The brain is arguably the most mysterious entity in the universe. It surprises us every time we believe we have got a handle on how it does whatever it is that it does. But the determination of the brain to remain an enigma is matched by the zeal of neuroscientists to decode its riddles. And what better way to announce the unravelling of a brain puzzle than by a catchy title that epitomises the discovery. Let us therefore celebrate 10 landmark neuroscience breakthroughs with 10 perceptively catchy neuroscience titles from the literature – both vintage and fresh.
Reawakening the Sleeping Beauty in the Adult Brain
This headline, whilst alluding to a fairy tale, highlights a real neuroscience breakthrough. The headline comes from a paper published in 2015 in the journal Current Opinions in Genetics and Development, and it has the full title “Reawakening the sleeping beauty in the adult brain: neurogenesis from parenchymal glia“. And at the centre of the paper is the concept of converting primary glial or supporting cells into ‘proper’ nerve cells. Talk of neuroscience alchemy, but this is neither a mythical story, nor a pipe dream. The authors of the paper acknowledged that “the brain’s capacity for spontaneous regeneration is extremely limited”, but they cited studies which have shown that “under certain circumstances” such as brain injury and stroke, “parenchymal astrocytes and NG2 glia can generate neuronal progeny“. This story will have a happy ending when neuroscientists develop the capability for “reprogramming-induced neurogenesis“; this will be achieved by deploying “neurogenic reprogramming factors” to convert glial cells into nerve cells. All that is missing from the story so far is Prince Charming…to plant a reviving kiss on the injured brain cells.
CNS Immune Privilege: Hiding in Plain Sight
One of the greatest misconceptions about the nervous system is the idea that the brain is somehow a detached command and control entity, firing off commands to its minions from whom it derives no benefits. Nowhere is this false idea most entrenched than in the assumption that the brain’s immune system is autonomous, uncoupled from the systemic immune system. And there isn’t a more eloquent way to dispel this false picture of immune privilege than this headline, the title of a review article published in 2006 in the journal Immunological Reviews. The authors of the paper cited several lines of evidence which they say have revealed that “the CNS is neither isolated nor passive in its interactions with the immune system”. Rather, the brain is hiding in plain sight, its unique microglial immune system disregarding the elaborate blood brain barrier to join forces with the body’s immune system. The editorialists stress that this new immune paradigm holds the promise of “opening the door for therapies” which may improve the outcome of such disorders as Alzheimer’s disease. Away with immune privilege, and in with the plebeians.
Uncovering the Secrets of the Brain Drain
One of the pillars of the now discarded concept of immune privilege was the idea that the brain does not have a lymphatic drainage system. How the brain got rid of its waste was therefore a riddle, the resolution of which was made much harder by the hubristic idea that the brain was exceptional. It was therefore a major comedown for the brain when a group of researchers discovered that it indeed has a lymphatic system; and this is expressed most lucidly in the headline above, the title of an editorial published in 2015 in the journal Nature Reviews Neurology. The editorial was commenting on the breakthrough study published in the journal Nature, which showed that the brain’s lymphatics drain directly into the systemic lymphatic vessels, where they presumably exchange immune ideas. Realising that the brain has a sewage system comes with many upsides, the author of the editorial stating that it “could have important implications for understanding the mechanisms underlying neurodegenerative and neuroinflammatory disease”. The brain drain is therefore a plumbing that is clearly worthier than its name.
The Inside Track
What is the cause of Parkinson’s disease (PD)? This is one of the most vexing neuroscience teasers which has exasperated, and continues to exasperate, generations of neuroscientists. There is no doubt that we now know a lot about the pathological features of PD; we are certain, for example, that it is associated with Lewy bodies, and that these are composed of the abnormal protein called α-synuclein. But we still do not know whether α-synuclein is the cause of PD, an innocent bystander, or the defence mechanism mounted by the brain to protect itself from an altogether faceless aggressor. Whatever the case, α-synuclein is a ubiquitous presence in the brains of people with PD. But why is it depicted in the headline above, the title of a review article published in 2013 in the journal Brain Pathology, as a long-distance runner? The answer lies in the almost alien sightings of α-synuclein in such far-flung places as the gut. One explanation for this observation is that α-synuclein starts life in the abdomen, and then undertakes a tortuous migration, a long-distance race, to get to the brain, where it wreaks its havoc. The review particularly discusses the possible prion-like fashion by which α-synuclein runs the race – moving from one cell to the next, leaving a trail of destruction in its wake. But the vexing question remains: is α-synuclein setting the pace in this marathon, or is it chasing a sneaky and malevolent front-runner? We are exactly where we started: what is the cause of PD?
When Distress Becomes (Un)sympathetic Pain
For most neurologists, fibromyalgia is a nebulous concept which they can neither prove nor disprove. But it serves as a convenient ‘get-out-of-jail-free‘ card when a long investigative process fails to unearth a neurological diagnosis for patients with a multitude of symptoms – prominent of which is diffuse pain. In such cases fibromyalgia becomes a ‘respectable‘ label with which to shoo the patient on to another specialist – far, far away. It is therefore with trepidation that neurologists will learn that fibromyalgia is no longer an obscure entity lingering in the shadows of medicine, but a ‘proper‘ disease with well-defined biological mechanisms. And the headline above, from the title of a detailed review article published in 2012 in the journal Pain Research and Treatment, is an indicator that dysfunction of the sympathetic nervous system is right at the heart of fibromyalgia. The article describes how the body transforms stress into pain via such mechanisms as sympathetic hyperactivity. The author of the review therefore makes a strong case that fibromyalgia is “a sympathetically maintained neuropathic pain syndrome“. It must be a good thing then that the biology of fibromyalgia is becoming clearer, but the neurologist now has to come up with a different escape plan.
