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

The case for testing serum neurofilament light protein in MS

I am yet to request serum neurofilament light protein (NfL) in my practice. I am not sure yet why I should, but until now I confess I really haven’t looked for a reason to do so. I however know that some MSologists now tick it, along with other blood tests, when they investigate people they suspect may have multiple sclerosis (MS). NfL are proteins that are released by damaged neurones. Should I be requesting NfL in my clinical practice? I sniffed around to find the case for testing serum NfL, and below is what I found.

By GerryShaw – Standard tissue culture and immunofluorescencePreviously published: Unpublished, CC BY-SA 3.0,

Many studies have looked at the value of NfL in MS. One such very well-planned study that addresses many of my questions is that by Guili Disanto and colleagues, published in the journal Annals of Neurology in 2017. In the paper, titled Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis, the authors studied >380 people with MS and >150 healthy controls, and report four important findings.

By GerryShaw – Own work, CC BY-SA 3.0,
  1. The levels of NfL in serum strongly correlate with the levels in cerebrospinal fluid (CSF) of people with MS.
  2. People with more active and more severe MS had higher levels of NfL.
  3. People with MS on disease modifying treatment (DMT) had lower NfL levels than those who were not on treatment.
  4. In people with MS who had their serum NfL tested serially over time, the level of NfL predicted those who will develop frequent relapses or progressive MS.

The authors concluded, with enough justification I think, that serum NfL is a “sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS“.

Culture rat hippocampal neuron. ZEISS Microscopy on Flickr.

The strong correlation between cerebrospinal fluid (CSF) and serum NfL was also confirmed by a study published in the journal Neurology, by Lenka Novakova and colleagues titled Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. As the title indicates, they discovered that serum NfL is as good as CSF NfL in monitoring the progression of MS.

Neuron. NICHD on Flickr.

The observation that NfL predicts the course of MS is supported by many other studies, such as the one by Kristin Varhaug and colleagues in the journal Neurology Neuroimmunology and  Neuroinflammation whose title is also self-explanatory: Neurofilament light chain predicts disease activity in relapsing-remitting MS. A more recent paper, also published in Neurology, further reinforces the benefit of serum NfL in disease course prediction. It is titled Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. In this paper, Jehns Kuhle and colleagues practically confirm all the above stated benefits of NfL, concluding that “our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response”.

“Neuron” by Roxy Paine. Christopher Neugebauer on Flickr.

As for long term outcome, the 10 year follow up study by Alok Bahn and colleagues, published in the Multiple Sclerosis Journal in 2018, is most informative. In their paper titled Neurofilaments and 10-year follow-up in multiple sclerosis, the authors noted that “CSF levels of NfL at the time of diagnosis seems to be an early predictive biomarker of long-term clinical outcome and conversion from RRMS to SPMS”. Further support for the long term prognostic value of serum NfL comes from a paper published in 2018 in the journal Brain titled Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. The authors, Christian Barro and colleagues, studied more than 250 people with MS and concluded that “the higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss“.

Nervous Tissue: Spinal Cord Motor Neuron. Berkshire Community College on Flickr.

It is pertinent to note that the MS sphere is not the only one in which NfL is making waves. It has been found to be elevated in many other disorders such as motor neurone disease (MND), multiple system atrophy (MSA), hereditary spastic paraplegia (HSP), stroke, active small vessel disease, and peripheral neuropathy (PN). With these disclaimers in place, it may just be time to start ticking that NfL box.


By GerryShaw – Own work, CC BY-SA 3.0,


What are the pitfalls and perils of intracranial pressure?

Crudely speaking, the nervous system is made up of two parts. The peripheral nervous system, composed of nerves and muscles, is rather robust and roams free, exposed to the elements. On the other hand, the central nervous system, consisting of the brain and spinal cord, is delicate and fragile. It is therefore protectively cocooned in a rigid skull and a hardy vertebral skeleton. But even this tough fortress isn’t secure enough for these dainty neurones; they are, after all, the command and control system for the whole body. Therefore, to further insulate them from the physical and physiological perturbations that continuously threaten them, nature has further sequestered them within a very exquisitely regulated irrigation system, the cerebrospinal fluid (CSF).

