Category Archives: Neurology & Psychiatry

What is schizophrenia really like ?

The recent tragic death of John Nash and his wife warrants reposting the following written 11 October 2009

“I feel that writing to you there I am writing to the source of a ray of light from within a pit of semi-darkness. It is a strange place where you live, where administration is heaped upon administration, and all tremble with fear or abhorrence (in spite of pious phrases) at symptoms of actual non-local thinking. Up the river, slightly better, but still very strange in a certain area with which we are both familiar. And yet, to see this strangeness, the viewer must be strange.”

“I observed the local Romans show a considerable interest in getting into telephone booths and talking on the telephone and one of their favorite words was pronto. So it’s like ping-pong, pinging back again the bell pinged to me.”

Could you paraphrase this? Neither can I, and when, as a neurologist I had occasion to see schizophrenics, the only way to capture their speech was to transcribe it verbatim. It can’t be paraphrased, because it makes no sense, even though it’s reasonably gramatical.

What is a neurologist doing seeing schizophrenics? That’s for shrinks isn’t it? Sometimes in the early stages, the symptoms suggest something neurological. Epilepsy for example. One lady with funny spells was sent to me with her husband. Family history is important in just about all neurological disorders, particularly epilepsy. I asked if anyone in her family had epilepsy. She thought her nephew might have it. Her husband looked puzzled and asked her why. She said she thought so because they had the same birthday.

It’s time for a little history. The board which certifies neurologists, is called the American Board of Psychiatry and Neurology. This is not an accident as the two fields are joined at the hip. Freud himself started out as a neurologist, wrote papers on cerebral palsy, and studied with a great neurologist of the time, Charcot at la Salpetriere in Paris. 6 months of my 3 year residency were spent in Psychiatry, just as psychiatrists spend time learning neurology (and are tested on it when they take their Boards).

Once a month, a psychiatrist friend and I would go to lunch, discussing cases that were neither psychiatric nor neurologic but a mixture of both. We never lacked for new material.

Mental illness is scary as hell. Society deals with it the same way that kids deal with their fears, by romanticizing it, making it somehow more human and less horrible in the process. My kids were always talking about good monsters and bad monsters when they were little. Look at Sesame street. There are some fairly horrible looking characters on it which turn out actually to be pretty nice. Adults have books like “One flew over the Cuckoo’s nest” etc. etc.

The first quote above is from a letter John Nash wrote to Norbert Weiner in 1959. All this, and much much more, can be found in “A Beatiful Mind” by Sylvia Nasar. It is absolutely the best description of schizophrenia I’ve ever come across. No, I haven’t seen the movie, but there’s no way it can be more accurate than the book.

Unfortunately, the book is about a mathematician, which immediately turns off 95% of the populace. But that is exactly its strength. Nash became ill much later than most schizophrenics — around 30 when he had already done great work. So people saved what he wrote, and could describe what went on decades later. Even better, the mathematicians had no theoretical axe to grind (Freudian or otherwise). So there’s no ego, id, superego or penis envy in the book, just page after page of description from well over 100 people interviewed for the book, who just talked about what they saw. The description of Nash at his sickest covers 120 pages or so in the middle of the book. It’s extremely depressing reading, but you’ll never find a better description of what schizophrenia is actually like — e.g. (p. 242) She recalled that “he kept shifting from station to station. We thought he was just being pesky. But he thought that they were broadcasting messages to him. The things he did were mad, but we didn’t really know it.”

Because of his previous mathematical achievments, people saved what he wrote — the second quote above being from a letter written in 1971 and kept by the recipient for decades, the first quote from a letter written in 12 years before that.

There are a few heartening aspects of the book. His wife Alicia is a true saint, and stood by him and tried to help as best she could. The mathematicians also come off very well, in their attempts to shelter him and to get him treatment (they even took up a collection for this at one point).