Is Amyloid Beta-protein the Beginning or the End?
Amyloid beta (Aβ) protein is caught in the same chicken and egg scenario that hounds all neurodegenerative brain diseases in which abnormal proteins aggregate. And this conundrum is as true today as it was in 2006 when the article from which this headline was derived was published in the Annals of the New York Academy of Science. The author of the review considered several lines of evidence which he argued supported a causative role for amyloid beta protein in the genesis of Alzheimer’s disease. There are of course many other lines of evidence pointing to exactly the opposite conclusion, that Aβ protein is the innocent victim of a large-scale conspiracy to blame it for the crime of cognitive vandalism. The author was therefore gracious enough to acknowledge that “human clinical trials may be required to finally settle the issue“. He even suggested the kinds of clinical trials that will be required – those which will test “the efficacy or lack thereof of drugs that prevent Aβ generation, aggregation, or neurotoxicity”. In other words, eliminate Aβ protein and see what happens to the clinical manifestations of the disease. Since then of course, several such trials have been carried out which, alas, have demonstrated that eliminating Aβ protein does not correlate in any way with clinical benefit. Indeed, in some cases, eliminating Aβ protein made things worse. We are therefore still at the very beginning of the amyloid beta fairy tale, with the end nowhere in sight.
From Vestigial Remnant to Vital Organ?
There can be no doubt that this headline is referring to the only structure in the body that has been slandered with the term vestige, and that is the vermiform appendix. And only one neurological disorder had benefited from the smear campaign that has labelled the appendix a relic, a ghost from our evolutionary past, and that is Parkinson’s disease (PD). The headline above suggests not only that eons of calumny against the maligned entity is at an end, but also that PD has no more hiding place. The headline comes from the title of a detailed review article published in 2019 in the Journal of Parkinson’s Disease which makes the point that the appendix, far from being a redundant artefact, is an important secondary lymphoid organ where the gut microbiome, the immune system, and the vagus nerve interact. The article further makes the argument that the appendix is not a bit player on the wings in the theatre of PD, but the director calling the shots behind the scenes. To support their contention, the authors cite studies which have shown that the appendix is frequently packed with α-synuclein – the abnormal protein that characterises the pathology of PD. This hypothesis postulates that the appendix is the powerhouse which generates α-synuclein, and that this misfolded protein then travels up the vagus nerve to deposit in the brain. Also supporting this hypothesis are the studies which have shown that people who have had an appendectomy are less likely to develop PD. The appendix hypothesis is however quite contentious, other lines of evidence dismissing it outright. If, per chance, it does turn out to have merit, the reviewers promise that potential therapies may follow: I hear the sounds of surgeons sharpening their scalpels at that thought.
![](http://By Mikael Häggström, <a href="//commons.wikimedia.org/wiki/User:B_jonas" title="User:B jonas">B jonas</a> - <span class="int-own-work" lang="en">Own work</span>. This is a trivial derivative I created from <a href="//commons.wikimedia.org/wiki/File:Colon_(anatomy).svg" title="File:Colon (anatomy).svg">File:Colon_(anatomy).svg</a>, which was released to the public domain by its creator Mikael Häggström. My changes probably don't even create new copyright over it, but if they do, I hereby release the image under the Creative Commons CC0 1.0 Universal Public Domain Dedication., <a href="http://creativecommons.org/publicdomain/zero/1.0/deed.en" title="Creative Commons Zero, Public Domain Dedication">CC0</a>, <a href="https://commons.wikimedia.org/w/index.php?curid=72091328">Link</a>)
Friend or Foe?
This headline may as well have been titled ‘chicken or egg‘. It comes from an editorial published in 2014 in the journal Movement Disorders, which is a commentary on the recently described antibody disorder, IgLON5 disease. A disease that seems to know no bounds, it has such diverse manifestations from sleep and movement disorders, to cognitive and autonomic disturbances. But the authors of the editorial, with their neuroscience caps firmly on, were less curious about the clinical features of the disease, and more fascinated by the unusual characteristics of the antibody that is driving it. After providing a detail description of the breakthrough study they were commenting on, the authors raised the key question: “are the IgLON5 antibodies here cause or consequence“. One reason for their question was that, unlike other pathogenic antibodies that cause disease by targeting surface proteins involved in “synaptic transmission, plasticity, or excitability“, IgLON5 antibodies do not seem to target such functions. The authors were also intrigued by the observation that reducing the levels of the antibodies by immunotherapy did not result in clinical improvement. Biomarker or biohazard? The jury is still out.
Spicing Up Endogenous Neural Stem Cells
This headline comes from the title of an editorial published in 2014 in the journal Stem Cell Research and Therapy, and it addresses the major neurological challenge of reversing brain damage that arises following stroke. The editorial argued that every emerging reparative avenue needs to be pursued in view of the limitations of current approaches. And in this case, the editorialist had in mind a study published in the same journal which reported that aromatic turmerone, the active compound of the familiar herb turmeric, has the potential to induce the proliferation of neural stem cells. Even more remarkable is that the effect of tumerone is demonstrable both in a dish (in vitro), and in adult (in vivo) rats. This is clearly a window into what the future of stroke treatment may hold, a veritable neuroplasticity tool. However, one thing it is not, is an invitation to over-spice dinner!
The Neurology Lounge 
wonderful blog, creative presentation.
LikeLike
Thanks Dr. Sarma
LikeLike