Special issue: Research reportAsymmetry within and around the human planum temporale is sexually dimorphic and influenced by genes involved in steroid hormone receptor activity
Introduction
The planum temporale (PT), a triangular shaped area on the superior surface of the posterior temporal lobe, has long been recognized as one of the most anatomically asymmetrical regions of the human cerebral cortex (Geschwind & Levitsky, 1968). In most people the PT on the left side is larger than the right (Galaburda, 1993, Steinmetz, 1996), although varying definitions of the precise structure have resulted in different estimates of its asymmetry (Galaburda, 1993, Shapleske et al., 1999). The left PT overlaps with Wernicke's classically defined language region (Geschwind & Levitsky, 1968), which is part of the broadly left-lateralised speech and language network present in the majority of people. At least some of the PT is regarded as secondary auditory cortex in terms of cyto-architecture (Shapleske et al., 1999). The PT has been characterized as a computational hub for processing spectrotemporal variation in auditory perception (Griffiths & Warren, 2002), as well as having a role in mapping acoustic speech signals to frontal lobe articulatory networks (Hickok & Poeppel, 2007), and in auditory attention (Hirnstein, Westerhausen, & Hugdahl, 2013).
Given these important roles of the PT in speech and language, and its asymmetrical nature in the typically developed brain, there has been much interest in whether individual differences in PT asymmetry are associated with traits that involve changes in language cognition, including dyslexia, reduced verbal ability, and schizophrenia (Eckert et al., 2008, Frank and Pavlakis, 2001, Hasan et al., 2011, Kawasaki et al., 2008, McCarley et al., 2002, Oertel et al., 2010, Shapleske et al., 1999, Sommer et al., 2001). These studies have shown that alterations in PT asymmetry may be relevant to some etiological subtypes of these complex traits, although are not necessarily a universal feature of them (Bishop, 2013). It also remains unclear to what extent associations between PT asymmetry and language-related cognitive disorders may arise from shared genetic, versus environmental, influences.
In fact the molecular and developmental basis of human brain asymmetry is almost completely unknown, as are the causes of variation in cerebral asymmetries within the population. Although present to a degree in other primates (Gannon et al., 1998, Lyn et al., 2011), a population-level bias towards leftward PT asymmetry is pronounced in the human brain and is already visible in third trimester foetuses (Bossy, Godlewski, & Maurel, 1976). Various other studies have shown foetal and infant asymmetries in the perisylvian region, sylvian fissure, and superior temporal sulcus (Dubois et al., 2008, Dubois et al., 2010, Habas et al., 2012, Kasprian et al., 2011, Li et al., 2014). These early developmental asymmetries clearly indicate a role for genetic mechanisms, but very few individual genes have so far been implicated in any aspect of lateralization of the human brain (Francks et al., 2007, Ocklenburg et al., 2013, Scerri et al., 2011, Sun et al., 2005, Sun and Walsh, 2006). Language lateralization appears to develop largely independently of early embryonic mechanisms that pattern left-right asymmetry of the viscera (heart, lungs etc.; Tanaka, Kanzaki, Yoshibayashi, Kamiya, & Sugishita, 1999). Genetic studies of PT asymmetry therefore offer a potential route to discovering novel, fundamental mechanisms that underlie lateralization of the human brain, which provides a basic organizing principle for much of human cognition (Gunturkun, 2003).
Males have sometimes been reported to show a subtle mean increase in leftward lateralization of the PT relative to females (de Courten-Myers, 1999, Good et al., 2001, Shapleske et al., 1999). Consistent with this, foetal testosterone levels have been linked to gray matter volumes within some putatively, sexually dimorphic regions of the human brain, including the PT (Lombardo et al., 2012). Prenatal testosterone levels have also been implicated in language delay in males (Whitehouse et al., 2012). However, some studies have not found an effect of sex on PT asymmetry (Watkins et al., 2001), and a meta-analysis of thirteen earlier studies did not find significant evidence for sexual dimorphism of PT asymmetry (Sommer, Aleman, Somers, Boks, & Kahn, 2008). Publication bias was suggested to have established a sex difference of PT asymmetry in the literature (Sommer et al., 2008, Watkins et al., 2001). Furthermore, a recent review concluded that overall results from studies on regional grey matter distribution, using voxel-based morphometry (VBM), indicate no consistent differences between males and females in language-related cortical regions (Wallentin, 2009).