Internet Archive book Images on Flickr.

The CSF is actually a fine filtrate of the blood that flows in the arteries. The sieve is the very forbidding blood-brain barrier (BBB) which turns away all the blood cells, and carefully sets a target on how much protein and glucose to let in. The pressure within the CSF is also very finely tuned, not too high…and not too low; that is how the neurones like it.


By Dr. Johannes Sobotta – Atlas and Text-book of Human Anatomy Volume III Vascular System, Lymphatic system, Nervous system and Sense Organs, Public Domain,


Alas, as with all systems, the CSF is vulnerable to external miscreants; infections such as meningitis,  encephalitis, and brain abscesses which cause brain swelling or cerebral edema. The CSF is also largely defenceless to internal insurgents, fifth columnists, such as a brain tumours, haematomas (bleeds), and cerebral vein thrombosis (venous clots). The smooth flow of the CSF may also be obstructed, resulting in hydrocephalus or enlargement of the brain’s ventricular system. In all these circumstances, the intracranial pressure is often elevated, a situation aptly dubbed intracranial hypertension. Very often, intracranial hypertension may occur without any obvious cause, and this condition is referred to as idiopathic intracranial hypertension (IIH). Because IIH threatens vision, neurologists have abandoned its old and misleading name, benign intracranial hypertension (BIH).

By BruceBlaus. When using this image in external sources it can be cited staff (2014). “Medical gallery of Blausen Medical 2014“. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. – Own work, CC BY 3.0, Link

Intracranial hypertension is no walk in the park as it portends disaster, whatever its cause. As it is a  potentially fatal state, the early warning signs are drilled into all doctors in medical school…when their brains are still malleable. These red flag features are severe headache, impaired consciousness, progressive visual loss, dilated or blown pupils, papilledema (swelling of the optic nerve head), and neck stiffness. The standard operating procedure for intracranial hypertension is to deflate the pressure as quickly as possible, by hook or by crook. This may be medical, with infusions such as mannitol, or surgical, with procedures such as decompressive craniectomy (removal of part of the skull). The terminal stage of intracranial hypertension, the most ominous neurological emergency, is cerebral herniation: this is the catastrophic compression of the brainstem into the narrow and tight spinal canal: a physical state that is incompatible with life.

By Ambika S., Arjundas D., Noronha V. –, CC BY-SA 2.0,

As with all waves, intracranial pressure also has its lows, and it is a no-brainer that neurologists call this intracranial hypotension. This is not as hazardous as intracranial hypertension, but it is worthy of respect in view of its devastating morbidity. The usual cause, and again no prizes for guessing this, is a leak. The puncture in this case is often iatrogenic, in other words, the whodunnit is the doctor. This may be deliberate, such as when the doctor attempts to remove some CSF to test, via a procedure called a  lumbar puncture (LP). It may also be accidental, such as when your friendly anaesthetist performs an epidural to relieve pain. In both situations, the dura protecting the CSF is perforated, causing spinal fluid leakage. This manifests as postural or orthostatic headache; by definition, this is a headache that sets in within 15 minutes of standing up, and resolves within 15 minutes of lying down flat. The treatment in such cases is strict bed rest, drinking loads of fluids, including caffeinated drinks, and waiting for the dura to heal itself…usually within one week. If this does not happen, then an intravenous caffeine infusion may be required. An epidural blood patch may also be carried out, again by your friendly anaesthetist, who squirts a little of the victims blood around the site of the leak, to, well, ‘patch it up’. In extremis, surgery may be needed to seal the leak, but this is way beyond my pay grade.

