Monumental breakthroughs in the history of neuroscience

It is difficult to really say when neuroscience began, but most sources trace the first account of the nervous system to what is now known as the Edwin Smith papyrus; this is an Egyptian text written around 1700 B.C which documents surgical procedures for brain trauma. Since then, neuroscience breakthroughs have come at breakneck speed. The sources I have consulted for this blog post, referenced at the end, name innumerable discoveries made by countless innovators. To attempt to put a number to the most important breakthroughs will therefore be a well-nigh impossible task. So I came up with the idea of chunking key discoveries under distinct sections or systems of the nervous system.

By Jeff Dahl – Edited version of Image:EdSmPaPlateVIandVIIPrintsx.jpg, Public Domain, Link

But even this plan to chunk key breakthroughs came with strong challenges. For example, it is not always clear when a discovery was first made, or who crossed the finishing line first. This is because there are often several contenders in a tight race to the finish, and only a few discoveries were definite one-man paradigm-changing works. On the contrary, most discoveries were made by two or three pioneers working in a creative partnership, or by larger groups of people working in innovative collaborations. A further challenge was establishing what or where the finishing line was, as this is not always well-defined; this is understandable because most scientific advances were made over centuries, in small incremental steps, in a gradual progression from basic observation to complex synthesis.

Achievement. Gregory Vozzo on Flickr.

To overcome these challenges, I have avoided too much emphasis on the ‘who first‘ conundrum that drives, and sometimes mires, science. I have also side-stepped the ‘when first‘ problem by noting only a few dates just to maintain some sense of chronology. I did a lot of picking and choosing for this post, and it is inevitable that somebody’s favourite discovery, or discoverer, would be missing; take heart and exult in the collective effort that has gone into these monumental breakthroughs in the history of neuroscience.


Cerebrospinal fluid (CSF)

It is difficult to pinpoint who first described the cerebrospinal fluid (CSF) circulation but Nicolo Massa, Lewis Weed, Gustav Retzius, Francois Magendie and Albrecht von Haller have all been cited. The names associated with accurately describing the constituents of CSF are William Halliburton and William Mestrezat. Franciscus de la Boe Sylvius is credited with describing the aqueduct of Sylvius, and Alexander Monro for describing the foramen of Monro. Antonio Pacchioni discovered arachnoid granulations, whilst Guilio Cesare and Thomas Willis are credited for describing the anatomy and function of the choroid plexus. The accurate description of the blood brain barrier has been attributed to both Max Lewandowsky and Paul Erlich.

By © Nevit Dilmen, CC BY-SA 3.0, Link

Brain mapping

Cerebral localisation of functions has always been, and continues to be, a key neuroscience task. As brain functions become increasingly recognised as network-based, rather than region-based, cerebral localisation is taking more of a back seat in neuroscience. But it is still worthwhile to acknowledge the pioneers who identified key brain areas. Paul Broca is credited with the first description of the cortical speech area, whilst motor function localisation is traced to the works of Eduard HitzigGustav Fritsch, David Ferrier, and Victor Horsley. The classification of cerebral areas into 52 parts was done by Korbinian Brodmann, whilst it was neurosurgeon Wilder Penfield who defined the cortical maps of the motor and sensory homunculus.

By BkroegerOwn work, CC BY-SA 3.0, Link

Central nerves

Both Rudolph Virchow and Heinrich Müller are credited with describing neuroglia. The credit for classifying these into microglia and oligodendroglia goes to Pio del Rio Hortega, whilst that for describing dendrites and axons goes to Otto Friedrich Karl Deiters. Camillo Golgi introduced the critical silver nitrate method of staining nerve cells, a technique advanced by Santiago Ramon y Cajal, who developed the gold chloride-mercury method for staining astrocytes. The description of the synapse is attributed to the truly great Charles Scott Sherrington. W. Bevan Lewis, Vladimir Betz and Johannes Purkinje have all been credited with describing the giant motor nerves of the cortex.

PSA+NCAM+neuron. Jason Snyder on Flickr.

