History of neuroscience

Hieroglyphic for the word "brain" (c.1700 BC)

The Edwin Smith Surgical Papyrus, written in the 17th century BC, contains the earliest recorded reference to the brain. The hieroglyph for brain, occurring eight times in this papyrus, describes the symptoms, diagnosis, and prognosis of two patients, wounded in the head, who had compound fractures of the skull. The assessments of the author (a battlefield surgeon) of the papyrus allude to ancient Egyptians having a vague recognition of the effects of head trauma. While the symptoms are well written and detailed, the absence of a medical precedent is apparent. The author of the passage notes "the pulsations of the exposed brain" and compared the surface of the brain to the rippling surface of copper slag (which indeed has a gyral-sulcal pattern). The laterality of injury was related to the laterality of symptom, and both aphasia ("he speaks not to thee") and seizures ("he shudders exceedingly") after head injury were described. Observations by ancient civilizations of the human brain suggest only a relative understanding of the basic mechanics and the importance of cranial security. Furthermore, considering the general consensus of medical practice pertaining to human anatomy was based on myths and superstition, the thoughts of the battlefield surgeon appear to be empirical and based on logical deduction and simple observation.[1][2]

During the second half of the first millennium BC, the Ancient Greeks developed differing views on the function of the brain. However, due to the fact that Hippocratic doctors did not practice dissection, because the human body was considered sacred, Greek views of brain function were generally uninformed by anatomical study. It is said that it was the Pythagorean Alcmaeon of Croton (6th and 5th centuries BC) who first considered the brain to be the place where the mind was located. According to ancient authorities, "he believed 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...the 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] In the 4th century BC, Hippocrates believed the brain to be the seat of intelligence (based, among others before him, on Alcmaeon's work). During the 4th century BC Aristotle thought that, while the heart was the seat of intelligence, the brain was a cooling mechanism for the blood. He reasoned that humans are more rational than the beasts because, among other reasons, they have a larger brain to cool their hot-bloodedness.[3]

In contrast to Greek thought regarding the sanctity of the human body, the Egyptians had been embalming their dead for centuries, and went about the systematic study of the human body. During the Hellenistic period, Herophilus of Chalcedon (c.335/330–280/250 BC) and Erasistratus of Ceos (c. 300–240 BC) made fundamental contributions not only to brain and nervous systems' anatomy and physiology, but to many other fields of the bio-sciences. Herophilus not only distinguished the cerebrum and the cerebellum, but provided the first clear description of the ventricles. Erasistratus used practical application by experimenting on the living brain. Their works are now mostly lost, and we know about their achievements due mostly to secondary sources. Some of their discoveries had to be re-discovered a millennium after their death.[2]

During the Roman Empire, the Greek anatomist Galen dissected the brains of sheep, monkeys, dogs, swine, among other non-human mammals. He concluded that, as the cerebellum was denser than the brain, it must control the muscles, while as the cerebrum was soft, it must be where the senses were processed. Galen further theorized that the brain functioned by movement of animal spirits through the ventricles. "Further, his studies of the cranial nerves and spinal cord were outstanding. He noted that specific spinal nerves controlled specific muscles, and had the idea of the reciprocal action of muscles. For the next advance in understanding spinal function we must await Bell and Magendie in the 19th Century."[2][3]

Islamic medicine in the middle ages was focused on how the mind and body interacted and emphasized a need to understand mental health. Circa 1000, Al-Zahrawi, living in Islamic Iberia, evaluated neurological patients and performed surgical treatments of head injuries, skull fractures, spinal injuries, hydrocephalus, subdural effusions and headache.[4] In Persia, Avicenna (Ibn-Sina) presented detailed knowledge about skull fractures and their surgical treatments.[5] Avicenna is regarded by some as the father of modern medicine. He wrote 40 pieces on medicine with the most notable being the Qanun, a medical encyclopedia that would be a staple at universities for nearly a hundred years. He also explained phenomena such as, insomnia, mania, hallucinations, nightmare, dementia, epilepsy, stroke, paralysis, vertigo, melancholia and tremors. He also discovered a condition similar to schizophrenia, which he called Junun Mufrit, characterized by agitation, behavioral and sleep disturbances, giving inappropriate answers to questions, and occasional inability to speak. Avicenna also discovered the cerebellar vermis, which he simply called the vermis, and the caudate nucleus. Both terms are still used in neuroanatomy today. He was also the first person to associate mental deficits with deficits in the brain's middle ventricle or frontal lobe.[6] Abulcasis, Averroes, Avenzoar, and Maimonides, active in the Medieval Muslim world, also described a number of medical problems related to the brain.