I was also very pleased to see rather sympathetic portraits of the docs who took care of him. No 20/20 hindsight is to be found. They are described as doing the best for him that they could given the limited knowledge (and therapies) of the time. This is the way medicine has been and always will be practiced — we never really know enough about the diseases we’re treating, and the therapies are almost never optimal. We just try to do our best with what we know and what we have.

I actually ran into Nash shortly after the book came out. The Princeton University Store had a fabulous collection of math books back then — several hundred at least, most of them over $50, so it was a great place to browse, which I did whenever I was in the area. Afterwards, I stopped in a coffee shop in Nassau Square and there he was, carrying a large disheveled bunch of papers with what appeared to be scribbling on them. I couldn’t bring myself to speak to him. He had the eyes of a hunted animal.

Why making money in the stock market is as stressful than a missile attack (for me)

I made a ton of money in stock market in the past 7 weeks. I hated every minute of it. I found the stress very hard to take, particularly the anxiety and the inability to think of little else. As wives often do, my wife told me I’m nuts. “Don’t you remember how hard you worked for those neurosurgeons? This is the easiest money you’ve ever made”. I made probably more than half a year’s salary from them in absolute amount, and I was well paid.

But that was 25 years ago. For details see https://luysii.wordpress.com/2015/04/19/hilarys-stroke/. Yes, I was on every other night and probably was out between midnight and 8 AM every third night on call with a full day’s work to follow before sleep. It was physically demanding, but not particularly stressful mentally. “All you could lose was money, but in practice you could lose a life”. True, but I knew that I’d never make a mistake of omission, or commission or due to lack of knowledge (fairly arrogant but true, I really kept up with the literature in practice). Decisions didn’t always work out, initial diagnoses weren’t always correct, untoward reactions ensued (particularly to drugs), but I always knew that I given it my best shot. The stress came from doing everything right but still being unable to help, watching helplessly as patients deteriorated.

Thinking this over, after what my wife said, I realized that I was very much like a patient who really educated me.

Neurologists see headaches, lots of headaches. This young man came to see me about them, complete with his own (correct) diagnosis of their cause — a divorce in progress. Taking the history always starts things off, and a standard question is “When did the headaches start?” Oh, just after I got back from Riyadh. (This was during the Gulf War). Riyadh? Wasn’t there a missile attack that killed people while you were over there? Yes. Didn’t you have headaches then? No, but this divorce is killing me, doc. He was right.

So just like the shrinks say, it isn’t the situation itself, but how you perceive it.

Don’t get your hopes up — but

Amyotrophic lateral sclerosis (ALS) is a God-awful disease, where patients progressively weaken and die because they aren’t strong enough to breathe, remaining mentally intact the entire time. A recent paper [ Science vol. 348 pp. 239 – 242 ‘ 15 ] showed that a drug already released by the FDA for treating hypertension — Wytensin (Guanabenz) was of benefit in a mouse model of the disease. So the drug is out there. If I were still in practice, I’d certainly give it a shot in my patients — off-label use be damned. Even better, enterprising organic chemists synthesized an analogue of Wytensin (Sephin1) which doesn’t lower blood pressure, but which still works in the mouse model.

Here’s why you shouldn’t get your hopes up too high. [ Nature vol. 4564 pp. 682 – 685 ’08 ] The work using SOD1 mutant mice (the mouse model of ALS mentioned above) is quite sloppy and nearly 12 drugs with benefit in mouse models have had no benefit in clinical trials. Minocycline which was effective in 4 studies in mice actually made things worse in a clinical trial of over 400 patients .

Now for a bit of background. Most cases of ALS aren’t familial, but a few are. One protein Superoxide Dismutase 1 (SOD1) was found to mutated in about 20% of familial ALS. It’s been studied out the gazoo, and some 140 different mutations have been found in its 153 amino acids in familial cases.