Cranial nerves

Rufus of Ephesus is named as the first person to describe and name the optic chiasma. Other cranial nerve achievements are the discovery of the tenth cranial nerve by Marinus, and the description of seven cranial nerves by Rhazes. The trochlear and abducens nerves were described by Gabriele Falloppio, and it was Samuel Thomas von Soemmerring who introduced the current classification of the twelve cranial nerves.

By OpenStax –, CC BY 4.0, Link

Peripheral nerves

The credit for distinguishing between myelinated and unmyelinated nerves goes to Robert Remak, whilst the credit for describing myelin formation goes to Theordor Schwann. It was Louis-Antoine Ranvier who described the gaps between myelin sheaths called the nodes of Ranvier. The different types of sensory nerves were described by Herbert Gasser, and it was Friedreich Merkel who described the sensory receptors now known as Merkel corpuscles. Credit for describing the cutaneous distribution of sensory nerves goes to Henry Head, and it was Francois Magendie who recognised the different functions subserved by the dorsal and ventral nerve roots of the spinal cord.

By BruceBlausOwn work, CC BY 3.0, Link

Nerve conduction

The early understanding of how nerves function has a lot to do with the description by Hermann Helmholtz of the electrical nerve impulse velocity. The resting membrane potential was described by Julius Bernstein and Walter Nernst, whilst Keith Lucas and Edgar Adrian measured peripheral nerve impulses, Adrian going on to confirm that nerve impulses are all or none. Alan Hodgkin and Andrew Huxley are credited with describing the mechanisms of action potentials, whilst Joseph Erlanger and Herbert Spencer Gasser described the function of single nerve fibers.

By JanbroggerOwn work, Public Domain, Link

Chemical neurotransmission 

Whilst nerve function is electrical, it is chemicals that bridge the gap between nerves. The chemical neurotransmitters of peripheral nerves, norepinephrine and acetylcholine, were isolated by George Barger and Henry Dale. The credit for establishing chemical neurotransmission between nerves and muscles, at the neuromuscular junction, goes to Otto Loewi‘s dream-inspired work on Vagusstoff. The discovery of the central nervous system neurotransmitter GABA is credited to Eugene Roberts and Jorge Awapara. Most of the later work on neurotransmitters were made by Julius Axelrod, Bernard Katz and Ulf Svante von Euler, and the credit for elucidating the function of ion channels goes to Erwin Neher and Bert Sakmann.

By Doctor Jana –, CC BY 4.0, Link

Special senses

The visual system is fundamental to neuroscience, and credit for describing its mechanism goes to Ragnar Granit, Halden Hartline and George Wald. The merit for elucidating the details of visual processing goes to David Hubel and Torsten Wiesel. The sense of smell is similarly important, and initial work on this was made by David Ferrier, but it is to Linda Buck and Richard Axel that kudos go for discovering odour receptors, and for describing the configuration of the olfactory system.


By Wiley – Wikimedia, CC BY-SA 3.0, Link

Memory, pain, and prions

The acclaim for establishing the anatomical foundations of memory goes to Brenda Milner for her work on Patient HM. It is however Eric Kandel who has the honour of working out the functional process of memory formation. The gate control theory of pain was established by Ronald Melzack and Patrick Wall, whilst credits for establishing the nature of prion diseases go to the lively Daniel Carleton Gajdusek, and the indefatigable Stanley Prussiner.

Prion Proteins and Mouse Nerve Cells. NIH Image Gallery on Flickr.

Navigation, mirror neurones, and growth factors

The brain’s positioning system was discovered by John O’Keefe, Edvard Moser, and May-Britt Moser. Cedit for discovering mirror neurones goes to Giacomo Rizzolatti, whilst Rita Levi-Montalcini and Stanley Cohen were the first to isolate nerve growth factor.


Compass rose. Margaret W. Carruthers on Flickr.

 Brain circulation and brain waves

Thomas Willis, Henry Duret and Johann Heubner first described the arterial circulation of the brain, whilst the electrical brain wave activity of the brain was first recorded by Hans Berger, incidentally when he was investigating telepathy.

