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Extramission and the Eye (400 BC - 200 AD)

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Extramission and the Eye (400 BC - 200 AD)

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The debate around the eye and how it saw came about as early as 4th century BC. Plato believed the eye gave off light, which essentially grabbed what it saw¹. Aristotle deviated from this idea of extramission, and believed eyes took rays instead of giving them off¹.

The idea of extramission would return and become more prominent with Galen¹. Galen believed in the idea of extramission and that there were "'pneuma" or or spirits traveling through hollow nerves¹. These spirits flowed between the eyes and the brain via the optic nerve¹. Galen's high status in society is presumably why his theory was so widely accepted².

Pictured below is a depiction of Galen's animal spirit theory ². The animal spirits start in the lateral ventricles². When they leave, they travel along the hollow optic nerve and then spread throughout the retinal vessels². Then they "bathe" in the crystalline lens and move into the empty space of air in front of the lens where it will take in the information before traveling back to the brain². Galen put the lens in the center of the eye, which we know today is not true².

CITATIONS:

[1]:https://web.stanford.edu/class/history13/earlysciencelab/body/eyespages/eye.html

[2]:http://nivea.psycho.univ-paris5.fr/FeelingSupplements/AncientVisions.htm

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Galen and his theory of "pneuma" was the prevalent theory of how the nerves, including the optic nerve, functioned for almost 1500 years in Europe (until the 17th century)¹. However, in 1021, Arab scholar Ibn-al-Haytham would provide the first evidence that vision resulted from light hitting the eye². Intromission would later be reintroduced in the West.

Ibn-al-Haytham (Egypt) was influential for his work on optics. He designed the camera obscura, a box which allows light in through a small hole and creates an inverted image³. His design was similarly constructed to that of the eye, and from this he concluded that light came to the eye, NOT from the eye³. He rejected this idea from Galen and others of "extramission"³.His experiment suggested that it was not animal spirits traveling down the nerves, but light information.

He was the first to suggest that the brain is where vision occurred in his Book of Optics ⁴. In his book he depicted that the information from the eyes traveled to the retina, and then to the brain via the optic nerve⁴. His drawing ⁵ is shown below. He also believed that vision was a combination of info from the eye and what information the brain stored from previous experiences⁵.

CITATIONS:

[1]:https://neurophilosophy.wordpress.com/2006/11/16/exorcising-animal-spirits-the-discovery-of-nerve-function/

[2]:https://www.rockefeller.edu/our-scientists/h-keffer-hartline/2487-nobel-prize/

[3]:https://historyofneuroscience.umwblogs.org/early-history-of-nueroscience/medieval-neuroscience/

[4]: Masic I. Ibn al-Haitham--father of optics and describer of vision theory. Med Arh. 2008;62(3):183-8. https://pubmed.ncbi.nlm.nih.gov/18822953/

[5]:https://www.aspetar.com/journal/viewarticle.aspx?id=386#.YAkrFi2z2u5

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In 1802, Thomas Young, a British polymath, did research to seek understanding of how the eye functioned¹. He discovered the lens of our eye changed shape in response to light, and that the retina had three different photoreceptors that only responded to three different ranges of wavelengths and made us see all colors¹. What he discovered were cones-- photoreceptors that allow us to see color¹.

In 1850, Hermann von Helmholtz, a German physicist would further this theory². He classified these three photoreceptors. He called these different types "short preferring" (blue), "middle preferring" (green), or "long preferring" (red)¹. He theorized that the brain interpreted these different intensities of wavelengths to make up the visible color that we see². One of Helmholtz's drawing, showing different the three wavelengths picked up by the cones is shown below ³.

This theory of three photoreceptors (cones) for color vision, became known as the Young-Helmholtz Theory or the Trichromatic Theory of Color Vision¹.

CITATIONS:

[1]:https://www.biologyonline.com/dictionary/young-helmholtz-theory-of-colour-vision

[2]:https://psychology.wikia.org/wiki/Young-Helmholtz_theory

[3]Lee B. B. (2008). The evolution of concepts of color vision. Neurociencias, ⁴(4), 209–224.:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095437/

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With the discovery of Broca's area (1861) for language production¹, the now pseudoscience of phrenology (1796) by Franz Gall saying different mental functions and personality traits were were localized², the idea of localization became prominent and an area of research for many scientists.

The debate on localization was for vision function as well. David Ferrier (Scotland, 1875) noticed electrical stimulation of the lateral parietal lobes caused eye movement, so he concluded this was where vision was processed³. Hermann Munk (Germany, 1880) would find that cortical lesions in the occipital lobe of monkeys would lead to blindness⁴. His drawing of retinal projections and the visual cortex is below ⁵. The two would disagree on what the central region for vision was⁴.

However, it was Bartolemeo Panizza (Italy) that first published "Osservazioni sul nervo ottico" (Observations on the Optic Nerve) in 1855 which he detailed his findings on the brains of patients who became blind after stroke⁶. He followed the path of vision from the optic nerve to the brain, from which he deduced the posterior cortex as being the location of vision⁷. He confirmed his findings through animal models⁶. He is credited with the discovery of the visual cortex today⁶.

