Thursday, May 10, 2012

Spindle Neurons in Macaques?

Spindle neurons, or Von Economo neurons (VENs), are a unique type of large, bipolar neuron found primarily in layer Vb in the anterior cingulate cortex and the frontoinsular cortex of humans.1 In 1999, Nimchinsky and colleagues discovered that among the 28 nonhuman primate species they examined, only great apes had VENs [see Spindle Neurons: The Next New Thing?].

Spindle neurons are also seen in humpback, fin, sperm, and killer whales (Hof & Van der Gucht, 2007), elephants (Hakeem et al., 2009), and cetaceans such as the bottlenose dolphin, Risso’s dolphin, and the beluga whale (Butti et al., 2009).

Because VENs are only found in large-brained, highly evolved social species, and are potentially implicated in certain neurological and psychiatric disorders, their hypothesized functions include empathy, conscious awareness, and self-referential processing. A 2011 review by Allman and colleagues reiterated that only great apes (bonobos, chimpanzees, gorillas, orangutans) have VENs and suggested they...
...may be a specialization related to very large brain size. The large size and simple dendritic structure of these projection neurons suggest that they rapidly send basic information from FI [frontoinsular cortex] and LA [limbic anterior area] to other parts of the brain, while slower neighboring pyramids send more detailed information. Selective destruction of VENs in early stages of frontotemporal dementia (FTD) implies that they are involved in empathy, social awareness, and self-control, consistent with evidence from functional imaging.

VENs: Not Only for Great Apes Any More!

But now, a new study has identified these special neurons in the insular cortex of macaque monkeys (Evrard et al., 2012).

Figure 1 (Evrard et al., 2012). The Von Economo Neuron Is Present in Layer 5b in a Restricted Portion of the Agranular Anterior Insula in the Macaque Monkey (A) High-magnification photomicrographs demonstrating the identical morphology of the macaque and human VENs. Scale bar represents 25 μm.

Why weren't they found in the earlier studies that looked for them?

Three reasons: (1) they're a lot smaller in monkeys; (2) they're more fragile in monkeys; and (3) they're confined to a more limited anatomical region.
First, the large human VENs unambiguously stand out at low microscope magnifications. Searching for relatively smaller VENs among the densely packed cell population in layer 5 in the monkey required the highest microscope magnification, which would be unusual for anyone accustomed to examining the more obvious VENs in hominids. Second, the cytoskeletal matrix of the small monkey VENs might be more fragile during histological processing than that of the larger human VENs. ... Third, in the major prior study, the number of VENs in humans and great apes was counted in consecutive sections that were apparently spaced at 1 mm intervals ... such a sampling paradigm would likely have been inadequate for the identification of VENs within the small VEN-containing region of the ventral AAI that measures ∼2 × 2 × 1 mm3 in macaques.

The authors pointed out a major advantage of their new discovery, namely that more invasive studies are now possible (i.e., you can't do single cell neurophysiology in dolphins or bonobos).

But wait... are they really VENs?
The morphology, size, laminar distribution, and proportional distribution of the monkey VEN suggest that it is at least a primal anatomical homolog of the human VEN.

Allman, Hof, and colleagues might have something more to say on the matter, based on their earlier findings (e.g., Allman et al., 2011):
The VENs are illustrated at higher magnification in Figure 3, which shows that they have very similar morphology in the great apes and humans. In primates, the VENs are present in FI only in great apes and humans. This is the same taxonomic distribution as was found for the VENs in LA, which suggests that the VENs emerged as a specialized neuron type in the common ancestor of great apes and humans.

Figure 3 (Allman et al., 2011). VENs in area FI of humans and great apes.

The new paper concedes that:
The presence of VENs in the macaque does not discredit prior evidence for a crucial role of the VENs and AIC in the emergence of self-awareness and social cognition in humans (Craig, 2009; Allman et al., 2011). VENs in humans appear to be disproportionally slightly larger than in macaques (see above); they may also have an enhanced immunopositivity (and perhaps gene expression) for proteins that are typically involved in homeostasis, which perhaps favors higher interoceptive sensitivity.
Are they confined to the anterior insula in macaques? No, VENs were also found in the ACC, but that will be reported separately (a lesson for all you junior scientists).

Now that they've been found in monkeys [and can be studied physiologically], will spindle neurons finally catch up with their more glamorous elder cousins, the mirror neurons? Are they really the next new thing? Six years ago, I pondered these points:
Somehow, the "spindle neuron" meme hasn't caught on like the "mirror neuron" meme. Is it because spindle neurons have been only been described anatomically (not physiologically), while the reverse is true for mirror neurons? Anatomically speaking, do we know much about mirror neurons?
Evrard, Forro, and Logothetis are all over it:
...invasive studies of their organization, hodology, and physiology could provide significant insights into the evolutionary basis for self-awareness and empathy in humans. Regarding the latter, it would be particularly interesting to examine whether the VENs share functional similarities with the “mirror” neurons of the ventral premotor cortex (Gallese et al., 2004).