It’s hard to conceive of them all acting the same way, and literally thousands of papers have been written on the subject. It does seem clear that aggregated proteins occur in the dying neurons of ALS patients, but whether they are made mostly of SOD1 remains controversial (although it is present in the inclusions to some extent). Mature SOD1 is a 32 kiloDalton homodimeric metalloenzyme, in which each monomer contains Cu and Zn and one intrasubunit disulfide bond. It is one of the most abundant cellular proteins. It has a tendency to aggregate when overexposed.

The mouse results are impressive, as it improved established disease. In vivo, Sephin1 prevented the motor morphological and molecular defects of two unrelated protein misfolding diseases in mice (Charcot Marie Tooth 1B and ALS ! ! !). The mice had a mutant SOD1 (G93A). SOD1 mutants bind to Derlin1 on the the cytosolic side of the endoplasmic reticulum (ER) membrane blocking degradation of ER proteins causing ER stress. Very impressive ! ! ! !

The neuron as motherboard

Back in the day when transistors were fairly large and the techniques for putting them together on silicon were primitive by today’s standards, each functionality was put on a separate component which was then placed on a substrate called the motherboard. Memory was one component, the central processing unit (CPU) another, each about the size of a small cellphone today. Later on as more and more transistors could be packed on a chip, functionality such as memory could be embedded in the CPU chip. We still have motherboards today as functionality undreamed of back then (graphic processors, disc drives) can be placed on them.

It’s time to look at individual neurons as motherboards rather than as CPUs which sum outputs and then fire. The old model was to have a neuron look like an oak tree, with each leaf functioning as an input device (dendritic spine). If enough of them were stimulated at once, a nerve impulse would occur at the trunk (the axon). To pursue the analogy a bit further, the axon has zillions of side branches (e.g,. the underground roots) which than contact other neurons. Probably the best example of this are the mangrove trees I saw in China, where the roots are above ground.

How would a contraption like this learn anything? If an impulse arrives at an axonal branch touching a leaf (dendritic spine) — e.g. a synapse, the spine doesn’t always respond. The more times impulses hit the leaf when it is responding to something else, the more likely the spine is to respond (this is called long term potentiation aka LTP).

We’ve always thought that different parts of the dendritic tree (leaves and branches) receive different sorts of information, and can remember (by LTP). Only recently have we been able to study different leaves and branches of the same neuron and record from them in a living intact animal. Well we can, and what the following rather technical description says, its that different areas of a single neuron are ‘trained’ for different tasks. So a single neuron is far more than a transistor or even a collection of switches. It’s an entire motherboard (full fledged computer to you).

Presently Intel can put billions of transistors on a chip. But we have billions of neurons, each of which has tends of thousands of leaves (synapses) impinging on it, along with memory of what happened at each leaf.

That’s a metaphorical way of describing the results of the following paper (given in full jargon mode).

[ Nature vol. 520 pp. 180 – 185 ’15 ] Different motor learning tasks induce dendritic calcium spikes on different apical tuft branches of individual layer V pyramidal neurons in mouse motor cortex. These branch specific calcium spikes cause long lasting potentiation of postsynaptic dendritic spines active at the time of spike generation.

Disentangling Heredity and Environmental effects on IQ

No sensible person thinks intelligence is completely determined by heredity or by environment. Recent Swedish work [ Proc. Natl. Acad. Sci. vol. 112 pp.4612 – 4617 ’15 ] tries to control for heredity while measuring environmental effects on IQ, assuming that IQ measures intelligence, a position some find contentious. Every Swedish 18 year old man is conscripted into the military apparently. IQ tests are given to all. Amazingly the authors found 436 sibships where the brothers had been raised apart.

The intelligence of the biological and adoptive parents wasn’t measured. Rather the surrogate of educational level was used instead. It was divided into 5 classes.

What did they find? Adopted sibs had an IQ 4.41 points higher than the nonAdopted sib (recall that average IQ is stated to be 100 points although it’s been rising, and that IQ levels of the population fall on the Bell (Gaussian) curve, with a standard deviation of 15 points). These results are not surprising, as few willingly give children up for adoption, so the adopted environment was quite likely better. The educational level of the adoptive parents was an average of 2.6 points higher.