CITATIONS:

[1]:https://www.britannica.com/science/Broca-area

[2]:https://thebrain.mcgill.ca/flash/capsules/pdf_articles/phrenology.pdf

[3]:https://royalsocietypublishing.org/doi/10.1098/rspb.1945.0002

[4]:https://neuroportraits.eu/portrait/hermann-munk.html

[5]:https://www.sciencedirect.com/science/article/pii/S0006899315006897?via%3Dihub

[6]:http://www.scholarpedia.org/article/Area_V1

[7]:https://pubmed.ncbi.nlm.nih.gov/11074799/

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The Neuron Doctrine: Changing Vision Research (1891)

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The Neuron Doctrine: Changing Vision Research (1891)

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The neuron doctrine was founded by Santiago Ramon y Cajal, a Spanish neuroscientist¹. His neuron doctrine stated that the nervous system was made of individual neurons-- they were not connected¹.

Prior to this, the cell theory was already established: cells come from other cells and are the basic functional unit of life². However, until the neuron doctrine, it was not known that this applied to the nervous system².

Ramon y Cajal, using the black stain developed by Camillo Golgi, drew detailed pictures of many cells he stained in the nervous system³. His drawing of the retina is pictured below ³. This was the first picture of the eye's complicated circuit³.

He described the retina in detail as having five layers, with three distinct layers of cells from the photoreceptors to the optic nerve⁴. His work with the neuron doctrine and the retina would set the stage for more research on vision.

CITATIONS:

[1]:https://embryo.asu.edu/pages/camillo-golgis-black-reaction-staining-neurons

[2]: https://www.famousscientists.org/theodor-schwann/

[3]:https://editions.covecollective.org/content/human-retina-santiago-ramon-y-cajal

[4]:]:https://www.britannica.com/science/photoreception/Structure-and-function-of-photoreceptors

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The 1900's would be a time where scientists furthered their understanding on Rods, the photoreceptors responsible for light vision¹.

In the 1930's, George Wald (New York) would discover rhodopsin, the molecule in Rods that allows for night vision and is light-sensitive². He found that when light hits rhodopsin, it changes conformation and signals a network of nerve cells and reactions before reaching the brain and creating an image². Rhodopsin would be regenerated in the absence of light. He used models of marine fish and frogs in his research³. His flowchart of rhodopsin and its chemical changes that cause excitation of nerve cells is depicted below ³.

George Wald would share the Nobel Prize in Physiology and Medicine in 1967 with Keffer Hartline, for their work on understanding the physiological and chemical processes behind vision¹.

CITATIONS:

[1]:https://www.rockefeller.edu/our-scientists/h-keffer-hartline/2487-nobel-prize/

[2]:https://www.nobelprize.org/prizes/medicine/1967/wald/facts/

[3]::https://www.nap.edu/read/9977/chapter/18#304

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Keffer Hartline (pictured below)¹ was born in Pennsylvania in 1903.
He went to Lafayette College, and was encouraged by his Biology professor to undertake research¹. He published his first paper, on the visual response of land isopods¹.His early work focused on Marine Biology and he spent summers doing research¹.

He enrolled in Johns Hopkins for medical school in 1923, and continued doing research¹. He began to study retinal action potentials in a wide variety of animals like frogs and cats¹. He even studied human retinal potentials.1

Following his graduation from medical school, he received a fellowship that allowed him to continue research and take math and physics courses to strengthen his background¹. He never practiced medicine².

He took on a position at the University of Pennsylvania (1931), where he furthered his research on vision1. His contributions to the study of vision are highlighted in subsequent artifacts.

He would win the Nobel Prize in Physiology or Medicine (1967) for his research on the chemical and physiological processes in vision, especially understanding individual photoreceptors and nerves². His research spanned three decades.

CITATIONS:

[1]:https://www.nobelprize.org/prizes/medicine/1967/hartline/biographical/

[2]:https://www.britannica.com/biography/Haldan-Keffer-Hartline

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Hartline's Horseshoe Crab and Single Optic Nerve Fibers (1932)

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Hartline's Horseshoe Crab and Single Optic Nerve Fibers (1932)

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Edgar Adrian and Rachel Matthews in 1927 would be the first to successfully record electrical activity from an optic nerve in an eel¹. However, their work, although significant, was lacking in the fact that it was recorded from a whole nerve trunk¹.

Hartline and a colleague, Clarence Graham would be inspired by this and try to repeat this¹. However, they were able to record activity from a single optic nerve fiber, unlike Adrian and Matthews¹. Their initial findings were that the intensity of light was proportional to the rate of nerve firing¹.

Hartline used a model of a Limulus or Horseshoe Crab, pictured below ². He used this model because it had large photoreceptors and a long optic nerve - making it easy to work with³. Hartline would use this model for the next two decades in his work.