Finally, a commentary in Neuron by Critchley and Seth (2012) wonders if studies of the macaque insula will reveal the neural mechanisms of self-referential processes underlying conscious awareness. If VENs indeed mediate self-referential processing, then they were largely involved in writing this post.

More Reading

Spindle Neurons: The Next New Thing?

Spindle Neurons in Humpback Whales

Spindle Neurons and Frontotemporal Dementia

Spindle Neurons and Science Writing

Spindle Neurons in Elephants and Dolphins: Convergent Evolution in Large-Brained Mammals?


1 The VENs and other large pyramidal cells in cortical layer V are projection neurons that provide output to more distant regions.


Allman JM, Tetreault NA, Hakeem AY, Manaye KF, Semendeferi K, Erwin JM, Park S, Goubert V, Hof PR. (2011). The von Economo neurons in the frontoinsular and anterior cingulate cortex. Ann NY Acad Sci. 1225:59-71.

Butti, C., Sherwood, C., Hakeem, A., Allman, J., & Hof, P. (2009). Total number and volume of Von Economo neurons in the cerebral cortex of cetaceans. Journal of Comparative Neurology 515:243-259.

Evrard, H., Forro, T., & Logothetis, N. (2012). Von Economo Neurons in the Anterior Insula of the Macaque Monkey. Neuron, 74 (3), 482-489 DOI: 10.1016/j.neuron.2012.03.003

Hakeem, A., Sherwood, C., Bonar, C., Butti, C., Hof, P., & Allman, J. (2009). Von Economo Neurons in the Elephant Brain. The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology 292:242-248.

Hof PR, Van Der Gucht E. (2007). Structure of the cerebral cortex of the humpback whale, Megaptera novaeangliae (Cetacea, Mysticeti, Balaenopteridae). Anatom Rec Part A, 290:1-31.

Nimchinsky EA, Gilissen E, Allman JM, Perl DP, Erwin JM, Hof PR. (1999). A neuronal morphologic type unique to humans and great apes. Proc Natl Acad Sci 96:5268-73.

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At May 10, 2012 8:13 AM, Blogger jonathan said...

This comment has been removed by the author.

At May 10, 2012 8:15 AM, Blogger jonathan said...

I wonder if VEN's could possibly be implicated in autism. Frontotemporal dementia and autism have symptoms in common, of course developmental lesions are different than adult lesions. From your description it sounds like they might be involved in autism. There is evidence that mirror neurons may be somehow involved in autism, wonder if this is the case for VENs.

At May 10, 2012 9:30 AM, Blogger TheCellularScale said...

Great post. What actually makes a VE neuron a VE neuron is a particularly interesting question. It could be that smaller animals have chemically homologous neurons, but that these neurons don't have to be big and spindle-like in a mouse or rat.
I try to argue this possibility here:

At May 10, 2012 11:44 AM, Anonymous Arvid said...

Have a look at the first commentator – does he want to make you a link farm?

At May 10, 2012 12:00 PM, Blogger The Neurocritic said...

Arvid - Thanks. You're right, dr mustafa eraslan is spam. I can't even select the text to translate it from Turkish to English. Delete.

At May 10, 2012 1:22 PM, Blogger The Neurocritic said...

TheCellularScale - Thanks for linking to your great post on the topic!

jonathan - There have been speculations that VENs might be involved in autism, but conflicting studies have found greater, fewer, or the same number of VENs. Kind of hard to interpret that. Allman et al. said:

"There are many features of autism that suggest that the VENs may be involved in this disorder. An initial stereological study of the number of VENs in area FI in four autistic subjects plus controls did not confirm this conjecture. However, a second stereological study of VENs in dorsal ACC in nine autistic subjects plus controls found that the autistic subjects fell into two groups, one with significantly higher numbers of VENs than controls, and the other with significantly fewer VENs than controls. Thus the controls occupied a middle zone with little overlap with the high or low VEN autism groups."

When in doubt, postulate distinct subgroups.

At May 22, 2012 1:06 PM, Anonymous Suresh said...

I don't think it will be easy with current technology to do single-cell in-vivo neurophysiology from this small area with such a seemingly sparse density of VENs. Perhaps with whole-cell recordings accompanied by mountains of luck ... anyone have any better ideas ?


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