Next, the authors measured the effect of the surrogate marker for intelligence (educational level) on IQ. For each point in the 5 point scale that the adoptive parent was at a higher educational level than the biologic ones there was an increase in IQ of the adopted sib relative to the unadopted one. This is as unequivocal evidence as we have for the effect of environment and educational level on IQ.

We’ll never have perfect data, and many caveats about this work are possible, but it is an impressive effort. 436 sibs is a huge number compared to the twins who’ve been reared apart and studied this way.

Just how large an effect do you think it was? I’ve already told you everything you need to know.

Each additional unit of rearing parental education was associated with 2 IQ units. Are you surprised? I was, because I thought the effect would be much larger. So environment is important in determining intelligence, just not so much.

Hillary’s stroke

Hillary Clinton had a stroke toward the end of 2012. It was not due to the faint she had presumably because of the flu in mid December. The information given out at the time was extremely sketchy and confusing (see the copy of the post of 31 Dec ’12 at the end).

She fainted while giving a speech in Buffalo according to one account and at her home in Washington according to another and was not hospitalized. She is said to have suffered a concussion when she fell. Then on the 30th of December she was hospitalized because a blood clot was found (more later) and placed on blood thinners. She suffered double vision and had to wear corrective glasses (Fresnel lenses) for congressional testimony 23 January 2013.

So she had a blood clot in her head and a neurologic deficit persisting for a few weeks. That’s what a stroke is.

Could it have been due to the head trauma? This is extremely doubtful based on an intense 42 month experience managing acute head injuries.

To get my kids through college, I took a job working for two busy neurosurgeons. When I got there, I was informed that I’d be on call every other night and weekend, taking first call with one of the neurosurgeons backing me up. Neurologists rarely deal with acute head trauma although when the smoke clears we see plenty of its long term side effects (post-traumatic epilepsy, cognitive and coordination problems etc. etc.). I saw plenty of it in soldiers when I was in the service ’68 – ’70, but this was after they’d been stabilized and shipped stateside. Fortunately, my neurosurgical backup was excellent, and I learned and now know far more about acute head trauma than any neurologist should.

We admitted some of the head trauma cases to our service, but most cases had trauma to other parts of the body, so a general surgeon would run the show with our group as consultants. The initial consultant in half the cases was me. If I saw them initially, I followed the patients until discharge. On weekends I covered all our patients and all our consults, usually well over 20 people.

We are told that Hillary had a clot in one of the large draining veins in the back of her head (venous sinuses actually). In all the head trauma I saw (well over 300 I’d guess), I never saw a clot develop there. I’ve spoken to two neuroradiologists still in practice, and they can’t recall seeing such a clot without a skull fracture near the vein. Nothing like this was mentioned at any time about Hillary.

Hillary’s neurologic deficit involved a nerve going to the muscles of her left eye. These start in the brainstem, a part of the brain quite near the site where she is said to have the clot in her vein. The brainstem is crucial in maintaining consciousness, and it is far more likely that the faint in early December was a warning sign of the stroke she had subsequently.

I can’t believe that she would not have been hospitalized had she complained of double vision when she fainted in early December, so it must have come on later.

So the issue is why did she have the stroke, and how likely is it to recur. I seriously doubt that it had anything to do with the head injury she sustained when she fainted. We’ve have two presidents neurologically impaired by stroke in the past century (Woodrow Wilson after World War I and Franklin Delano Roosevelt at Yalta). The results were not happy for the USA or the World.

Certainly all this would be cleared up if her medical records were released. Only Hillary can do this, but at least she cannot destroy them, as although she ‘owns’ them, they are not in her sole possession.

The following is a post written 31 December ’12 when the news of Hillary’s illness first broke showing how fragmentary the information about it was back then (it isn’t a good deal better now).