By Paul Anthony Stewart – Own work, CC BY-SA 4.0,

Intracranial hypotension may however develop without any apparent cause, and this is called spontaneous intracranial hypotension (SIH). The causes of SIH include unpredictable dural tears, ruptured meningeal diveticuli (outpouchings of the dura), and direct CSF-venous fistulae (don’t ask!) There are a variety of risk factors for SIH such as connective tissue diseases and bariatric surgery. It is very helpful that SIH leaves characteristic tell-tale clues on brain MRI scans, and these include subdural hygroma (plain fluid collections under the dura); subdural haematoma (blood under the dura); meningeal enhancement with contrast dye; engorgement of the pons and pituitary; and the interesting dinosaur tail sign on fat suppression T2 MRI (FST2WI). The gold standard test to localise the site of leakage in SIH is radionuclide cisternography. In the absence of this rather sophisticated test, a CT myelogram may be considered. Treatment is similar to that of other forms of intracranial hypotension, but other measures that may be required to seal the leak, including the use of fibrin sealeant.

By Hellerhoff – Own work, CC BY-SA 3.0,

If you have reached the end of this blog post, then you deserve a prize. Four prizes actually: recent interesting reports in the field of SIH to explore:

  1. The use of transorbital ultrasound in making a diagnosis.
  2. Treatment of complicated SIH with intrathecal saline infusion.
  3. SIH complicated by superficial siderosis.
  4. Severe SIH complicated by sagging brain causing causing postural loss of consciousness.
By © Nevit Dilmen, CC BY-SA 3.0,



What should we really know about cerebral aneurysms?

Cerebral aneurysms are scary things. It is alarming enough that they exist, but it is more spine-chilling that they enlarge with time. The most infamous aneurysm arises from the posterior communicating artery, the so-called PCOM aneurysm. And it signifies its sinister intent when it gradually enlarges and compresses its vascular neighbour, the third cranial nerve, otherwise known as the oculomotor nerve. A dysfunctional third nerve manifests with a droopy eyelid (ptosis) and double vision (diplopia). The reason for the double vision becomes obvious when the neurologist examines the eyes; one eyeball is out of kilter and is deviated downwards and outwards; it is indeed down and out! The pupil is also very widely dilated (mydriasis). These are among the most worrying red flags in medicine, and a very loud call to arms. Cerebral aneurysms however often wave no flags, red or otherwise. Indeed the most malevolent of them will expand quietly until they reach horrendous proportions, and then, without much ado, just rupture. They are therefore veritable time bombs…just waiting to go off.

By Tiago Etiene Queiroz – Own work, CC BY-SA 3.0,

Cerebral aneurysm however do not need to reach large proportions to rupture; some just rupture when they feel like. Aneurysms under 7mm in diameter however are less prone to rupture. A rupturing aneurysm presents with very startling symptoms. The most ominous is a sudden onset thunderclap headache (TCH), subjects reporting feeling as if they have been hit on the back of the head with a baseball or cricket bat. It is not quite known what non-sporting patients experience-for some reason they never get aneurysms in neurology textbooks! More universally appropriate, a ruptured aneurysm may manifest as sudden loss of consciousness. Both symptoms result from leakage of blood into the cerebrospinal fluid (CSF) space, a condition known as a subarachnoid haemorrhage (SAH).

By Lipothymia – Anonymised CT scan from my own practice, CC BY-SA 3.0,

You may breath a small sigh of relief here because the vast majority of people with thunderclap headaches do not have subarachnoid haemorrhage. Unfortunately, every person who presents with a thunderclap headache must be investigated- to exclude (hopefully), or confirm (ruefully), this catastrophic emergency. The first test is a CT head scan which identifies most head bleeds. The relief of a normal scan is however short-lived because some bleeds do not show on the CT. The definitive test to prove the presence or absence of a bleed is less high tech, but more invasive: the humble spinal tap or lumbar puncture (LP). This must however wait for least 12 hours after the onset of headache or blackout. This is the time it takes for the haemoglobin released by the red blood cells to be broken down into bilirubin and oxyhaemoglobin. These breakdown products are readily identified in the biochemistry lab, and they also impart on the spinal fluid a yellow tinge called xanthochromia. The test may be positive up to 2 weeks after the bleed, but the sensitivity declines after this time. A positive xanthochromia test is startling and sets off an aggressive manhunt for an aneurysm-the culprit in most cases. 