By OpenStax College – Anatomy & Physiology, Connexions Web site., Jun 19, 2013., CC BY 3.0, Link


And so ends this rapid whizz through the annals of neuroscience. This is just the condensed tip of the iceberg; to learn more about the fascinating giants who defined the glorious history of neuroscience, you may wish to slowly digest the following sources:


Milestones in Neuroscience Research

A Short History of European Neuroscience


Minds Behind the Brain

Dates in Neurology

What is so distinctive about anti-MUSK myasthenia gravis?

Myasthenia gravis (MG) is an iconic neurological disorder. It is classical in its presentation, weakness setting in with exertion and improving with rest. This fatigability is demonstrable in the laboratory when repetitive nerve stimulation (RNS) of the muscles results in a progressively decremental response. Clinically, myasthenia gravis is often a benign disorder which restricts itself to the muscles of the eyes: this ocular MG manifests just with droopy eyelids (ptosis) and double vision (diplopia). At the extreme however is generalised MG, a severe and life-threatening condition that justifies its grave appellation

By Posey & Spiller – Posey & Spiller: Fatigue (Ptosis) in a patient with MG (ed. 1904), Public Domain, Link

Myasthenia gravis depletes the energy reserve of muscles, something which is entirely dependent on acetylcholine (ACh), a chemical released at nerve endings. After release, ACh traverses the neuromuscular junction (NMJ) to attach itself to the acetylcholine receptor (AChR), which is comfortably nestled on the surface of the muscle. This binding of chemical to receptor is a significant event, setting sparks flying, and muscles contracting. In myasthenia gravis, this fundamental process is rudely disrupted by the onslaught of acetylcholine receptor antibodies. These aggressive AChR antibodies, produced by the thymus gland in the chest, vent their rage by competitively binding to the receptor, leaving acetylcholine high and dry. Eventually, the rampaging antibodies destroy the receptor in an act of unjustified savagery.

Drosophilia Neuron. NICHD on Flickr.

In tackling myasthenia gravis, it is no wonder that neurologists first have to hunt down the ferocious AChR antibodies. They whisk off an aliquot of serum to a specialist laboratory, but waste no time in planning a counteroffensive, confident that the test will return as positive. The strategy is to boost the level of acetylcholine in the NMJ, tilting the balance in favour of ACh against the antibodies. The tactic is to zealously despatch a prescription for a drug that will block acetylcholine esterase inhibitor, the enzyme which breaks down acetylcholine. The neurologist then closely observes the often dramatic response, one of the most gratifying in clinical medicine; one minute as weak as a kitten, the next minute as strong as an ox. MG is therefore one disorder which debunks the wicked jibe that neurologists know so much…but do so little to make their patients better!

Drosophilia Neuromuscular Junction. NICHD on Flickr.

Unfortunately for the neurologist, every now and then, the AChR antibody test result comes back as negative. In the past, the dumbfounded and befuddled, but nevertheless undaunted neurologist, will march on, battling a diagnosis of antibody-negative MG. Nowadays however, this not a comfortable diagnosis to make because AChR antibody is no longer the only game in town. We now know that there are many other antibodies that are jostling for commanding positions in the anti-myasthenia coalition. These include anti LRP4, cotarctin, titin, agrin, netrin 1, VGKC, and ryanodine. However, the clear frontrunner in this melee is anti-MUSK antibody, responsible for 30-50% of MG in which there are no AChR antibodies.