Medical tribulations of politicians — degrees of transparency

Remarkably on the last day of the year, 3 political figures and their medical problems are in the news. Here they are in order of medical transparency (highest first).

l. George Bush Sr. — the most transparent. We are told what he has (pneumonia), when he was admitted to hospital when he was in the ICU, when he came out. Docs call pneumonia ‘the old man’s friend’ not out of cynicism, but because its a mode of death with (relatively) little suffering. The patient lapses into unconsciousness and usually dies quickly and quietly. It took my cellist’s father only a day or two to pass away this month. Clearly it isn’t invariably fatal, and Bush Sr. was now out of the ICU at last count (he’s 88).

2. Hillary Clinton — admitted to the hospital yesterday with a ‘blood clot’ somewhere, said to be a complication of the concussion she suffered a few weeks ago. Also said to be under treatment with anticoagulants. Most clots due to head trauma are inside the head and treating them with anticoagulants is a disaster. The most likely type of clot given the time from the concussion is a subdural hematoma. It is possible that she’s been so inactive since the concussion that she developed thrombophlebitis in her legs, in which case anticoagulation would be indicated.

More disturbingly, is that her passing out a few weeks ago is a sign of something more serious going on. Hopefully not.

The powers that be should have told us where the clot actually is.

Update 5:50 PM EST — Well the powers that be did open up and it is a most unusual complication of head injury (and one I’d never seen in nearly 4 decades of practice) — a venous thrombosis in the head. I’m not even sure it’s due to her head injury. It might have even caused her syncope, but presumably she had some sort of radiologic study of her head when she fainted, which should have picked it up. The venous sinuses draining the brain in the back of the head are notoriously asymmetric, so a narrowing attributable to a clot could just be a variant anatomy. One very bad complication of cerebral venous thrombosis back there (which I saw as a complication of chronic mastoid bone infection — not head trauma) is pseudotumor cerebri. I really wonder if these guys have the right diagnosis.

3. Hugo Chavez — Yesterday it was announced that he’s had a third complication since his surgery for cancer 3 weeks ago. Naturally, we’re not told just what this complication actually is. This is consistent with the information that has been released about his case. We know almost nothing about his actual tumor (except that he has one). He most assuredly is not free of cancer as he stated last fall. He is said to have have a bleeding problem and a lung infection as the first two complications.

My guess for this third complication is that it is a dehiscence of his abdominal incision, which must have been fairly large for a 6 hour operation. Dehiscence just means that the wound has spontaneously opened up exposing abdominal contents (which means that peritonitis is not far behind). Why should this happen? Two reasons — he’s had radiation to the area which inhibits wound healing, and he’s been on high dose steroids in the past (and perhaps presently) which also inhibits wound healing.

I don’t think he’s going to be able to take office 10 days hence, and doubt that he’ll come back to Venezuela alive. Transparency has been zilch. Hopefully the people of Venezuela are beginning to realize just how misleading the information they’ve been fed about his health has been.

This is the sort of thing physicians taking care of really sick people deal with daily, which may explain why your doc friends aren’t as jolly as you are at the New Year’s Eve parties you’re about to attend.

Nonetheless, Happy New Year to all ! ! ! !

One reason our brain is 3 times that of a chimpanzee

Just based on the capacity of the skull, our brain is 3 – 4 times larger than that of our closest primate relative, the chimp. Most of the increase in size occurs in the cerebral cortex (the gray matter) just under the skull. Our cortex is thrown into folds because there is so much of it. Compare the picture of the mouse brain (smooth) and ours, wrinkled like a walnut http://www.nsf.gov/discoveries/disc_summ.jsp?cntn_id=130442.

We now may have part of the explanation. A fascinating paper http://www.sciencemag.org/content/347/6229/1465.full.pdf studied genetic differences between the progenitor cells from which the cortex arises (radial glia) in man and mouse. They found 56 protein coding genes expressed in our radial glia not present in the mouse (out of 20,000 or so).

