Thursday, February 01, 2007

Minicolumns, Genius, and Autism

In earlier posts I wrote about Autism and Minicolumns and Autism and the Evolution of the Brain, based on research by Dr. Casanova et al. Minicolumns are the basic organizational unit of the cortex, and are vertical arrays of pyramidal cells (neurons). The underlying argument in these posts was that those with ASD have a higher number of minicolumns than average, but that those minicolumns are of a narrower than average width, with smaller neurons but the same average number of neurons per minicolumn. The net result is a brain structure that skews in favour of processing stimuli that require discrimination, potentially at the expense of generalizing the salience of a particular stimulus. Smaller and more densely packed minicolumns could also allow for more complex information processing.

These attributes come at a potential cost. The reduction in width is a result of a reduction in the minicolumn’s peripheral zone of inhibitory and disinhibitory activity. The inhibitory fibers act to keep stimuli within individual minicolumns, and the reduction in this space increases the chance of stimuli overflowing to adjacent minicolumns, providing an amplifier effect and potential hypersensitivity. Narrower minicolumns may also result in an increased number of minicolumns per macrocolumn, which can also result in an amplification of thalamic input, and as each minicolumn’s response to thalamic input is modulated by the activity of neighbouring columns, a reduction in GABAergic inhibitory activity could also result in a loss of inhibition and greater amplification. Stimuli ‘spill’ and greater amplification could result in the increased incidence of seizures in autistics.

An additional factor is the reduction in neuron size, which reduces the ability of neurons to sustain connections over distances. Smaller neurons result in a metabolic bias favouring shorter connections at the expense of both longer distance and inter-hemispheral connectivity. The result is that autistic brains have a bias towards local (intra-regional) over global (inter-regional) connectivity and processing. Short intra-regional processing functions include mathematical calculations and visual processing. Cognitive functions that require inter-regional processing would be less metabolically efficient, including language, face recognition, and joint attention (Casanova - Abnormalities Of Cortical Circuitry In The Brains Of Autistic Individuals). Given the high metabolic cost of the brain (2.5% of our body weight but 22% of our resting metabolism - Leonard and Robertson 1992, p 186), smaller neurons may be a response to resource constraints.

Of note, while reduced minicolumnar width appears to be a prerequisite for ASD, the reported minicolumn widths found within autistic brains are still within the normal distribution of minicolumnar width, albeit at the tail end (Casanova, 2006). In other words, people with narrow minicolumnar widths are not necessarily on the ASD spectrum.

Narrower Minicolumns Without ASD

Confirmation of this is suggested in "Comparison of the Minicolumnar Morphometry of Three Distinguished Neuroscientists and Controls", a new research paper by Dr. Casanova et al, currently in review. The research in question involved analyzing and comparing the minicolumns of three distinguished neuroscientists ("supernormals") and six normative controls. The ‘supernormals’ are described as:

"researchers of high distinction within the neurosciences. Although personal history and interviews with those who knew these neuroscientists emphasize their wide range of knowledge (polymaths) and divergent thinking no claim is made regarding their intelligence or creativity."

That being said, the descriptions of the three individuals in question clearly suggest that they were very intelligent, focused, productive, and intellectually self-assured.

The research found the following:

"Overall, there were significant differences (p < 0.001) between the comparison groups in both minicolumnar width (cw) and mean cell spacing (mcs). Although our supernormals did not exhibit deficits in communication or interpersonal skills the resultant minicolumnar phenotype bears similarity to that described for both autism and Asperger’s syndrome."

The findings in this paper are fascinating (at least to me) in that they clearly indicate both similarities and differences between the brains of autistics and those of the three neuroscientists, suggesting some answers and raising some interesting questions. The major reported similarity is the finding of narrow minicolumnar widths. As stated in the paper, "A minicolumnar phenotype that provides for discrimination and/or focused attention may help explain the savant abilities observed in the intellectually gifted." It is unknown at this point whether two other characteristics linked to narrower width minicolumns in autistics – i.e. smaller neurons and a higher number of minicolumns – also occurred in these neuroscientists’ brains, but it is a logical assumption that these characteristics were present too. Smaller neurons are hypothesized by Dr. Casanova to be a requirement for the existence of narrower width minicolumns, based on laws of conservation for brain grows and evolution (from personal correspondence, with permission).


There were also significant minicolumnar differences between the neuroscientist brains and ASD brains. First, the neuroscientists had a lower mean cell spacing (MCS) – i.e. a smaller average distance between neurons - than the controls. In other words, their neurons were closer together than in typical minicolumns with large mean cell spacing. Previously analyzed ASD brains had ‘normal’ or typical mean cell spacing. Unfortunately, no direct numerical comparisons of MCS between this research and previous analyses are possible due to the difference in age between the neuroscientists (58, 84, and 89) and the autistic patients (average age being 12 years).

