Is bigger always better? The importance of cortical configuration with respect to cognitive ability
Introduction
There is a long history of scientific curiosity about the neural underpinnings of individual differences in intelligence or general cognitive ability (GCA). Elucidating those brain-behavior relationships, including their genetic and environmental underpinnings, is important for understanding normal and pathological development and aging, and neuropsychiatric disorders.
Studies of associations between GCA and neocortical (hereafter referred to as cortical) gray matter size are growing in number. There are more studies of cortical thickness (CT) than of cortical surface area (SA). Studies of CT have been mixed, with reports of positive, negative, and no associations with GCA (Vuoksimaa et al., 2015). Although there are fewer studies of SA–GCA relationships, those have consistently shown significant positive SA–GCA associations (Vuoksimaa et al., 2015). Although there is some evidence in support of the predominant view that “bigger is better” when it comes to cortical-GCA associations, it seems likely that the cortical underpinnings of GCA are not so simple. A fundamental conundrum, for example, is the fact that men do not have higher average GCA than women despite having larger brains and larger cortex. Our view is that we need to think in terms of complex configurations of SA and CT in order to develop a more complete picture of the cortical underpinnings of GCA. At a minimum, this would seem to require a combined examination of both SA and CT (see Schnack et al., 2015, Vuoksimaa et al., 2015), but that has been rare in studies of cortical-GCA associations.
At the global level, SA and CT are genetically independent (Panizzon et al., 2009), and SA appears to be the primary driver of the phenotypic and genetic association between cortex size and GCA (Vuoksimaa et al., 2015). However, there is also evidence that there are some, generally inverse SA–CT associations in some subregions (Panizzon et al., 2009). The relationship between regional SA and CT may be affected by the phenomenon of cortical stretching whereby cortical thinning is presumed to be caused by regional areal expansion. This phenomenon is seen throughout adulthood (Hogstrom, Westlye, Walhovd, & Fjell, 2013) and is most pronounced in some prefrontal regions (Hogstrom et al., 2013, Panizzon et al., 2009); also when looking at the relative SA and CT (Winkler et al., 2010). Further evidence for the importance of looking at both relative SA and relative CT comes from studies of gyrification (Tallinen et al., 2014, Jalil Razavi et al., 2015). Gyrification of the cortex, an important characteristic of the human brain, is positively correlated with SA but negatively with CT (Hogstrom et al., 2013). A recent work suggests that gyrification patterns are a function of relative cortical expansion and relative thickness (Tallinen et al., 2014). In the presence of tangential expansion, thinner cortex buckles and folds more easily than thicker cortex, which results in more gyrification (Zilles et al., 2013). In short, studying both cortical SA and CT is needed for greater understanding of brain morphometry and its behavioral correlates such as cognitive ability.
Both animal and human studies have demonstrated an anterior–posterior (A–P) gradient of genetic effects on cortical areal expansion. The same genes that cause anterior SA expansion also cause posterior contraction and vice versa (Bishop et al., 2002, Chen et al., 2011, Chen et al., 2012, Chen et al., 2013, O'Leary et al., 2007). We have also demonstrated that, relatively orthogonal to the A–P gradient of areal expansion, there is a dorsal–ventral (D–V) gradient of genetic influences on CT in the human brain indicating that the same genetic effects that make cortex relatively thicker in dorsal regions also make cortex relatively thinner in ventral regions and vice versa (Chen et al., 2013). In animal and human studies, these gradients from positive to negative correlations are observed only after global effects are taken into account, i.e., total SA and mean CT, respectively. Otherwise, the gradients simply shift from more strongly positive to less strongly positive: i.e., the same genetic effects that cause SA expansion in one region also cause SA expansion in other regions, and the same genetic effects that make cortex thicker in one region also make cortex thicker in other regions (Eyler et al., 2012). In order to elucidate relative regional effects, it is necessary to examine regional values in the context of global size. However, studies of the relationship between GCA and either SA or CT have not accounted for total SA or mean CT (reviewed by Vuoksimaa et al., 2015).
One recent finding regarding SA is the observation that better visuo-spatial reasoning ability was associated with greater areal expansion in prefrontal, lateral temporal, and inferior parietal cortices (Fjell et al., 2015). The authors pointed out that these are regions that have undergone the greatest expansion during evolution and human postnatal development. Indeed, it seems that the highly non-uniform areal expansion of the cortex follows the same pattern across species (humans versus non-human primates) and within human development (Chaplin et al., 2013, Fjell et al., 2015, Hill et al., 2010). Moreover, in humans the relatively high-expanded cortical regions also tend to be lightly and later myelinated, whereas relatively low-expanded regions tend to include regions that are more heavily and early myelinated (Glasser & Van Essen, 2011). Highly expanded/lightly myelinated regions include prefrontal, lateral temporal and inferior parietal cortices; relatively low-expanded/heavily myelinated regions include occipital and medial temporal cortices as well as regions in and around the central sulcus (Fjell et al., 2015, Glasser and Van Essen, 2011, Hill et al., 2010).