By Ben Mills – Own work, Public Domain,

Many people with cerebral aneurysms have a family history of these, or of subarachnoid haemorrhage. Some others may have connective tissue diseases such as Ehler’s Danlos syndrome (EDS), adult polycystic kidney disease (APCKD), or the rare Loeys-Dietz syndrome. This family history is a window of opportunity to screen family members for aneurysms. The screening is usually carried out with a CT angiogram (CTA) or MR angiogram (MRA). People are often not born with aneurysms, but tend to develop them after the age of 20 years. Aneurysm surveillance therefore starts shortly after this age, and many experts advocate repeating the screening test every 5-7 years until the age of 70-80 years.

By Nicholas Zaorsky, M.D. – Nicholas Zaorsky, M.D., CC BY-SA 3.0,

How are aneurysms treated? This will be the subject of a future blog post so watch this space!


Fronto-temporal brain sagging syndrome

Frontotemporal dementia (FTD) is a progressive untreatable condition. It causes the frontal and temporal lobes of the brain to shrink and it manifests as a behavioural disorder or with speech difficulties. I was unaware of any mimics of FTD  (differential diagnoses) that were not equally untreatable.

"LobesCaptsLateral" by Sebastian023. Licensed under CC BY-SA 3.0 via Commons -
“LobesCaptsLateral” by Sebastian023. Licensed under CC BY-SA 3.0 via Commons –


I was therefore surprised by this article in Neurology which reported 8 patients with the frontotemporal brain sagging syndrome. In this condition, FBSS, there is leakage of cerebrospinal fluid (CSF) which results in low pressure in the brain (intracranial hypotension). The result is that the brain, well, sags.

"1317 CFS Circulation" by OpenStax College - Anatomy & Physiology, Connexions Web site., Jun 19, 2013.. Licensed under CC BY 3.0 via Commons -
“1317 CFS Circulation” by OpenStax College – Anatomy & Physiology, Connexions Web site., Jun 19, 2013.. Licensed under CC BY 3.0 via Commons –


It i typically the back of the brain that sags in intracranial hypotension, and this leads to distortion of the brainstem. In FBSS however there is in addition, somehow, a reduction in the metabolic activity of the frontal lobe of the brain. It is this frontal hypometabolism that produces the clinical picture that mimics frontotemporal dementia.

"NPH MRI 272 GILD" by © Nevit Dilmen. Licensed under CC BY-SA 3.0 via Commons -
“NPH MRI 272 GILD” by © Nevit Dilmen. Licensed under CC BY-SA 3.0 via Commons –


There is an added twist to the story as reported, again in Neurology, of a patient whose syndrome spontaneously resolved when he accidentally fell and hit his chest on a chair. The authors said ‘…the fall may have caused a contusion injury and given him an auto-blood patch‘. In plain English, his injury caused a bleed which clotted and (again somehow), sealed the site of cerebrospinal fluid leakage.

Surely a not-to-miss differential next time you are about to diagnose frontotemporal dementia. A reversible dementia! 


Chronic fatigue syndrome and the brain

Chronic fatigue syndrome gets short shrift from neurologists. Admit it, we dismiss it with a wink and a nod. We put our noses up at its diagnostic criteria, call it ‘low moral fiber’, and move on to ‘proper’ neurological stuff.

But what if there really is something going on in the brains of patients with this label.

Well this paper in Radiology suggests there is. It reports white matter atrophy and increased functional anisotropy (whatever that means) in the right arcuate and right longitudinal fasciculus. The authors go as far as to suggest this may be a biomarker for the disease. OK, but you need more than 15 patients to go that far!

While still on chronic fatigue syndrome, some researchers have found cerebrospinal fluid (CSF) abnormalities in the disorder. The report from Molecular Psychiatry (no, not the JNNP) shows an increase in the cytokine CCL11, amongst other things, suggesting immune activation of the central nervous system-their words. And this presumably underlies the cognitive dysfunction in chronic fatigue syndrome (CFS, not CSF mind you).

Now all this must be getting too close for comfort for some!