By PyMol, CC0, Link

Anti MUSK syndrome has many distinguishing features that set it apart from the run-of-the-mill myasthenia gravis. Below are five distinctive markers of anti-MUSK syndrome:

  1. Subjects with anti-MUSK syndrome are typically middle-aged women in their 3rd or 4th decades. This is younger than the usual age of people with AChR MG. Indeed neurologists now recognise typical myasthenia as a disease of older people.
  2. People with anti-MUSK syndrome present with acute and prominent involvement of head and neck muscles. This results in marked swallowing and breathing difficulties. They are therefore at a higher risk of myasthenia crisis.
  3. Single fiber electromyogram (sfEMG), a specific and reliable neurophysiological test of MG, is often normal in anti-MUSK syndrome. This is partly because the limb muscles are usually spared in anti MUSK syndrome.
  4. People with anti-MUSK myasthenia often do not benefit from, nor do they tolerate, the  acetylcholinesterase inhibitors which are used to treat MG. Indeed, these drugs may worsen anti-MUSK syndrome.
  5. Thymectomy, removal of the thymus gland, is not beneficial in people with anti-MUSK syndrome, unlike its usefulness in AChR MG.
Thymus gland 2. RachelHermosillo on Flickr.

All this is just the tip of the evolving myasthenia gravis iceberg. You may explore more of myasthenia in our previous blog posts:

How is innovative neurology research energising myasthenia?

What is the startling research unsettling the treatment of myasthenia gravis?

What is the relationship of pregnancy to myasthenia gravis?

Is Zika virus infection a risk factor for myasthenia gravis?

What does the EMG show in LRP4 myasthenia gravis?

What’s evolving at the cutting-edge of autoimmune neurology?

What are the most iconic neurological disorders?


You may also explore anti-MUSK, and all the other myasthenia gravis subtypes, in neurochecklists. Go on…you know you want to know more!

Antibody lights. Isabelle on Flickr.


How is innovative neurology research energising myasthenia?

Myasthenia gravis (MG) is one of the best characterised neurological disorders. The hallmark of MG is fatigable weakness. This manifests as intermittent ptosis (droopy eyelids), diplopia (double vision), and limb weakness. There are two main types-ocular MG affects just the eyes and eyelids, and generalised MG affects the body, including the bulbar functions of  breathing and swallowing.

By Doctor Jana -, CC BY 4.0,
By Doctor Jana –, CC BY 4.0,


The problem in MG is straightforward lack of communication; the nerves and muscles aren’t talking to each other. The two meet up at the neuromuscular junction (NMJ) where the nerves send packages of acetylcholine to bind with acetylcholine receptors (AChR) on the surface of the muscles. The muscles usually acknowledge this by contracting and producing action, but in MG this response is blocked by antibodies to the acetylcholine receptor (AChR antibodies). Like all culprits, it has wily accomplices such as anti-muscle specific kinase (anti-MUSK) antibody.

By No machine-readable author provided. S. Jähnichen assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., Public Domain,
By No machine-readable author provided. S. Jähnichen assumed (based on copyright claims). – No machine-readable source provided. Own work assumed (based on copyright claims)., Public Domain,


AChR antibodies are produced by a gland in the chest called the thymus. Disturbingly, this rather shabby-looking tissue may become enlarged (thymic hyperplasia), or cancerous (thymoma). The neurologist is therefore quick to request a CT chest scan as soon as MG is confirmed. Alas, the thymus is often normal or even shrivelled, to the delight of the patient who escapes the cardiothoracic surgeon. The neurologist is however ambivalent because surgery often gives a one-off cure, and saves the neurologist from a life-long commitment to monitor toxic treatments. The life of a Neurologist!

With so much known about MG, one would think there is very little on the horizon to put a smile on the faces of people with MG. But this old dog still has a few new tricks, and here are 4 energising reports I came across.

1. Predicting generalisation of ocular MG

By BruceBlaus. When using this image in external sources it can be cited staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762. - Own work, CC BY 3.0,
By BruceBlaus. When using this image in external sources it can be cited staff. “Blausen gallery 2014“. Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762. – Own work, CC BY 3.0,


Neurologists are aware that ocular MG could transform to generalised MG, they just don’t know who is at risk. Generalised MG is obviously a worse condition and requires more heavy-duty treatments. After much speculation, a report in JAMA Neurology has found the predictor of MG generalisation. Titled Clinical Utility of Acetylcholine Receptor Antibody Testing in Ocular Myasthenia Gravis, the authors confirmed, for the first time ever, that the risk of generalisation is linked to higher AChR antibody levels. I know, you were expecting some new, cutting-edge test or technology: sorry for the dampener, but sometimes it’s the little things that count. 

2. Linking MG to muscular dystrophy

By Cbenner12 - Own work, CC BY-SA 3.0,
By Cbenner12Own work, CC BY-SA 3.0,


Congenital myasthenia is a slightly different kettle of fish from conventional MG. For one, the diversity of genetic mutations that cause congenital myasthenia is mind-boggling; there are >20 genetic forms of MG such as DOK 7, RAPSYN, LAMB 2, and AGRIN. And these all differ in their presentation and response to treatment. An addition to this long list of congenital myasthenic syndromes should therefore normally not be exciting news. But there is something different in the recent report in the journal Brain about GMPPB (you really don’t want to know what this stands for). The paper, titled Mutations in GMPPB cause congenital myasthenic syndrome, opens up a can of worms because GMPPB also plays a role in causing muscular dystrophy. The authors see this as a bridge between myasthenia and muscular dystrophy. All rather complicated stuff, not quite sure what the implications are, but that’s the reason neurologists exist!

3. Leflunomide for drug-resistant MG

By MarinaVladivostok - Own work, CC0,
By MarinaVladivostokOwn work, CC0,


Immunosuppression is the ultimate treatment for MG because it reduces the production of the MG-causing antibodies. And the neurologist has a list, an arm length, of immunosuppressive agents to try. This variety of options is helpful because earlier choices may be ineffective, intolerable, or impractical. Azathioprine, methotrexate, mycophenolate …these roll out easily from the neurologist’s pen. Leflunomide would however sound very strange in neurological circles; it is more familiar to rheumatologists who use it to treat rheumatoid arthritis. Neurologists, ever peeping into the rheumatology recipe book, thought why not try Leflunomide in MG. They reported their findings in Journal of Neurology as Leflunomide treatment in corticosteroid-dependent myasthenia gravis: an open-label pilot study. And the recipe worked; 9 of 15 people with severe, steroid-dependent, MG improved on Leflunomide. Great news for when the going gets tough.

3, 4 Diaminopyridine for anti-MUSK MG

Thankfully not all MG treatment involves immunosuppression. One approach is to prevent the break down of the enzyme (esterase) that breaks down acetylcholine-got it? In this way there will be more acetylcholine available to counter the effect of AChR antibodies. Medications that work in this way are called acetylcoline esterase inhibitors (ACEI). It’s OK to  re-read all this before proceeding!

Pyridostigmine is the quintessential ACEI. But this is not effective in the more severe anti-MUSK MG where typical MG treatments don’t work so well. Neurologists have tried all sorts, including Rituximab, to varying success. What to do when all fails? A paper in the journal Neurology offers some hope that anti-MUSK MG may respond to 3,4 Diaminopyridine. This will be heart-warming news to all neurologists, if they ignore the fact that it is a single case report! But hey, from little acorns grow giant oak trees.

Want to dig deeper into MG? Try this update on myasthenia gravis.

So what is so remarkable about neurology anyway?

There is an astounding variety of reasons why a patient may be referred to a neurologist. The neurologist is easily identified as a brain doctor, and the patient may, after all, just have some tingling in the feet or some flickering of the muscles. Many patients may only have heard of prominent neurologists such as Oliver Sacks.

9.13.09 Oliver Sacks By Luigi Novi
9.13.09 Oliver Sacks By Luigi Novi


Or perhaps that man Sigmund Freud-or was he a psychoanalyst?

"Sigmund Freud LIFE" by Max Halberstadt - Licensed under Public Domain via Commons -
“Sigmund Freud LIFE” by Max Halberstadt – Licensed under Public Domain via Commons –


Apart from the fact that both are bearded, there is absolutely nothing similar to the practice of Sacks and Freud. You may refer to my post on the 100 all-time most influential neurologists for a flavour of the diverse and prominent neurologists.