GCA is highly polygenic trait (Davies et al., 2011) and increased GCA has been positively selected in human evolution (Joshi et al., 2015). The patterning of cortical SA in humans also differs as a function of regions that are more strongly influenced by single nucleotide polymorphisms in more versus less evolutionarily conserved regions of the genome (Chen et al., 2015). However, the links among patterns of expansion/myelination, GCA, SA and CT have not yet been examined in combination, particularly with respect to genetic influences. In the current study, we took the novel approach of examining the cortical maps of the relationship between GCA and both CT and SA while taking global size into account. Specifically, in line with the animal literature and our own earlier work, we scaled regional SA in relation to total SA and regional CT in relation to mean CT in order to investigate if the configuration of high-expanded and low-expanded regions relative to global size is related to GCA. We then statistically compared these maps to maps of regions with high- versus low-expansion/light- versus heavy-myelination. Finally, we used the power of our twin design to examine the contribution of genetic and environmental factors in the observed cortical-GCA associations.
We hypothesized that cortical-GCA relationships would be determined by the configuration of the cortex such that we would observe both positive and negative correlations in relation to global effects of total SA and mean CT when examining SA and CT, respectively. Thus, cortical-GCA relationships would not simply be consistently positive (i.e., “bigger is better”). Specifically, we hypothesized that: 1) the gradients from positive to negative correlations between relative SA and GCA would be consistent with the non-uniform cortical expansion patterns across evolution and human development (i.e., high-expanded regions having positive correlation with GCA and low-expanded regions having negative correlations with GCA); 2) relatively thinner cortex in high-expanded regions would be associated with better GCA; and 3) genetic factors would play a significant role in regional cortical-GCA associations.
In short, the current evidence of A–P and D–V gradients (Chen et al., 2011, Chen et al., 2013) and of the dynamics between relative SA and CT in the configuration of the cortex (Tallinen et al., 2014) suggests that investigating relative SA and CT in combination can shed light onto the fundamental characteristics of cortical development. However, no studies have used the approach of looking at both relative SA and CT in the context of cognitive abilities. We use the term relative regional effects to indicate associations based on regional values relative to global size (e.g., the ratio of the SA at a vertex or a region of interest [ROI] to total SA).
Section snippets
Participants
Brain imaging and cognitive data at ages 51–60 were obtained for 534 men from the Vietnam Era Twin Study of Aging (VETSA 1: 2002–2008) (Kremen et al., 2013). Of those, 513 had analyzable MRI data for creating continuous cortical maps: 130 monozygotic (MZ); 96 dizygotic (DZ) twin pairs; and 61 unpaired individual twins. DNA-based zygosity was available for 92% of the pairs; for others it was determined by questionnaire and blood group. The VETSA sample is representative of U.S. men in their age
Relationships between GCA and absolute areal expansion and thickness
Continuous maps of absolute regional cortical-GCA associations unadjusted for global size indicated that phenotypic correlations were positive at each vertex for the SA–GCA and for CT–GCA associations (Fig. 2A). These positive associations were driven by genetic correlations, which indicate the extent to which the same genetic factors influence different phenotypes. The genetic correlations were positive at every vertex for the SA–GCA associations and over 99% of vertices for CT–GCA
Size matters
We extended our finding that GCA was significantly associated with total SA rather than mean CT in this sample of middle-aged men (Vuoksimaa et al., 2015) by demonstrating that vertex-wise absolute SA and CT measures were positively correlated with GCA, and that those associations were stronger for SA than for CT. These findings are consistent with the fact that the volume of the human cortex is greater than in other primates, and that the cross-species volume expansion is more strongly related
Conclusions
Our results complement, rather than contradict, findings regarding the relationship between absolute cortex size and GCA. Although “bigger is better” throughout the cortex when it comes to absolute size (Vuoksimaa et al., 2015), the primary new finding from our current analyses highlights the incompleteness of that explanation. The situation may be analogous to factor analytic studies of cognition in which there are consistent findings of a general factor plus specific ability factors that are
Acknowledgments
Funding
This work was supported by NIA grants R01 AG018386, AG022381, AG022982, AG050595 to WSK, R01 AG018384, AG050595 to MJL, K08 AG047903 to MSP, and R01 GM104400 to WKT, and Academy of Finland grant 257075 to EV, and resources of the VA San Diego Center of Excellence for Stress and Mental Health Healthcare System. The Cooperative Studies Program of the US Department of Veterans Affairs provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry.
Notes
References (56)
- et al.
Genetic influences on cortical regionalization in the human brain
Neuron
(2011) - et al.
Cortical surface-based analysis. I. Segmentation and surface reconstruction
NeuroImage
(1999) - et al.
An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest
Neuroimage
(2006) - et al.
Does degree of gyrification underlie the phenotypic and genetic associations between cortical surface area and cognitive ability?
NeuroImage
(2015) - et al.
Cortical surface-based analysis. II: inflation, flattening, and a surface-based coordinate system
NeuroImage
(1999) - et al.
Cortical gyrification and its relationships with cortical volume, cortical thickness, and cognitive performance in healthy mid-life adults
Behav. Brain Res.
(2015) - et al.
Genetic and environmental influences on the size of specific brain regions in midlife: the VETSA MRI study
NeuroImage
(2010) - et al.
Area patterning of the mammalian cortex
Neuron
(2007) - et al.
Genetic and environmental influences of general cognitive ability: is g a valid latent construct?
Intelligence
(2014) - et al.
Cortical thickness is influenced By regionally specific genetic factors
Biol. Psychiatry
(2010)