The Limits of Neuroplasticity

Neuroplasticity is in.


Books tell us about The Brain That Changes Itself or advise us on how to Train Your Mind, Change Your Brain.

Now there's no doubt that the brain is plastic, able to rewire itself in response to damage or training, and that it's more so than was generally believed, say, 20 years ago. It's clearly an important and interesting field, but a little caution is warranted. Neuroplasticity can't fix everything.

If the brain were infinitely plastic, brain damage would be no big deal. You'd get over it pretty quickly, so long as some of your brain was intact and able to rewire itself to compensate. Unfortunately, that's rarely what happens. Well, unfortunately unless you're a neurologist; they'd be out of a job if it were otherwise...

Swiss neurologists Bindschaedler et al have provided a nice example of the limits of neuroplasticity in a new paper: Growing up with bilateral hippocampal atrophy: From childhood to teenage.

Patient "VJ" was diagnosed with bilateral atrophy of the hippocampus at age 8. The damage almost certainly dated back a few hours after his birth which followed a normal pregnancy and delivery:

VJ had convulsions, then an episode of apnoea, which required treatment by phenobarbital and mask-assisted ventilation respectively. Hypertonia and hyperreactivity were followed by a period of hypotonia and somnolence during the 8 following days.

He seemed to make a full recovery, and never suffered another seizure. However, as he grew up, his parents noticed that he was forgetful and had difficulty concentrating. At the age of 8, he was referred for an MRI scan, which revealed severe atrophy of the hippocampus, and the related structures the fornix and the mammilary bodies, on both sides of the brain.

The diagnosis was hypoxic-ischaemic encephalopathy: a lack of oxygen. For some reason, the hippocampus is especially vulnerable to this; selective hippocampal damage is also common after carbon monoxide poisoning.

VJ is a bit like a childhood version of the famous adult patient HM, however, there are important differences. Apart from occurring much earlier, obviously, VJ's damage was less severe. Unlike HM he did not lack the nearby entorhinal cortex or parahippocampal cortex.

The authors followed him up to age 17, and did lots of tests of his cognitive function. The pattern that emerged is that VJ showed a selective impairment of memory for personal events (episodic memory). He learned to read normally, and he scored well on tests of general knowledge. So he had preserved semantic memory, memory for facts. His IQ was normal.

Even his episodic memory impairment was selective, however. He was severely impaired on tests of memory recall, i.e. "What did you do yesterday?". But on tests of recognition - "Have you ever seen this picture before?" - he did perfectly well.

This fits with lots of previous studies showing that the hippocampus is required for recall while the nearby cortex is more important for recognition. When asked to describe events in his past, he was essentially unable to do so, unless he was provided with "clues" or "reminders" to trigger recognition.

So VJ's brain couldn't rewire itself to compensate for the lack of a hippocampus, despite the fact that the damage occurred at birth, and the brain is considered to be at its most plastic during childhood.

This is not all that surprising really. The hippocampus is a unique region, containing specialized circuitry which is just not found anywhere else in the brain. Most of the evidence for large-scale neuroplasticity concerns the cerebral cortex. When part of the cortex is damaged, other cortical areas can sometimes compensate for the loss: but the cortex can't turn itself a substitute hippocampus.

Bindschaedler, C., Peter-Favre, C., Maeder, P., Hirsbrunner, T., & Clarke, S. (2010). Growing up with bilateral hippocampal atrophy: From childhood to teenage Cortex DOI: 10.1016/j.cortex.2010.09.005

The Tree of Science

How do you know whether a scientific idea is a good one or not?


The only sure way is to study it in detail and know all the technical ins and outs. But good ideas and bad ideas behave differently over time, and this can provide clues as to which ones are solid; useful if you're a non-expert trying to evaluate a field, or a junior researcher looking for a career.

Today's ideas are the basis for tomorrow's experiments. A good idea will lead to experiments which provide interesting results, generating new ideas, which will lead to more experiments, and so on.

Before long, it will be taken as granted that it's true, because so many successful studies assumed it was. The mark of a really good idea is not that it's always being tested and found to be true; it's that it's an unstated assumption of studies which could only work if it were true. Good ideas grow onwards and upwards, in an expanding tree, with each exciting new discovery becoming the boring background of the next generation.