One in particular called by the awful name ARHGAP11B is particularly fascinating. Why? Because it’s the product of a gene duplication of ARHGAP11A. When did this happen — after the human line split off from the chimp 6 million years ago. Chimps have no such duplication, just the original

Put ARHGAP11B into a developing mouse and its cortex expands so much it forms folds.

There has been all sorts of work on the genetic difference between man and chimp. There almost too many — [ Nature vol. 486 pp. 481 – 482 ’12 ] — some 20,000,000. Finding the relevant ones is the problem. ARHGAP11A is by far the best we’ve found to date.

Another fascinating story is the ‘language gene’ discovered in a family suffering from a speech and language disorder. It’s called FOXP2. Since the last common ancestor of humans and mice (70 megaYears ago) there have been only 3 changes in the 715 amino acids comprising the protein. 2 of them have occurred in the human lineage since it split with the chips 6 megaYears ago. So far no one has put the human FOXP2 gene into a chimp and got it to talk. For more details see http://en.wikipedia.org/wiki/FOXP2

There is all sorts of fascinating molecular biology about what these two genes actually do in the cell, but that would make this post too long,. This is, in part, a chemistry blog and just what FOXP2 and ARHGAP11A actually do involves some beautiful and elegant chemistry — look up RhoGAP and Winged Helix transcription factors. Ferrari’s are beautiful cars, and become even more beautiful when you understand what’s going on under the hood. Chemistry gives you that for molecular, cellular and organismal biology.

Why we imperfectly understand randomness the way we do.

The cognoscenti think the average individual is pretty dumb when it comes to probability and randomness. Not so, says a fascinating recent paper [ Proc. Natl. Acad. Sci. vol. 112 pp. 3788 – 3792 ’15 ] http://www.pnas.org/content/112/12/3788.abstract. The average joe (this may mean you) when asked to draw a random series of fifty or so heads and tails never puts in enough runs of heads or runs of tails. This leads to the gambler’s fallacy, that if an honest coin gives a run of say 5 heads, the next result is more likely to be tails.

There is a surprising amount of structure lurking within purely random sequences such as the toss of a fair coin where the probability of heads is exactly 50%. Even with a series with 50% heads, the waiting time for two heads (HH) or two tails (TT) to appear is significantly longer than for an alternation (HT or TH). On average 6 tosses will be required for HH or TT to appear while only an average of 4 are needed for HT or TH.

This is why Joe SixPack never puts in enough runs of Hs or Ts.

Why should the wait be longer for HH or TT even when 50% of the time you get a H or T. The mean time for HH and TT is the same as for HT and TH. The variance is different because the occurrences of HH and TT are bunched in time, while the HT and TH are spread evenly.

It gets worse for longer repetitions — they can build on each other. HHH contains two instances of HH, while alterations do not. Repetitions bunch together as noted earlier. We are very good at perceiving waiting times, and this is probably why we think repetitions are less likely and soon to break up.

The paper goes a lot farther constructing a neural model, based on the way our brains integrate information over time when processing sequences of events. It takes into consideration our perceptions of mean time AND waiting times. We average the two. This produces the best fitting bias gain parameter for an existing Bayesian model of randomness.

See, you’re not as dumb as they thought you were.

Another reason for our behavior comes from neuropsychology and physiological psychology. We have ways to watch the electrical activity of your brain and find out when you perceive something as different. It’s called mismatch negativity (see http://en.wikipedia.org/wiki/Mismatch_negativity for more detail). It a brain potential (called P300) peaking .1 -.25 seconds after a deviant tone or syllable.

Play 5 middle c’s in a row followed by a d than c’s again. The potential doesn’t occur after any of the c’s just after the d. This has been applied to the study of infant perception long before they can speak.

It has shown us that asian and western newborn infants both hear ‘r’ and ‘l’ quite well (showing mismatch negativity to a sudden ‘r’ or ‘l’ in a sequence of other sounds). If the asian infant never hears people speaking words with r and l in them for 6 months, it loses mismatch negativity to them (and clinical perception of them). So our brains are literally ‘tuned’ to understand the language we hear.