Second, the neuroscientists differ from those with ASD in terms of the horizontal spacing between neurons (relative dispersion of cells). The neuroscientist minicolumns were similar to typical minicolumns in that they had a small relative dispersion, i.e. cells tended to be clustered closer to the axis of the column. Those with ASD have a large relative dispersion, with cells distributed more uniformly within the minicolumn core.

Figure 1 (below, based on Fig 2 from the research paper) is a hypothetical representation of both mean cell spacing and relative dispersion in minicolumns, (after disregarding both neuroscientist and ASD reduced minicolumnar width). The neuroscientist and typical minicolumns have a smaller relative dispersion than the ASD minicolumn (i.e. tighter clustering toward the column axis vs. more uniform distribution). The neuroscientist column also has a smaller mean cell spacing, with cells being closer to each other than in the other two minicolumnar types, regardless of their distribution around the minicolumn axis.

I would speculate that the differences between the neuroscientist and ASD minicolumns would have a significant - but incomplete - explanatory role in accounting for the differences between the two groups. In both groups, narrower width would increase the risk of ‘spill’ between minicolumns. But the reduced mean cell spacing in the neuroscientists would presumably result in greater integrity of processing within the column (as well as potentially an increase in speed), while the tighter grouping of neurons around the axis would increase the distance between the neurons and those in adjacent columns, maximizing the zone of interneuronal inhibitory activity between the adjacent vertical arrays of pyramidal cells. This is significant, in that this maximized inhibitory zone could at least partially compensate for any reductions due to the narrower column width.

In contrast, the higher ASD MCS could result in comparatively lower signal intensity and - along with a more uniform horizontal dispersion – result in a higher risk that neurons in adjacent columns might in fact be closer in distance than neurons within the same column, increasing the risk of ‘spill’. Plus, the more uniform horizontal dispersion would result in more neurons being found towards the outer periphery of the column, with an even smaller zone of inhibitory activity between these outer neurons and adjacent minicolumns.

More Questions

This still leaves some significant questions for further research regarding differences between the neuroscientist and ASD minicolumns. For one, as the paper suggests:

"the widespread morphometric changes in our scientists suggest that any brain-related ability they may have possessed (e.g., cross-discipline learning, abstracting, dimensional thinking) involved multiple cortical regions. In developing these abilities the various association cortices acted as nodes or epicenters, binding multimodal information, within a neural network (Mesulam 1994; 1998). Contrary to earlier formulations, modern observations suggest that higher cognitive processes are encoded in flexible distributed networks rather than rigid convergent ones (Mesulam, 1994; 1998)."

As such, the neuroscientists had brains capable of exceptional thinking, combining deep focus and discrimination, but linked to distributed (global) processing. If the neuroscientist neurons were smaller, biasing against global connectivity, then was there a compensatory effect? Spindle neurons serve to connect more distant, non-neighbouring regions of the brain (Casanova - Big Brains Manuscript, in preparation for submission). From Wikipedia:

"Spindle cells appear to play a central role in the development of intelligent behavior and adaptive response to changing conditions and cognitive dissonance. They emerge postnatally [emphasis added] and eventually become widely connected with diverse parts of the brain, evidencing their essential contributions to the superior capacity of hominids to focus on difficult problems."

Spindle neurons are known to be found in reduced numbers in those with ASD. Perhaps they helped the neuroscientists compensate for – and even exploit the benefits of – the bias towards local processing inherent in reduced width minicolumns?

Another potential difference between the two groups might be found within their corpus callosi, the structure that connects the left and right cerebral hemispheres, which have consistently shown to be smaller in autistics. The research paper suggested that "the fact that the left hemisphere lags in development behind the right hemisphere may offer an alternate explanation to savant skills (Geschwind & Galaburda, 1986)." Examining the corpus callosi of the neuroscientists might also provide some insights regarding similarities and differences in connectivity between them and those with ASD.

Evolutionary Benefit and Risk

The neuroscientist finding also potentially answers some evolutionary questions. In my Autism, Genetics, and Evolution post, I suggested that the alleles that cause autism could have been with humanity for at least 40,000 years.

"Assuming 30 to 35 years per generation (which is conservative), there have been 1100 to 1300 generations since the two populations diverged. This presumably should have been enough time to eliminate the various alleles that cause autism from the gene pool, if they are in fact deleterious.

Obviously this has not occurred. This means that the individual alleles that in combination cause autism must individually or in lesser combinations have had a beneficial effect to compensate for the reduced reproductive rates of autistics."