Astronomers don't go around testing whether light travels at a finite speed as opposed to an infinite one; rather, if it were infinite, their whole set-up would fail.

Bad ideas generate experiments too, but they don't work out. The assumptions are wrong. You try to explain why something happens, and you find that it doesn't happen at all. Or you come up with an "explanation", but next time, someone comes along and finds evidence suggesting the "true" explanation is the exact opposite.

Unfortunately, some bad ideas stick around, for political or historical reasons or just because people are lazy. What tends to happen is that these ideas are, ironically, more "productive" than good ideas: they are always giving rise to new hypotheses. It's just that these lines of research peter out eventually, meaning that new ones have to take their place.

As an example of a bad idea, take the theory that "vaccines cause autism". This hypothesis is, in itself, impossible to test: it's too vague. Which vaccines? How do they cause autism? What kind of autism? In which people? How often?

The basic idea that some vaccines, somewhere, somehow, cause some autism, has been very productive. It's given rise to a great many, testable, ideas. But every one which has been tested has proven false.

First there was the idea that the MMR vaccine causes autism, linked to a "leaky gut" or "autistic enterocolitis". It doesn't, and it's not linked to that. Then along came the idea that actually it's mercury preservatives in vaccines that cause autism. It doesn't. No problem - maybe it's aluminium? Or maybe it's just the Hep B vaccine? And so on.

At every turn, it's back to square one after a few years, and a new idea is proposed. "We know this is true; now we just need to work out why and how...". Except that turns out to be tricky. Hmm. Maybe, if you keep ending up back at square one, you ought to find a new square to start from.

Genes To Brains To Minds To... Murder?

A group of Italian psychiatrists claim to explain How Neuroscience and Behavioral Genetics Improve Psychiatric Assessment: Report on a Violent Murder Case.

The paper presents the horrific case of a 24 year old woman from Switzerland who smothered her newborn son to death immediately after giving birth in her boyfriend's apartment. After her arrest, she claimed to have no memory of the event. She had a history of multiple drug abuse, including heroin, from the age of 13.

Forensic psychiatrists were asked to assess her case and try to answer the question of whether "there was substantial evidence that the defendant had an irresistible impulse to commit the crime." The paper doesn't discuss the outcome of the trial, but the authors say that in their opinion she exhibits a pattern of "pathologically impulsivity, antisocial tendencies, lack of planning...causally linked to the crime, thus providing the basis for an insanity defense."

But that's not all. In the paper, the authors bring neuroscience and genetics into the case in an attempt to provide

a more “objective description” of the defendant’s mental disease by providing evidence that the disease has “hard” biological bases. This is particularly important given that psychiatric symptoms may be easily faked as they are mostly based on the defendant’s verbal report.

So they scanned her brain, and did DNA tests for 5 genes which have been previously linked to mental illness, impulsivity, or violent behaviour. What happened? Apparently her brain has "reduced gray matter volume in the left prefrontal cortex" - but that was compared to just 6 healthy control women. You really can't do this kind of analysis on a single subject, anyway.

As for her genes, well, she had genes. On the famous and much-debated 5HTTLPR polymorphism, for example, her genotype was long/short; while it's true that short is generally considered the "bad" genotype, something like 40% of white people, and an even higher proportion of East Asians, carry it. The situation was similar for the other four genes (STin2 (SCL6A4), rs4680 (COMT), MAOA-uVNTR, DRD4-2/11, for gene geeks).

I've previously posted about cases in which a well-defined disorder of the brain led to criminal behaviour. There was the man who became obsessed with child pornography following surgical removal of a tumour in his right temporal lobe. There are the people who show "sociopathic" behaviour following fronto-temporal degeneration.

However this woman's brain was basically "normal" at least as far as a basic MRI scan could determine. All the pieces were there. Her genotypes was also normal in that lots of normal people carry the same genes; it's not (as far as we know) that she has a rare genetic mutation like Brunner syndrome in which an important gene is entirely missing. So I don't think neurobiology has much to add to this sad story.

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We're willing to excuse perpetrators when there's a straightforward "biological cause" for their criminal behaviour: it's not their fault, they're ill. In all other cases, we assign blame: biology is a valid excuse, but nothing else is.