Between the 13th and 14th centuries, the first anatomy textbooks in Europe, which included a description of the brain, were written by Mondino de Luzzi and Guido da Vigevano.[7][8]

One of Leonardo da Vinci's sketches of the human skull

Work by Andreas Vesalius on human cadavers found problems with the Galenic view of anatomy. Vesalius noted many structural characteristics of both the brain and general nervous system during his dissections.[9] In addition to recording many anatomical features such as the putamen and corpus callosum, Vesalius proposed that the brain was made up of seven pairs of 'brain nerves', each with a specialized function. Other scholars furthered Vesalius' work by adding their own detailed sketches of the human brain. René Descartes also studied the physiology of the brain, proposing the theory of dualism to tackle the issue of the brain's relation to the mind. He suggested that the pineal gland was where the mind interacted with the body after recording the brain mechanisms responsible for circulating cerebrospinal fluid. Jan Swammerdam placed severed frog thigh muscle in an airtight syringe with a small amount of water in the tip and when he caused the muscle to contract by irritating the nerve, the water level did not rise but rather was lowered by a minute amount debunking balloonist theory. The idea that nerve stimulation led to movement had important implications by putting forward the idea that behaviour is based on stimuli.[10] Thomas Willis studied the brain, nerves, and behavior to develop neurologic treatments. He described in great detail the structure of the brainstem, the cerebellum, the ventricles, and the cerebral hemispheres.

The role of electricity in nerves was first observed in dissected frogs by Luigi Galvani, Lucia Galeazzi Galvani and Giovanni Aldini in the second half of the 18th century. In 1811, César Julien Jean Legallois for the first time define a specific function in a brain region. He studied respiration in animal dissection and lesions, and found the center of respiration in the medulla oblongata.[11] Between 1811 and 1824, Charles Bell and François Magendie discovered through dissection and vivisection that the ventral roots in spine transmit motor impulses and the posterior roots receive sensory input (Bell-Magendie law).[12] In the 1820s, Jean Pierre Flourens pioneered the experimental method of carrying out localized lesions of the brain in animals describing their effects on motricity, sensibility and behavior. At mid century, Emil du Bois-Reymond, Johannes Peter Müller, and Hermann von Helmholtz showed neurons were electrically excitable and that their activity predictably affected the electrical state of adjacent neurons.[13]

In 1848, John Martyn Harlow described that Phineas Gage had his frontal lobe pierced by an iron tamping rod in a blasting accident. He became a case study in the connection between the prefrontal cortex and executive functions.[14] In 1861, Broca heard of a patient at the Bicêtre Hospital who had a 21-year progressive loss of speech and paralysis but neither a loss of comprehension nor mental function. Broca performed an autopsy and determined that the patient had a lesion in the frontal lobe in the left cerebral hemisphere. Broca published his findings from the autopsies of twelve patients in 1865. His work inspired others to perform careful autopsies with the aim of linking more brain regions to sensory and motor functions. Another French neurologist, Marc Dax, made similar observations a generation earlier.[15] Broca's hypothesis was supported by observations of epileptic patients conducted by John Hughlings Jackson, who correctly deduced in the 1870s the organization of the motor cortex by watching the progression of seizures through the body. Carl Wernicke further developed the theory of the specialization of specific brain structures in language comprehension and production. Richard Caton presented his findings in 1875 about electrical phenomena of the cerebral hemispheres of rabbits and monkeys. In 1878, Hermann Munk found in dogs and monkeys that vision was localized in the occipital cortical area.[16] Modern research still uses the Korbinian Brodmann's cytoarchitectonic (referring to study of cell structure) anatomical definitions from this era in continuing to show that distinct areas of the cortex are activated in the execution of specific tasks.[15]