As the neuroscientist paper indicates, the same narrower width minicolumnar structure found in ASD may be a competitive advantage in the case of the neuroscientists. If the same alleles that contribute to ASD can result in a competitive advantage in other circumstances through (intellectual) fitness, this would easily explain the continued existence of ASD over time. The research paper quotes T.G West from In the Mind’s Eye (1997):

"One of the most important lessons to be learned from the genetic study of many diseases in recent years has been that the paradoxically high frequency of certain conditions is explained by the fact that important advantages conferred on those who carry the predisposition to these conditions may outweigh the obvious dramatic disadvantages."

My Autism and Minicolumns post suggested that a) ASD has a minicolumnar underpinning, b) this underpinning is required (i.e. no narrow minicolumns means no ASD), c) it originates in the first 40 days of fetal development (i.e. it is not itself acquired post-natally), d) that this difference falls within the normal range (i.e. that having it does not ‘cause’ a diagnosis, although it may very well result in diversity of thought and cognition, i.e. neurodiversity), e) that something else is therefore required (with no significant speculation as to what that something else may be, other than to generically label it as a ‘second hit’), and f) that research needs to prove or exclude causality among the population of the vulnerable, i.e. proving that something does not cause ASD in those who are invulnerable does not prove that it does not cause ASD in those who are vulnerable.

I would suggest that the Neuroscientist research lends significant credence to the above, especially to point d, and suggests that the differences between the neuroscientists and those with ASD may point to the ‘something else required’ that follows.


Kev said...

Thoroughly enjoyable read Ian. And fascinating. Is there any research to indicate what (if anything) Minicolumns are susceptible to? Does Dr C have a hypothesis?

Ian Parker said...

Hi Kev,

Thanks for stopping by and for the nice comment.

As to minicolumn susceptibility, I'll quote from the paper:

The genesis of minicolumns, their total number and constituent cells, is defined during brain development. Symmetrical divisions of germinal cells provide for the total number of minicolumns (Rakic & Kornack, 2001). A second phase of asymmetrical divisions provides for daughter cells that migrate into the cortex along radial scaffoldings with successive divisions accounting for the total number of cells within each minicolumn. Rakic and Kornack have enumerated a number of defining events that can alter minicolumnar phenotype (Rakic & Kornack, 2001):

1. the number of founder cells,
2. the duration of the cell division cycle,
3. the number of cell cycles during neurogenesis,
4. modes of cell division, and
5. selective cell death.

This list suggests the interplay of numerous genes and environmental factors mediating the minicolumnar phenotype. In effect, analysis of minicolumnar width across a sample of the normal population shows a continuous variation suggesting that multiple interdependent variables characterize the dynamics of minicolumnar morphometry (Casanova et al., 2006). Minicolumnar variability is therefore a dimensional trait that occurs within a continuum. In this normal distribution our supernormals fall at the tail end of smaller minicolumns.

And from another paper (Casanova - Big Brains Manuscript, in preparation for submission), he wrote that:

Variations in minicolumnar morphometry may therefore be due to the additive effects of many genetic and environmental factors. This means that patterns of inheritance for some minicolumnopathies are not as predictable as for conditions following simple Mendelian inheritance . It may be that genetics has a primary influence on the number of minicolumns and their constituent cells, but environmental influences modulate their activities.

Ms. Clark said...

I would need much more than bland reassurances to believe that these "supernormals" didn't have several significant ASD traits, perhaps they had the ability to fake normality in some situtations. I would guess that they'd be BAP, but they might have perfectly normal social skills, and no issues with eye-contact, no particular stims, etc.

I wonder what the brains of ASD scientists look like. There are LOTS of ASD people working at Universities, I know of a "low functioning" (by many people's standards) medical doctor who was in the UK. He used to post to an autism Yahoo! group, like 4 years ago. He mostly worked with lab specimens but he could see patients (he worked with leukemia). A dad reported seeing this doctor and how the doctor watched the child with leukemia through his flicking fingers. This doctor couldn't figure out how to get dressed in the morning unless someone laid out his clothes in the right order. He didn't know how to put his socks on before his shoes, for instance. He quit being a doctor when his partner (boyfriend) died, because he didn't have anyone to lay out his clothes for him any more (and probably for other reasons).

I'm saying that fully autistic people can be scientists, too. I don't like the term "supernormal" here either, it smacks of eugenics. These guys could have been below normal in kindness or artistic appreciation or musical ability or lots of other things.

I admire your grasp of minicolumns, though, Ian. Nice work (for an Aspie). :-D

Ian Parker said...

Hi Camille,

Thanks for stopping by and for the comment (and compliment).

You wrote:

"I would need much more than bland reassurances to believe that these "supernormals" didn't have several significant ASD traits, perhaps they had the ability to fake normality in some situtations. I would guess that they'd be BAP, but they might have perfectly normal social skills, and no issues with eye-contact, no particular stims, etc."