CITATIONS:

[1]:http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/hartline-haldan.pdf

[2]:https://horseshoecrab-kayla-westerlund.weebly.com/eye-research.html

[3]:Liu, J. S., & Passaglia, C. L. (2009). Using the horseshoe crab, Limulus Polyphemus, in vision research. Journal of visualized experiments : JoVE, (29), 1384. https://doi.org/10.3791/1384

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Hartline and The Receptor  Potential (1935)

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Hartline and The Receptor  Potential (1935)

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Hartline (with colleague) would expand on this work with single optic nerve fibers in Horseshoe Crabs¹. As mentioned before, one of his early findings with optic nerve fibers was with Graham in which they determined light intensity had a linear relationship with the rate of firing of optic nerve cells (1932)¹.

Hartline's interest in receptor potentials was renewed with the invention of micropipette electrodes that could be used for intracellular recording². Graham and Hartline's earlier work was with external electrode, but now receptor potentials could be studied directly and in much more detail².

Using this new technique, Hartline and colleagues were able to determine that the intensity of the stimulus was related to the strength of the nerve impulse (it was graded)³. One of their micropipette recordings is pictured below ³. In Horseshoe crabs, light depolarizes but in humans, light hyper-polarizes. However, this research would set the basic principle that sensory data processing begins in sensory receptors³.

CITATIONS:

[1]:http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/hartline-haldan.pdf

[2]:https://digitalcommons.rockefeller.edu/cgi/viewcontent.cgi?article=1030&context=harvey-lectures

[3]:https://www.nobelprize.org/uploads/2018/06/hartline-lecture.pdf

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Hartline would switch experimental models from the Horseshoe Crab due to the difficulty when isolating single nerve fibers¹. His frog model would prove much more easy in this aspect due to its anatomy¹.

However, Hartline's findings were unexpected. He found that all fibers within a nerve did not produce the same response, but the response varied². He determined that the nerve activity was a summation of the individual fibers². It was this integration of signals that resulted in vision². Some responded only to the onset or removal of a light stimulus, others responded at a constant rate to light.²

Using this, he mapped receptive fields¹. An example of his receptive field map is pictured below ¹. The retina is in the middle (gray dot) and light stimulus was applied from different distances. He concluded that visual processing began in the retina but specialized ganglion cells can receive different type of inputs (excitatory and inhibitory) which converge into the common optic nerve¹.
This would lay the groundwork for the concept of parallel processing2 , or the way the brain understands multiple different aspects of a stimulus at once³.

CITATIONS:

[1]:https://digitalcommons.rockefeller.edu/cgi/viewcontent.cgi?article=1030&context=harvey-lectures

[2]:http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/hartline-haldan.pdf

[3]:https://study.com/academy/lesson/what-is-parallel-processing-definition-model.html

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The Hartline-Ratliff Equation and Lateral Inhibition (1949)

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The Hartline-Ratliff Equation and Lateral Inhibition (1949)

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Hartline's most significant contributions was the discovery of lateral inhibition¹. Lateral inhibition is when a stimulus excites a neuron, and that neuron subsequently inhibits surrounding neurons². In vision, this increases contrast and resolution². So when you look at a light in a dark room, this process makes the light brighter and clearer and the darkness in the surround seems darker².

This process explains the Hermann Grid Illusion (1870), pictured below ³. When skimming the photo, all the gray squares in between the white lines appear. When focusing on one gray dot, it disappears. Everything in our periphery blends, making it look like gray dots are there when there are none to begin with.

Hartline and Floyd Ratliff quantified this process, into what became the Keffer-Hartline equation¹. This algebraic equation essentially described the opposite activity of two photoreceptors (one inhibited), and eventually could describe more than two/a network¹.

CITATIONS:

[1]:http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/hartline-haldan.pdf

[2]:https://link.springer.com/referenceworkentry/10.1007%2F978-0-387-79948-3_1379

[3]:https://www.businessinsider.com/cornsweet-optical-illusion-lateral-inhibition-2013-12

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Stem cell therapies have been researched in many different diseases, and diseases causing vision loss is an example¹. Understanding the complex vision process has allowed scientists to develop and research very targeted therapies. There has been investigations with growth factors like Nerve growth factor (NGF) in trying to successfully grow photoreceptors that can survive and incorporate into the retina, for retinal degenerative disease¹. The process of differentiation from stem cells to photoreceptors is simplified below ¹.

At Harvard, researchers theorized that the limbus, a structure around the cornea that contains stem cells could be used for transplants because they can differentiate into cornea cells². However, these stem cells can differentiate in more: blood cells, pigment cells, etc². Taking the wrong cells could do more harm than good.

They found a molecule unique to cornea generating stem cells: ABCB5². Mice given ABCB5 stem cells developed clear corneas while those without ABCB5 did not². As of 2019, early clinical trials began².

CITATIONS:

[1]:Fatemeh Forouzanfar, Mana Shojapour, Zahra Sadat Aghili and Samira Asgharzade*, “Growth Factors as Tools in Photoreceptor Cell Regeneration and Vision Recovery”, Current Drug Targets (2020) 21: 573. https://doi.org/10.2174/1389450120666191121103831

[2]: https://hsci.harvard.edu/news/restoring-vision-clinical-trial