Studies of the brain became more sophisticated after the invention of the microscope and the development of a staining procedure by Camillo Golgi during the late 1890s that used a silver chromate salt to reveal the intricate structures of single neurons. His technique was used by Santiago Ramón y Cajal and led to the formation of the neuron doctrine, the hypothesis that the functional unit of the brain is the neuron. Golgi and Ramón y Cajal shared the Nobel Prize in Physiology or Medicine in 1906 for their extensive observations, descriptions and categorizations of neurons throughout the brain. The hypotheses of the neuron doctrine were supported by experiments following Galvani's pioneering work in the electrical excitability of muscles and neurons. In 1898, British scientist John Newport Langley first coined the term "autonomic" in classifying the connections of nerve fibers to peripheral nerve cells.[17] Langley is known as one of the fathers of the chemical receptor theory, and as the origin of the concept of "receptive substance".[18][19] Towards the end of the nineteenth century Francis Gotch conducted several experiments on nervous system function. In 1899 he described the "inexcitable" or "refractory phase" that takes place between nerve impulses. His primary focus was on how nerve interaction affected the muscles and eyes.[20]

Heinrich Obersteiner in 1887 founded the ‘‘Institute for Anatomy and Physiology of the CNS’’, later called Neurological or Obersteiner Institute of the Vienna University School of Medicine. It was one of the first brain research institutions in the world. He studied the cerebellar cortex, described the Redlich–Obersteiner's zone and wrote one of the first books on neuroanatomy in 1888. Róbert Bárány, who worked on the physiology and pathology of the vestibular apparatus, attended this school, graduating in 1900. Obersteiner was later superseded by Otto Marburg.[21]

Neuroscience during the twentieth century began to be recognized as a distinct unified academic discipline, rather than studies of the nervous system being a factor of science belonging to a variety of disciplines.

Ivan Pavlov contributed to many areas of neurophysiology. Most of his work involved research in temperament, conditioning and involuntary reflex actions. In 1891, Pavlov was invited to the Institute of Experimental Medicine in St. Petersburg to organize and direct the Department of Physiology.[22] He published The Work of the Digestive Glands in 1897, after 12 years of research. His experiments earned him the 1904 Nobel Prize in Physiology and Medicine. During the same period, Vladimir Bekhterev discovered 15 new reflexes and is known for his competition with Pavlov regarding the study of conditioned reflexes. He founded the Psychoneurological Institute at the St. Petersburg State Medical Academy in 1907 where he worked with Alexandre Dogiel. In the institute, he attempted to establish a multidisciplinary approach to brain exploration.[23] The Institute of Higher Nervous Activity in Moscow, Russia was established on July 14, 1950.

Charles Scott Sherrington's work focused strongly on reflexes and his experiments led up to the discovery of motor units. His concepts centered around unitary behaviour of cells activated or inhibited at what he called synapses. Sherrington received the Nobel prize for showing that reflexes require integrated activation and demonstrated reciprocal innervation of muscles (Sherrington's law).[24][25][26] Sherrington also worked with Thomas Graham Brown who developed one of the first ideas about central pattern generators in 1911. Brown recognized that the basic pattern of stepping can be produced by the spinal cord without the need of descending commands from the cortex.[27][28]

Acetylcholine was the first neurotransmitter to be identified. It was first identified in 1915 by Henry Hallett Dale for its actions on heart tissue. It was confirmed as a neurotransmitter in 1921 by Otto Loewi in Graz. Loewi demonstrated the ″humorale Übertragbarkeit der Herznervenwirkung″ first in amphibians.[29] He initially gave it the name Vagusstoff because it was released from the vagus nerve and in 1936 he wrote:[30] ″I no longer hesitate to identify the Sympathicusstoff with adrenaline.″

A graph showing the threshold for nervous system response.