So we are more likely to notice the T after a run of H’s, or an H after a run of T’s. We are also likely to notice just how long it has been since it last occurred.

This is part of a more general phenomenon — the ability of our brains to pick up and focus on changes in stimuli. Exactly the same phenomenon explains why we see edges of objects so well — at least here we have a solid physiologic explanation — surround inhibition (for details see — http://en.wikipedia.org/wiki/Lateral_inhibition). It happens in the complicated circuitry of the retina, before the brain is involved.

Philosophers should note that this destroys the concept of the pure (e.g. uninterpreted) sensory percept — information is being processed within our eyes before it ever gets to the brain.

Update 31 Mar — I wrote the following to the lead author

” Dr. Sun:

Fascinating paper. I greatly enjoyed it.

You might be interested in a post from my blog (particularly the last few paragraphs). I didn’t read your paper carefully enough to see if you mention mismatch negativity, P300 and surround inhibition. if not, you should find this quite interesting.

Luysii

And received the following back in an hour or two

“Hi, Luysii- Thanks for your interest in our paper. I read your post, and find it very interesting, and your interpretation of our findings is very accurate. I completely agree with you making connections to the phenomenon of change detection and surround inhibition. We did not spell it out in the paper, but in the supplementary material, you may find some relevant references. For example, the inhibitory competition between HH and HT detectors is a key factor for the unsupervised pattern association we found in the neural model.

Yanlong”

Nice ! ! !

Should pregnant women smoke pot?

Well, maybe this is why college board scores have declined so much in recent decades that they’ve been normed upwards. Given sequential MRI studies on brain changes throughout adolescence (with more to come), we know that it is a time of synapse elimination. (this will be the subject of another post). We also know that endocannabinoids, the stuff in the brain that marihuana is mimicking, are retrograde messengers there, setting synaptic tone for information transmission between neurons.

But there’s something far scarier in a paper that just came out [ Proc. Natl. Acad. Sci. vol. 112 pp. 3415 – 3420 ’15 ]. Hedgehog is a protein so named because its absence in fruitflies (Drosophila) causes excessive bristles to form, making them look like hedgehogs. This gives you a clue that Hedgehog signaling is crucial in embryonic development. A huge amount is known about it with more being discovered all the time — for far more details than I can provide see http://en.wikipedia.org/wiki/Hedgehog_signaling_pathway.

Unsurprisingly, embryonic development of the brain involves hedgehog, e,g, [ Neuron vol. 39 pp. 937 – 950 ’03 ] Hedgehog (Shh) signaling is essential for the establishment of the ventral pattern along the whole neuraxis (including the telencephalon). It plays a mitogenic role in the expansion of granule cell precursors during CNS development. This work shows that absence of Shh decreases the number of neural progenitors in the postnatal subventricular zone and hippocampus. Similarly conditional inactivation of smoothened results in the formation of fewer neurospheres from progenitors in the subventricular zone. Stimulation of the hedgehog pathway in the mature brain results in elevated proliferation in telencephalic progenitors. It’s a lot of unfamiliar jargon, but you get the idea.

Of interest is the fact that the protein is extensively covalently modified by lipids (cholesterol at the carboxy terminal end and palmitic acid at the amino terminal end. These allow hedgehog to bind to its receptor (smoothened). It stands to reason that other lipids might block this interaction. The PNAS work shows this is exactly the case (in Drosophila at least). One or more lipids present in Drosophila lipoprotein particles are needed in vivo to keep Hedgehog signaling turned off in wing discs (when hedgehog ligand isn’t around). The lipids destabilize Smoothtened. This work identifies endocannabinoids as the inhibitory lipids from extracts of human very low density lipoprotein (VLDL).