I’m inclined to agree with you. While the paper stated that "our supernormals did not exhibit deficits in communication or interpersonal skills", some of the other characteristics that they did exhibit sound quite BAP-ish. Case 1, as an example, is described in part as follows:

"He paid great attention to detail (hyperfocus) and was therefore able to see solution to problems that others had missed. He was “easily able to exclude from his field of attention, in fact from his life as a whole, anything that would not be pertinent to his focus…There was literally no chance for anybody to capture his interest once he was engaged in reflection” (Damasio & Galaburda, 1985). Many of his relationships, if not most, were in relation to interests and issue that engrossed him. These were mainly intellectual relationships where he was the dominant person. “The force of his character (or superego) was remarkable. He was a determined moral man, one who wanted to be right” (Damasio & Galaburda, 1985)."

I’d suggest that the difference between the neuroscientists and those with ASD relates to the absence of explicit DSM-IV listed criteria in the former group. One of my issues with the DSM-IV is that so many of the attributes of autism (especially but not limited to the positive ones) are not included as criteria. For example, many of Dr Mottron’s findings regarding autistic intelligence (which I quite like, BTW), do not touch specifically upon DSM-IV diagnostic criteria. And in my reading of the criteria, nothing in the DSM-IV suggests a requirement for superior local over global processing as part of the diagnosis, although this is obviously both a characteristic of ASD and can be a strength. Dr Courchesne’s findings regarding autistic head size are also not part of the criteria, even though head size is a potentially significant bio-marker. Regardless, while the neuroscientists may not have met the DSM-IV diagnostic criteria for ASD, that does not in any way rule out their being part of the BAP.

Instead, to me one of the points of the paper was that the neuroscientists possessed similar minicolumnar characteristics to those found in autistics, suggesting that these autistic characteristics are positively related to intelligence. In no way do I believe that Dr Casanova would suggest that those with ASD could not also possess high levels of intelligence.

Regarding ‘supernormal’, that was the term used in the paper. I’m not totally comfortable with it either, which is why I used it sparingly and always in quotes, preferring the term neuroscientists.

Ms. Clark said...

Thanks, Ian. You're awfully nice for a cold-blooded Aspie. (kidding)

I knew that "supernormal" was Casanova's term, I appreciate that you didn't like it too much, either.

The thing is, unless you had a detailed description (really detailed) of the scientists childhoods you couldn't say if they were ASD or not, but the passage you described sure made one of the neuroscientists sound like an ASD person. Dr. Amaral, for example, is probably a distinguied neuroscientist, but he's really not on the spectrum from what I have seen. Pessah has kind of a big head, but I haven't ever interacted with him... maybe BAP , maybe NT, but Pessah isn't exactly a neuroscientist...

I'd like to see photographs of the scientists in the paper. Big heads? Wide-set eyes? Malar hypoplasia? Low-set posteriorly rotated ears?

You know who looks autistic, big time? Lovaas ABA wunderkind Tristram Smith. He acts autistic, too, from the little I saw of him in person. But I don't know if he is.

There is social pressure to not label someone autistic, Casanova might be very reluctant to point out the fact that his neuroscientists had ASD traits, and others would be loathe to share the details of such traits with anyone.

Stacey said...

Your blog makes for a great read and I share much of your frustration over Ontario's IBI situation. My only complaint about your blog is that you don't post more often (selfishly!).

Ian Parker said...

Hi Stacey,

Thanks very much for stopping by and for the kind words.

Regarding the Ontario IBI situation, at least things moved a little bit with the recent announcement. The waiting list in our area moved by 'four' months. Only 'two' more months to go! Numbers are in quotes as list time is similar to the passage of time when theoretically traveling at the speed of light (a list 'month' can be considerably more time here on earth).

Regarding posting frequency, I'd like to post more often, but the monkeys pounding away at the keyboards in the back room are pretty slow at producing legible material for me to steal. ;-)

Stacey said...

I'm afraid that you exhibit far more patience than I have. Our family is one of the many who bailed on Ontario and flocked to Alberta, where I am happy to say we received full service within 3 months. I am not saying it's the perfect solution for everyone, but it's the best decision I ever made. I hope that your two months arrives in less!

Alyric said...

Hi Ian

Great post - you make Casanova accessible.

Based on all this - isn't it about time that people quit using a rat model of autism? Rats don't have minicolumns.

A question that is completely off topic. Didn't know where to direct this. What sort of television is available in Ontario Canada? Is it possible to get UK programs via a satellite subscription? The thought of 3 years of US television is unnerving you understand. My email is

Ian Parker said...

Hi Alyric,

Thanks for the nice comment. I agree on the rat comment, at least from the standpoint of 'connectivity'.

I replied by e-mail to your other question, so if you didn't receive it then please let me know.

Anonymous said...

Great reviews, Ian.
Just one thing - rats do have minicolumns! Number, connectivity, etc. are different, but the basic phenotype is there.