There seems to be a basic difference between the way in which we think about "biological" as opposed to "environmental" causes of behaviour. This is related, I think, to the Seductive Allure of Neuroscience Explanations and our fascination with brain scans that "prove that something is in the brain". But when you start to think about it, it becomes less and less clear that this distinction works.

A person's family, social and economic background is the strongest known predictor of criminality. Guys from stable, affluent families rarely mug people; some men from poor, single-parent backgrounds do. But muggers don't choose to be born into that life any more than the child-porn addict chose to have brain cancer.

Indeed, the mugger's situation is a more direct cause of his behaviour than a brain tumour. It's not hard to see how a mugger becomes, specifically, a mugger: because they've grown up with role-models who do that; because their friends do it or at least condone it; because it's the easiest way for them to make money.

But it's less obvious how brain damage by itself could cause someone to seek child porn. There's no child porn nucleus in the brain. Presumably, what it does is to remove the person's capacity for self-control, so they can't stop themselves from doing it.

This fits with the fact that people who show criminal behaviour after brain lesions often start to eat and have (non-criminal) sex uncontrollably as well. But that raises the question of why they want to do it in the first place. Were they, in some sense, a pedophile all along? If so, can we blame them for that?

Rigoni D, Pellegrini S, Mariotti V, Cozza A, Mechelli A, Ferrara SD, Pietrini P, & Sartori G (2010). How neuroscience and behavioral genetics improve psychiatric assessment: report on a violent murder case. Frontiers in behavioral neuroscience, 4 PMID: 21031162

Bionic Eye Lets Blind See

No, really. Read all about it in a remarkable (if awkwardly named) new paper from German team Zrenner et al, Subretinal electronic chips allow blind patients to read letters and combine them to words.

The device acts as an artificial retina. It's a tiny 3 x 3.1 mm panel (about ■ that size) containing an array of 1,500 individual light-sensitive microphotodiodes (38 x 40).

Each sensor converts incoming light into an electrical current - the brighter, the stronger - and outputs it through a tiny electrode. These currents stimulate nerve cells in the retina, in the same way that the eye's own photoreceptor cells normally do.

Of course, for this to be useful, you need to have a retina with functioning nerve cells, an intact optic nerve to convey the information to the brain, and working visual brain areas. This means that the technology is only useful for certain kinds of blindness caused by damage to photoreceptor cells. However, such blindness is quite common; retinitis pigmentosa, a genetic disorder, is one such.

Did it work? Yes. The chip was implanted in three patients, all of whom had been born sighted but had become almost completely blind due to retinal degeneration. In all three patients, the chip restored some degree of vision.

However, the benefits were most dramatic in Patient 2. He gained the ability to recognise everyday objects like spoons, bananas, and apples; he could read a clock to tell the time; and he could read letters (albeit special, extremely large letters about 8 cm high). "YouTube or it didn't happen?" Here you go...

The subretinal implant is not the only bionic eye idea in town, however. There have been various attempts to provide the blind with surrogate vision, like the camera attached to the tongue. Other researchers have been working on using - effectively - an external ("epiretinal") camera, which then interfaces with the optic nerve to transmit information to the brain.

However, Zrenner et al say that their method is better. Well, they would, but they make a good case. With an epiretinal device, you need to process the information into a form which the brain can recognise, but even after doing so, it takes some "getting used to".

Patients in this study were immediately able to make sense of what they saw, because the implant works much like a healthy retina. Also, epiretinal approaches have so far only provided up to 60 pixels.

Still, the chip has limitations. The image is greyscale, much less detailed than normal vision (38x40 pixels - an iPhone has 960x640), and being tiny, it only covers a small fraction of the normal visual field - although given that all detailed vision takes place in a tiny part of the retina called the fovea, this is not as much of a limitation as it first appears so long as you implant the chip where the fovea used to be; notably, this is what they did for Patient 2.

The chip also requires an external power supply, meaning that patients need to carry a battery pack around, and of course, they have a fairly hefty wire coming out of the side of their head. But really, that's not that important because this is a frickin' bionic eye, and it actually works.

Eberhart Zrenner, et al. (2010). Subretinal electronic chips allow blind patients to read letters and combine them to words Proc. R. Soc. B : 10.1098/rspb.2010.1747

Blue Morning

Recently, I wrote about diurnal mood variation: the way in which depression often waxes and wanes over the course of the day. Mornings are generally the worst.

