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In a previous post – Autism, Genius, and Minicolumns – I wrote about a research paper by Dr Casanova et al comparing the brains of three prominent neuroscientists vs. controls. One of the findings in this paper was a similarity (and differences) between the minicolumnar structures of the neuroscientists and those with ASD. I speculated based on the results that one of the differences between the neuroscientists and those with ASD might have been related to spindle cells (VENs). Since then the monkeys have been busy typing, and have another post ready. This post will explore the potential links between VENs, the Anterior Cingulate Cortex (ACC), Anterior Insular Cortex (AI), the frontopolar cortex, and autism. I will suggest that together they may explain the developmental origins of ASD.
Von Economo Neuron Morphology and Connectivity
Von Economo neurons (VENs) are large, bipolar neurons located in layer V of Brodmann Area 24 of the anterior cingulate cortex (ACC), and anterior insular cortex (AI) (Watson et al, 2006). A key difference between VENs and pyramidal neurons is that the former have only a single large basal dendrite (vs. an array of smaller basal dendrites in pyramidal cells). VENs have been found in the ACC of humans and all of the great apes, and in the AI of humans and some other apes. They were not found in any other primate species, nor in 30 non-primate mammalian species examined by Nimchinsky et al (1999). VENs have also recently been reported in the brains of several marine mammal species (humpback whales, fin whales, killer whales and sperm whales) in both the ACC and the AI, plus – unlike humans and apes – in the frontopolar cortex, as well as being sparsely distributed in other areas.
VENs are significantly more numerous in humans than in other apes. In the human ACC they occur most often in clusters of three to six neurons, are located in layer Vb, and are conspicuous because of an otherwise low cellular density in this layer. They account for 5.6% of the number of pyramidal cells in layer V of the ACC (Nimchinsky et al, 1999).
Although their function has not been definitively established, VEN morphology and location offer definite clues. The VENs in the ACC and AI appear to be a single population of cells - i.e. undifferentiated by region – (Watson et al, 2006), potentially suggesting a common origin (see VEN Development below). Unlike pyramidal cells, with relatively sparse apical dendrites and highly branched basal dendrites, VENs have long, narrow radial arborization, with similar profiles in their apical and basal dendrites in terms of 'branchiness' and length (Watson et al, 2006). Cell morphology is significant in that neuronal shape is directly related to the computations performed by the cells. Both spines and branches of neurons can operate as computational compartments, and VENs have fewer of both compared with layer V pyramidal cells.
Narrow arborization also impacts VEN connectivity. Minicolumnar structure tends to result in input into a column being relayed rapidly in a vertical direction, but not on a horizontal dimension. The narrow VEN dendritic trees suggest that they usually receive neurotransmission only within their individual minicolumns. Watson et al (2006) suggests that VENs could be a specialization that facilitates rapid output of minicolumnar processing.
This role is also suggested by the size of VENs. Their somas (cell bodies) are on average 4.6 times larger than layer V pyramidal cells, suggesting that they possess large and rapidly conducting axons. From Allman et al (2001), "Because cell body size is probably related to the size of the axonal arborization, the axonal arborization of the spindle cells may be extensive and on a scale with encephalization. This observation suggests that the spindle cells may have widespread connections with other parts of the brain". Allman et al (2005) postulated that the function of the VENs may be to provide a rapid relay to other parts of the brain of a simple signal derived from information processed within the AI and ACC. While it has not yet been firmly established where VENs project, their connections with the rest of the brain may be substantial.
VENs appear relatively late in human development. They first appear in very small numbers in the 35th week of gestation. At birth only about 15% of the final postnatal population are present, with potentially 95% of the total VEN population being present by four years of age (see Fig 1). The source of VENs is still unknown, but they could arise either from differentiation of a pre-existing cell type, or via migration, potentially from the ventricles. In human infants they often appear in pairs and sometimes in vertical chains of three or four neurons, suggesting that they may be following an anatomical or chemical path. Sometimes in infants they have long, undulating leading and trailing processes that resemble flagella, which also suggests migration.
Belmonte and Carper (1998) wrote that: