hounsfield and Allan Cormack [Figure 35] jointly received the Nobel Prize in 1979 for their groundbreaking contribution.
Figure 35: Allan Cormack.

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  1975 AD Top

Functional mapping of brain

Washington University molecular biologists Michael E. Phelps, Edward Hoffman, and Michael M. Ter-Pogossian built the first(PET) positron emission tomography camera for human studies in 1975. A year later (1976), working at the Brookhaven National Laboratory National Institutes of Health (NIH), Louis Sokoloff, Alfred Wolf, and Joanna S. Fowler designed and synthesized 18FDG for the first human studies of brain energy metabolism.

Cerebral PET imaging [Figure 36] and radiotracer development have improved the understanding, diagnosis, and treatment of a number of neurologic disorders, including PD, dementias, and epilepsy. Furthermore, technology and computer-based algorithms have enhanced image resolution and greatly improved the use of PET as a clinical tool. Combining PET with CT or MRI has helped to delineate both function and anatomic localization over the last two decades.
Figure 36: Cerebral PET scan of the human brain.

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  1977 AD Top

The birth of “Indomitable”

A highly versatile radiation-free cross-sectional imaging technique, particularly useful in the clinical realm of neuroimaging, the success story of MRI, and its clinical advancements is a journey that spans more than half a century. While the NMR phenomenon was first described in the 1930s, with Isador Rabi, Felix Bloch, and Edward Purcell taking the lead, it was Paul Lauterbur (1909–2007), a chemist working at the State University of New York at Stony Brook, who published the first true MR image in Nature in March, 1973; and Peter Mansfield (1933–2017), a physicist working at the University of Nottingham, who demonstrated the same year (1973) how a linear field gradient could be used to localize the NMR signal on a slice-by-slice basis by stacking multiple 1-mm-thick sheets of solid camphor into the bore of an NMR spectrometer.

While Lauterbur and Mansfield were the basic scientists, it was an American physician, Raymond V. Damadian [Figure 37], while working as an Associate Professor of Medicine at the State University of New York, Brooklyn, who defined the role of NMR from a different and original perspective – as a phenomenon that might be used to probe the body and diagnose human disease. In one of his landmark early papers (Science, 1971), Damadian demonstrated that cancer cells had longer T1 and T2 values than normal cells. In 1972, he filed a US patent application for his work and went on to build with his team by mid-summer, 1977, the first whole-body MR machine by the name of Indomitable.
Figure 37: American physician Raymond V. Damadian with his creation, the first clinical MR machine Indomitable.

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Since those early years, the science and clinical potential of MRI has grown in a phenomenal way, and today, the MR is in the forefront not simply as an anatomical imaging tool but also as a functional imaging technology.

  1990s Top

A spate of newer antiepileptic drugs

The 1990s and later years have witnessed the birth of a large number of antiepileptic drugs [Figure 38]. These include vigabatrin (1989), zonisamide (1989), lamotrigine (1990), oxcarbazepine (1990), gabapentin (1993), felbamate (1993), topiramate (1995), tiagabine (1998), levetiracetam (2000), stiripentol (2002), pregabalin (2004), rufinamide (2004), lacosamide (2008), eslicarbazepine (2009), and perampanel (2012).[11]
Figure 38: A number of new antiepileptic agents have entered the market in the last two decades.

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  1990–2000 AD Top

A decade dedicated to neurology

Designating the 1990s as the Decade of the Brain [Figure 39], the Library of Congress and the National Institute of Mental Health at the US NIH sponsored a unique interagency initiative, with a central theme “to enhance public awareness of the benefits to be derived from brain research” through “appropriate programs, ceremonies, and activities.” A variety of activities including publications and programs were run as a part of the public health initiative to familiarize the people of the cutting-edge research on neurological disorders and encourage public dialogue on the ethical, philosophical, and humanistic implications of the new discoveries.
Figure 39: The 1990s were declared the “Decade of the Brain,” a significant public health initiative.

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  2009 AD Top

Unraveling networks of brain

The Human Connectome Project (HCP) [Figure 40] was born in 2009 at the US NIH. Created with the overarching objectives of acquiring, analyzing, and freely sharing information about brain circuitry and connectivity, its theme is to map the hundreds of functionally distinct areas or “parcels” of the human brain and to understand how these areas are connected and how each contributes to the complex human behavior. The project is also aimed at understanding how the brain's complex functional systems go askew in neurological and psychiatric diseases such as dyslexia, autism, Alzheimer's disease, and schizophrenia. The HCP theme continues to make a steady progress building a new “HCP-style” neuroimaging paradigm across the full human lifespan – from the time a fetus begins its journey in its mother's womb to the geriatric years of life. This understanding of the physiological and pathological brain mechanisms may pave effective molecular treatments for many neurological disorders someday.
Figure 40: The goal of Human Connectome Project is to map the anatomical and functional connectivity of the human brain.