By Joaquín Sorolla (1863 - 1923) ([1]) [Public domain or Public domain], via Wikimedia Commons
Santiago Ramon y Cajal By Joaquín Sorolla (1863 – 1923) ([1]) [Public domain or Public domain], via Wikimedia Commons

And this is what baffles patients; their inability to pigeon-hole a neurologist. Most medical specialists are easily identified by the restricted range of patients they see but neurology has a bewildering diversity of specialties. A cardiologist or a nephrologist comes with a clear label on the box, but the neurologist deals with conditions that extend from the top of the head to the tips of the toes.

"Components of the Nervous System" by Jenna Fair - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons -
“Components of the Nervous System” by Jenna Fair – Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons –


Neurological conditions are broadly defined as either affecting the central nervous system (brain and spinal cord) or the peripheral nervous system. Each of these then has several subspecialties that are mind-boggling.

Charis Tsevis Wired Nerves for Harrison & star. Flikr.
Charis Tsevis on Flikr. Wired Nerves for Harrison & Star.


The peripheral nervous system for instance consists of a diversity of motor and sensory nerves, and these communicate with organs, muscles and tissues all over the body. And there is an overwhelming array of things that can go wrong at each point of the nervous system, resulting in a myriad of nervous system diseases.


Gontzal García del Caño on Flikr. Spinal cord and spinal nerves.
Gontzal García del Caño on Flikr. Spinal cord and spinal nerves.


Peripheral nerve dysfunction may therefore give rise to disorders of the anterior horn cell, the nerve root, the ganglion, the neuromuscular junction, muscles, small and large nerve fibers. Each of these are further subclassified, a reflection of the diversity of neurological disorders. Take a look for example at the complex neuromuscular junction below, and you will appreciate the literally countless things that may go amiss.

"Synapse diag4". Licensed under CC BY-SA 3.0 via Commons -
“Synapse diag4”. Licensed under CC BY-SA 3.0 via Commons –


The diversity of neurological problems was brought home to me when I took up the task of compiling a database of neurology checklists. I blame Atul Gawande‘s Checklist Manifesto for this excursion on my part. The process was like opening up a can of worms; below is the broad range of major neurological disease categories I found:

  • Epilepsy
  • Disorders of Cranial Nerves
  • Disorders of Cognition
  • Disorders of Consciousness
  • Neurological Infections
  • Neurological Toxicity
  • Sleep disorders
  • Developmental Disorders
  • Parkinsonism
  • Other movement Disorders
  • Neuro-inflammatory Disorders
  • Headache Disorders
  • Metabolic disorders
  • Autoimmune Disorders
  • Anterior Horn Cell disorders
  • Radicular disorders
  • Plexus Disorders
  • Peripheral Nerve Disorders
  • Neuromuscular Junction (NMJ) disorders
  • Muscle Disorders
  • Spinal Cord Disorders
  • Nervous System Tumours
  • Stroke
  • Other Vascular Disorders

Neurology also has significant overlaps with other specialties, and neurologists often have to deal with:

  • Disorders of Allied Neurological Specialties
  • Neurological Disorders and General Medicine

What is so remarkable about neurology? It encompasses an unimaginable diversity of diseases. Many such as as migraine, Parkinson’s disease (PD) and peripheral neuropathy are common. For a taste of the diversity of these common diseases, see my previous blogs on neurology guidelines and neurology review articles. Many neurological diseases are however rare and complicated; for a flavour of the rarer diseases, take a look at my previous blog post on the most esoteric neurological conditions.

Typhoon at English Wikipedia [CC BY-SA 3.0 ( or GFDL (], via Wikimedia Commons
Typhoon at English Wikipedia [CC BY-SA 3.0 ( or GFDL (, via Wikimedia Commons

These are the remarkable things neurologist try to sort out. But how do they do it? How do they go about teasing out what is what? What is in the neurological toolbox? The key is the neurological consultation, an assessment so alien, using tools so scary, that it takes many patients aback: watch out for my future blog on The 20 Bizarre Things Neurologists Do To Their Patients.