In this study we used region-of-interest probability masks derived from the Harvard–Oxford (HO) atlas (distributed with the FSL software package; http://fsl.fmrib.ox.ac.uk/fsl/), to perform a large-scale analysis of sex differences for human cerebral asymmetries, mapped over the entire cerebral cortex, in 2337 healthy human subjects. We refer to this method hereafter as HO. We unambiguously confirmed asymmetry within and around the PT as a subtly, sexually dimorphic trait, and this pattern replicated in two additional population samples. We then performed genome-wide association scanning (GWAS) for PT regional asymmetry in three datasets derived from a total of 3095 subjects from the Netherlands and Germany, and used the results to test for an enrichment of association in genes involved in steroid hormone biology, motivated by the sexual dimorphism of the trait. We also explored the brain-wide effects on grey matter volume of an individual polymorphism that was suggestively associated with PT asymmetry (rs785248, p = 1.6*10−7, see below), since we do not necessarily expect genetic effects to localize solely to cortical regions as defined in specific brain atlases.
Section snippets
Study datasets
The Brain Imaging Genetics (BIG) study was initiated in 2007 and comprises healthy volunteer subjects, including many university students, who participate in studies at the Donders Centre for Cognitive Neuroimaging, Nijmegen, The Netherlands (Franke et al., 2010). At the time of this study the BIG subject-pool consisted of 2337 self-reported healthy individuals (1248 females) who had undergone anatomical (T1-weighted) MRI scans, usually as part of their involvement in diverse smaller-scale
Sex and cerebral cortical asymmetry
Table 1 shows descriptive statistics of the HO left and right grey matter volumes, and AIs, for regions of the cerebral cortex at which the AI showed a significant mean difference between the sexes (Data for all regions, regardless of an effect of sex on the AI, are given in Supplementary Table A.1). The PT showed the strongest sexually dimorphic asymmetry out of all 48 cortical regions (Table 1). The probabilistic definition of the PT by the HO atlas is illustrated in Fig. 1. The voxels with
Discussion
GWAS for asymmetry of the PT offers the potential to identify novel molecular and developmental mechanisms that are involved in lateralizing the human brain, for aspects of function that include language. Sexual dimorphism of PT asymmetry has been reported (de Courten-Myers, 1999, Good et al., 2001, Shapleske et al., 1999), but also not found by some studies (Sommer et al., 2008, Wallentin, 2009, Watkins et al., 2001). A sex difference in PT asymmetry would suggest steroid hormone-related genes
Conflicts of interest
No conflicts of interest are declared.
Acknowledgements
Many thanks to Nathalie Tzourio-Mazoyer and Fabrice Crivello for advice and critical comments on this manuscript, and to Han Brunner for his involvement in the creation and growth of the BIG (Brain Imaging Genetics) dataset.
The BIG database was established in Nijmegen in 2007. This resource is now part of Cognomics, a joint initiative by researchers of the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience departments of the Radboud University Medical
References (77)
A fast diffeomorphic image registration algorithm
NeuroImage
(2007)Computational anatomy with the SPM software
Magnetic Resonance Imaging
(2009)- et al.
Voxel-based morphometry–the methods
NeuroImage
(2000) - et al.
Unified segmentation
NeuroImage
(2005) - et al.
The etiology of schizophrenia and the origin of language: overview of a theory
Comprehensive Psychiatry
(2003) - et al.
Prioritizing GWAS results: a review of statistical methods and recommendations for their application
American Journal of Human Genetics
(2010) - et al.
Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature
NeuroImage
(2010) - et al.
Structural asymmetries of perisylvian regions in the preterm newborn
NeuroImage
(2010) - et al.