A related phenomenon is late insomnia, or "early morning waking".

But this phrase is rather an understatement. Everyone's woken up early. Maybe you had a flight to catch. Or you were drunk and threw up. Or you just needed a pee. That's early morning waking, but not the depressive kind. When you're depressed, the waking up is the least of your problems.

Suddenly, you are awake, more awake than you've ever been. And you know something terrible has happened, or is about to happen, or that you've done something terribly wrong. It feels like a Eureka moment. You can be a level-headed person, not given to jumping to conclusions, but you will be convinced of this.

In a panic attack, you think you're going to die. Your heart is beating too fast, your breathing's too deep: your body is exploding, you can feel it too closely. With this, With this, you think you should die or even, in some sense, already have. It feels cold: you can no longer feel the warmth of your own body.

The moment passes; the terrible truth that you were so certain of five minutes ago becomes a little doubtful. Maybe it's not quite so bad. At this point, the wakefulness goes too, and you become, well, as tired as you ought to be at 3 am. You try to go back to sleep. If you're lucky, you succeed. If not, you lie awake until morning in a state of miserable contemplation.

While it's happening, you think that you're going to feel this way forever; bizarrely, you think you always have felt this way. In fact, this is the darkest hour.

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Why does this happen? There has been almost no research on early morning waking. Presumably, because it's so hard to study. To observe it, you would have to get your depressed patients to spend all night in your brain scanner (or, if you prefer, on your analyst's couch), and even then, it doesn't happen every night.

But here's my theory: the key is the biology of sleep. There are many stages of sleep; at a very rough approximation there's dreaming REM, and dreamless slow-wave. Now, REM sleep tends to happen during the second half of the night - the early morning.

During REM sleep, the brain is, in many respects, awake. This is presumably what allows us to have concious dreams. Whereas in slow wave sleep, the brain really is offline; slow waves are also seen in the brain of people in comas, or under deep anaesthesia.

When we're awake, the brain is awash with modulatory neurotransmitters, such as serotonin, norepinephrine, and acetylcholine. During REM, acetylcholine is present, while in slow-wave sleep it's not; indeed acetylcholine may well be what stops slow waves and "wakes up" the cortex.

But unlike during waking, serotonin and norepinephrine neurons are entirely inactive during REM sleep - and only during REM sleep. This fact is surprisingly little-known, but it seems to me that it explains an awful lot.

For one thing, it explains why drugs which increase serotonin levels, such as SSRI antidepressants, inhibit REM sleep. Indeed, high doses of MAOi antidepressants prevent REM entirely (without any noticeable ill-effects, suggesting REM is dispensable). SSRIs only partially suppress it.

Ironically, SSRIs can make dreams more vivid and colourful. I've been told by sleep scientists that this is because they delay the onset of REM so the dreams are "shifted" later into the night making you more likely to remember them when you wake up. But there could be more to it than that.

The fact that REM is a serotonin-free zone also explains wet dreams. Serotonin is well known to suppresses ejaculation; that's why SSRIs delay orgasm, one of their least popular side effects, although it's useful to treat premature ejaculation: every cloud has a silver lining.

So, having said all that: could this also explain the terror of early-morning waking? Suppose that, for whatever reason, you woke up during REM sleep, but your serotonin cells didn't wake up quick enough, leaving you awake, but with no serotonin (a situation which never normally occurs, remember). How would that feel?

Using a technique called acute tryptophan depletion (ATD), you can lower someone's serotonin levels. In most people, this doesn't do very much, but in some people with a history of depression, it causes them to relapse. Here's what happened to one patient after ATD:

[her] previous episodes of clinical depression were associated with the loss of important friendships had, while depressed, been preoccupied with fears that she would never be able to sustain a relationship. She had not had such fears since then.

She had been fully recovered and had not taken any medication for over a year. About 2 h after drinking the tryptophan-free mixture she experienced a sudden onset of sadness, despair, and uncontrollable crying. She feared that a current important relationship would end.

We don't know why tryptophan depletion does this to some people, or why it doesn't affect everyone the same way, and it's pure speculation that early morning waking has anything to do with this. But having said that, the pieces do seem to fit.