It certainly is a valid reason for women not to smoke pot while pregnant. The other problem with the endocannabinoids and exocannabinoids (e.g. delta 9 tetrahydrocannabinol), is that they are so lipid soluble they stick around for a long time — see https://luysii.wordpress.com/2014/05/13/why-marihuana-scares-me/

It is amusing to see regulatory agencies wrestling with ‘medical marihuana’ when it never would have gotten through the FDA given the few solid studies we have in man.

Scary stuff

While you were in your mother’s womb, endogenous viruses were moving around the genome in your developing developing brain according to [ Neuron vol. 85 pp. 49 – 59 ’15 ].

The evidence is pretty good. For a while half our genome was called ‘junk’ by those who thought they had molecular biology pretty well figured out. For instance 17% of our 3.2 gigaBase DNA genome is made of LINE1 elements. These are ‘up to’ 6 kiloBases long. Most are defective in the sense that they stay where they are in the genome. However some are able to be transcribed into RNA, the RNA translated into proteins, among which is a reverse transcriptase (just like the AIDS virus) and an integrase. The reverse transcriptase makes a DNA copy of the RNA, and the integrates puts it back into the genome in a different place.

Most LINE1 DNA transcribed into RNA has a ‘tail’ of polyAdenine (polyA) tacked onto the 3′ end. The numbers of A’s tacked on isn’t coded in the genome, so it’s variable. This allows the active LINE1’s (under 1/1,000 of the total) to be recognized when they move to a new place in the genome.

It’s unbelievable how far we’ve come since the Human Genome Project which took over a decade and over a billion dollars to sequence a single human genome (still being completed by the way filling in gaps etc. etc [ Nature vol. 517 pp. 608 – 611 ’15 ] using a haploid human tumor called a hydatidiform mole ). The Neuron paper sequenced the DNA of 16 single neurons. They found LINE1 movement in 4

Once a LINE1 element has moved (something very improbable) it stays put, but all cells derived from it have the LINE1 element in the new position.

They found multiple lineages and sublineages of cells marked by different LINE1 retrotransposition events and subsequent mutation of polyA microsatellites within L1. One clone contained thousands of cells limited to the left middle frontal gyrus, while a second clone contained millions of cells distributed over the whole left hemisphere (did they do whole genome on millions of cells).

There is one fly in the ointment. All 16 neurons were from the same ‘neurologically normal’ individual.

Mosaicism is a term used to mean that different cells in a given individual have different genomes. This is certainly true in everyone’s immune system, but we’re talking brain here.

Is there other evidence for mosaicism in the brain? Yes. Here it is

[ Science vol. 345 pp. 1438 – 1439 ’14 ] 8/158 kids with brain malformations with no genetic cause (as found by previous techniques) had disease causing mutations in only a fraction of their cells (hopefully not brain cells produced by biopsy). Some mosaicism is obvious — the cafe au lait spots of McCune Albright syndrome for example. DNA sequencing takes the average of multiple reads (of the DNA from multiple cells?). Mutations foudn in only a few reads are interpreted as part of the machine’s inherent error rate. The trick was to use sequencing of candidate gene regions to a depth of 300 (rather than the usual 50 – 60).

It is possible that some genetically ‘normal’ parents who have abnormal kids are mosaics for the genetic abnormality.

[ Science vol. 342 pp. 564 – 565, 632 -637 ’13 ] Our genomes aren’t perfect. Each human genome contains 120 protein gene inactivating variants, with 20/120 being inactivated in both copies.

The blood of ‘many’ individuals becomes increasingly clonal with age, and the expanded clones often contain large deletions and duplications, a risk factor for cancer.

Some cases of hemimegalencephaly are due to somatic mutations in AKT3.

30% of skin fibroblasts ‘may’ have somatic copy number variations in their genomes.

The genomes of 110 individual neurons from the frontal cortex of 3 people were sequenced. 45/110 of the neurons had copy number variations (CNVs) — ranging in size from 3 megaBases to a whole chromosome. 15% of the neurons accounted for 73% of of the CNVs. However, 59% of neurons showed no CNVs, while 25% showed only 1 or 2.

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