One major question for neuroscientists in the early twentieth century was the physiology of nerve impulses. In 1902 and again in 1912, Julius Bernstein advanced the hypothesis that the action potential resulted from a change in the permeability of the axonal membrane to ions.[31][32] Bernstein was also the first to introduce the Nernst equation for resting potential across the membrane. In 1907, Louis Lapicque suggested that the action potential was generated as a threshold was crossed,[33] what would be later shown as a product of the dynamical systems of ionic conductances. A great deal of study on sensory organs and the function of nerve cells was conducted by British physiologist Keith Lucas and his protege Edgar Adrian. Keith Lucas' experiments in the first decade of the twentieth century proved that muscles contract entirely or not at all, this was referred to as the all-or-none principle.[34] Edgar Adrian observed nerve fibers in action during his experiments on frogs. This proved that scientists could study nervous system function directly, not just indirectly. This led to a rapid increase in the variety of experiments conducted in the field of neurophysiology and innovation in the technology necessary for these experiments. Much of Adrian's early research was inspired by studying the way vacuum tubes intercepted and enhanced coded messages.[35] Concurrently, Josepht Erlanger and Herbert Gasser were able to modify an oscilloscope to run at low voltages and were able to observe that action potentials occurred in two phases—a spike followed by an after-spike. They discovered that nerves were found in many forms, each with their own potential for excitability. With this research, the pair discovered that the velocity of action potentials was directly proportional to the diameter of the nerve fiber and received a Nobel Prize for their work.[36]

Kenneth Cole joined Columbia University in 1937 and remained there until 1946 where he made pioneering advances modelling the electrical properties of nervous tissue. Bernstein's hypothesis about the action potential was confirmed by Cole and Howard Curtis, who showed that membrane conductance increases during an action potential.[37] David E. Goldman worked with Cole and derived the Goldman equation in 1943 at Columbia University.[38][39] Alan Lloyd Hodgkin spent a year (1937–38) at the Rockefeller Institute, during which he joined Cole to measure the D.C. resistance of the membrane of the squid giant axon in the resting state. In 1939 they began using internal electrodes inside the giant nerve fibre of the squid and Cole developed the voltage clamp technique in 1947. Hodgkin and Andrew Huxley later presented a mathematical model for transmission of electrical signals in neurons of the giant axon of a squid and how they are initiated and propagated, known as the Hodgkin–Huxley model. In 1961–1962, Richard FitzHugh and J. Nagumo simplified Hodgkin–Huxley, in what is called the FitzHugh–Nagumo model. In 1962, Bernard Katz modeled neurotransmission across the space between neurons known as synapses. Beginning in 1966, Eric Kandel and collaborators examined biochemical changes in neurons associated with learning and memory storage in Aplysia. In 1981 Catherine Morris and Harold Lecar combined these models in the Morris–Lecar model. Such increasingly quantitative work gave rise to numerous biological neuron models and models of neural computation.

Eric Kandel and collaborators have cited David Rioch, Francis O. Schmitt, and Stephen Kuffler as having played critical roles in establishing the field.[40] Rioch originated the integration of basic anatomical and physiological research with clinical psychiatry at the Walter Reed Army Institute of Research, starting in the 1950s. During the same period, Schmitt established a neuroscience research program within the Biology Department at the Massachusetts Institute of Technology, bringing together biology, chemistry, physics, and mathematics. The first freestanding neuroscience department (then called Psychobiology) was founded in 1964 at the University of California, Irvine by James L. McGaugh. Stephen Kuffler started the Department of Neurobiology at Harvard Medical School in 1966. The first official use of the word "Neuroscience" may be in 1962 with Francis O. Schmitt's "Neuroscience Research Program", which was hosted by the Massachusetts Institute of Technology.[41]

Over time, brain research has gone through philosophical, experimental, and theoretical phases, with work on brain simulation predicted to be important in the future.[42]

As a result of the increasing interest about the nervous system, several prominent neuroscience institutes and organizations have been formed to provide a forum to all neuroscientists. The largest professional neuroscience organization is the Society for Neuroscience (SFN), which is based in the United States but includes many members from other countries.

In 2013, the BRAIN Initiative was announced in the US. An International Brain Initiative was created in 2017,[46] currently integrated by more than seven national-level brain research initiatives (US, Europe, Allen Institute, Japan, China, Australia, Canada, Korea, Israel)[47] spanning four continents.

• Rousseau, George S. (2004). Nervous Acts: Essays on Literature, Culture and Sensibility. Basingstoke: Palgrave Macmillan. ISBN 1-4039-3454-1 (Paperback) ISBN 1-4039-3453-3
• Wickens, Andrew P. (2015) A History of the Brain: From Stone Age Surgery to Modern Neuroscience. London: Psychology Press. ISBN 978-1-84872-365-8 (Paperback), 978-84872-364-1 (Hardback), 978-1-315-79454-9 (Ebook)

• Media related to History of neuroscience at Wikimedia Commons
• A History of the Brain ten-part series of BBC radio programmes