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  2013 AD Top

The Human Brain Project

Launched on October 1, 2013, by the European Union, the “Human Brain Project” [Figure 41] is a global, collaborative initiative combining the fields of neuroscience, medicine and computing to understand the brain, its diseases, and its computational capabilities.
Figure 41: The Human Brain Project marshals exascale supercomputers to understand the human brain.

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It employs the exascale supercomputers computing systems capable of carrying out a billion–billion (i.e. a quintillion) calculations per second; and its core objective is to simulate the brain and to develop brain-inspired computing, data analytics, and robotics, and simultaneously, to gather, organize, and disseminate data describing the brain and its maladies.

  2014 AD Top

The stem cell repair shop

During the past one decade and more, efforts have been afoot to employ neural stem cells to promote the repair of injured or diseased central nervous system (CNS) tissue in a variety of clinical conditions. Characterized by their ability to self-renew and to generate the different cell types found in the CNS including both neural and glial subtypes, isolation and in vitro analysis of neural progenitor cell populations have been important for deciphering the cellular and molecular mechanisms underlying neurogenesis, and for optimizing stem-cell-based treatments.

In the adult mammalian brain, neural stem cells NSCs exist mainly in two neurogenic regions: the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Recently, the use of pluripotent stem cells [Figure 42] to make patient-derived neural progenitors has aided to generate more relevant “disease-in-a-dish” cellular models of many age-related neurological diseases. Success has simultaneously been found in the creation of three-dimensional neural cultures of human cortical spheroids (the Sergiu Pasca group) and neurons of the cerebellum from embryonic stem cells (the late Yoshiki Sasai group).
Figure 42: Stem cells carry a huge potential as reparative tools in central nervous system injuries and degenerative conditions.

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  2017 AD Top

A fountain of new molecules

During the year, the spring of neurology landscape was dotted with a number of new and effective therapeutic molecules [Figure 43]. While brivaracetam monotherapy received a nod in epilepsy, amantadine joined the bandwagon for treating levodopa-induced dyskinesia in patients with PD. The anti-PD medicine chest was richer with safinamide, specially approved for patients taking levodopa/carbidopa and experiencing motor fluctuations (OFF episodes).
Figure 43: Half a dozen new molecules joined the neurosciences therapeutic bandwagon in 2017.

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The treatment of Huntington's chorea found a new ally in deutetrabenazine, which received FDA's clearance, making it just the second molecule approved for the disease. In the difficult terrain of primary progressive multiple sclerosis, ocrelizumab, a humanized antibody, was the first drug approved. Based on antisense technology, nusinersin was approved for treatment of spinal muscular atrophy.

  2018 AD Top

Unfolding the layers of working memory

Working memory involves a series of functions: encoding a stimulus, maintaining or manipulating its representation over a delay, and finally making a behavioral response. While working memory engages dorsolateral prefrontal cortex, few studies have investigated whether these sub-functions are localized to different cortical depths [Figure 44] in this region. The theorem was used by National Institute of Mental Health, United States, researchers Emily S. Finn, Laurentius Huber, David C. Jangraw, and Peter A. Bandettini to interrogate the layer specificity of neural activity during different epochs of a working memory task in dorsolateral prefrontal cortex employing a high-resolution functional MRI. The researchers detected activity time courses that followed the hypothesized patterns: superficial layers were preferentially active during the delay period, whereas deeper layers were preferentially active during the response. Results demonstrate that layer-specific fMRI can be used in higher order brain regions to noninvasively map cognitive information processing along cortical circuitry in humans.[25]
Figure 44: Mapping the layers of memory by fMRI.

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  2019 AD Top

The Future

Blessed with greater understanding of the underlying pathological basis [Figure 45], the evolution of highly sensitive anatomical and functional imaging technologies, and a therapeutic box bejeweled with several new age molecules, three-dimensional neural stem-cell engineering, and perhaps, a “brain-on-a-chip” technology of the morrow, the science of neurology would qualify to become the elixir of life, offering a new lease of productive life even to those who might be hit with such degenerative hitherto unsurpassable conditions as multiple sclerosis and refractory PD. The birth of fingolimod for pediatric multiple sclerosis and continuous apomorphine infusion for refractory Parkinson's disease are just two of the many jewels that the mornings of tomorrow might smile upon.
Figure 45: Would a bionic man happen in this century: the quest seems unstoppable!

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  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25], [Figure 26], [Figure 27], [Figure 28], [Figure 29], [Figure 30], [Figure 31], [Figure 32], [Figure 33], [Figure 34], [Figure 35], [Figure 36], [Figure 37], [Figure 38], [Figure 39], [Figure 40], [Figure 41], [Figure 42], [Figure 43], [Figure 44], [Figure 45]


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