Manual and automated measures of superior temporal gyrus asymmetry: concordant structural predictors of verbal ability in children
NeuroImage
(2008) - et al.
Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain
Neuron
(2002)
Brain imaging in neurobehavioral disorders
Pediatric Neurology
Genetic variation in CACNA1C, a gene associated with bipolar disorder, influences brainstem rather than gray matter volume in healthy individuals
Biological Psychiatry
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
NeuroImage
Hypothalamic abnormalities in schizophrenia: sex effects and genetic vulnerability
Biological Psychiatry
Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains
NeuroImage
The planum temporale as a computational hub
Trends in Neurosciences
Planum temporale asymmetry to the right hemisphere in first-episode schizophrenia
Psychiatry Research: Neuroimaging
Hemispheric specialization for language: brain volume matters
Brain Research
Anomalous cerebral asymmetry in patients with schizophrenia demonstrated by voxel-based morphometry
Biological Psychiatry
Planum temporale grey matter asymmetries in chimpanzees (Pan troglodytes), vervet (Chlorocebus aethiops sabaeus), rhesus (Macaca mulatta) and bonnet (Macaca radiata) monkeys
Neuropsychologia
Decreased volume of left and total anterior insular lobule in schizophrenia
Schizophrenia Research
A probabilistic atlas of the human brain: theory and rationale for its development. The International Consortium for Brain Mapping (ICBM)
NeuroImage
Genetic influences on handedness: data from 25,732 Australian and Dutch twin families
Neuropsychologia
Handedness: a neurogenetic shift of perspective
Neuroscience & Biobehavioral Reviews
PLINK: a tool set for whole-genome association and population-based linkage analyses
American Journal of Human Genetics
A meta-analysis of sex differences in human brain structure
Neuroscience & Biobehavioral Reviews
The planum temporale: a systematic, quantitative review of its structural, functional and clinical significance
Brain Research. Brain Research Reviews
Towards a complete resolution of the genetic architecture of disease
Trends in Genetics
Sex differences in handedness, asymmetry of the Planum Temporale and functional language lateralization
Brain Research
Structure, functional and cerebral asymmetry: in vivo morphometry of the planum temporale
Neuroscience and Biobehavioral Reviews
Origin of body axes in the mouse embryo
Current Opinion in Genetics & Development
Dichotic listening in patients with situs inversus: brain asymmetry and situs asymmetry
Neuropsychologia
Putative sex differences in verbal abilities and language cortex: a critical review
Brain and Language
Chromosomal location and structural organization of the human deoxycytidylate deaminase gene
Journal of Biological Chemistry
Gene ontology: tool for the unification of biology. The Gene Ontology Consortium
Nature Genetics
Cerebral asymmetry and language development: cause, correlate, or consequence?
Science
Study of right-left asymmetry of the temporal planum in the fetus
Bulletin de l'Association des anatomistes
Genes related to sex steroids, neural growth, and social–emotional behavior are associated with autistic traits, empathy, and Asperger syndrome
Autism Research
Cited by (53)
Comparing brain asymmetries independently of brain size
2022, NeuroImageCitation Excerpt :These different results between our study and the literature can be explained by differences in raw AIs (e.g., putamen) or differences between samples (e.g., sample age). With such a large dataset, we reported more significant sex differences in asymmetries than in previous studies (Guadalupe et al., 2015; Koelkebeck et al., 2014; Kong et al., 2020): We found 55 regions with greater asymmetries in women and 67 with greater asymmetries in males. Although sex differences in asymmetries were generally consistent across segmentation algorithms and models, there were some exceptions: We observed a greater leftward asymmetry in males in the superior frontal gyrus surface area in the Destrieux atlas but not with the DKT atlas.
Structural asymmetries in normal brain anatomy: A brief overview
2022, Annals of AnatomySex/Gender differences in the human brain
2021, Encyclopedia of Behavioral Neuroscience: Second EditionDump the “dimorphism”: Comprehensive synthesis of human brain studies reveals few male-female differences beyond size
2021, Neuroscience and Biobehavioral Reviews