Hemispheric asymmetries in cortical gray matter microstructure identified by neurite orientation dispersion and density imaging
Introduction
The left and right hemispheres of the human brain differ in several functional aspects, the most popular being handedness and language lateralization (Güntürkün and Ocklenburg, 2017; Ocklenburg and Güntürkün, 2018). However, the ontogenetic determinants of functional hemispheric asymmetries remain rather unclear (Armour et al., 2014; Brandler et al., 2013; Ocklenburg et al., 2014; Schmitz et al., 2017). In addition to gray matter asymmetries (Ocklenburg et al., 2016b), the structure of inter- and intrahemispheric white matter pathways have been proposed to contribute to functional hemispheric asymmetries (Ocklenburg et al., 2016a). On the microstructural level, neurites, i.e. dendrites and axons, constitute the “building blocks of the computational circuitry of the brain” (Zhang et al., 2012). Neurite orientation dispersion and density imaging (NODDI) is a diffusion MRI technique for in vivo quantification of neurite morphology in humans (Zhang et al., 2012). Specifically, it allows for the estimation of neurite density (intra-neurite volume fraction, INVF), neurite orientation dispersion (ODI), a neurite tortuosity measure, and isotropic volume fraction (ISO). So far, no study has investigated hemispheric asymmetries in microstructure in vivo. However, the detection of microstructural asymmetry is an interesting marker not only for genetic and behavioral studies on hemispheric asymmetries, but also in the context of neurodevelopmental and psychiatric traits. Atypical microstructural asymmetry has been reported in schizophrenia patients (Chance, 2014; Chance et al., 2008; Cullen et al., 2006; Simper et al., 2011) and altered microstructure in autism spectrum disorder (Casanova et al., 2006; van Kooten et al., 2008) has been suggested to underlie atypical functional hemispheric asymmetries (Chance, 2014). In order to provide a reference for potential clinical studies, microstructural asymmetries in healthy subjects have to be established. Thus, the aim of the present study was the first whole brain investigation of gray matter microstructure by applying NODDI to two independent datasets constituting an overall sample of 520 healthy adults.
Several post mortem studies have reported hemispheric asymmetries in microstructure (Schenker et al., 2009) with focus on different brain areas and different markers for microcircuitry (for a comprehensive overview see Table 1). The analysis of cell density has been proposed as an indirect way to estimate the amount of neuropil, i.e. dendrites, axons and synapses. For example, the gray-level index (GLI) estimates the fraction of tissue volume that is occupied by Nissl-stained cell bodies with decreased cell density indicating an increased proportion of neuropil (Amunts et al., 1996). A common feature of mammalian cytoarchitecture is the columnar organization of neurons surrounded by neuropil across cortical layers VI to II. Single vertical rows of neurons with a width of about 60–90 μm are known as minicolumns. Macrocolumns are constituted of several minicolumns, forming thalamocortical or corticocortical columns with a width of about 600–800 μm (Hutsler and Galuske, 2003). Seldon (1981a) suggested greater distance between minicolumns to reflect a higher amount of neuropil. Few studies have investigated hemispheric asymmetries in dendritic branching directly using Golgi impregnations (Seldon, 1982).
Previous histological studies report greater right-hemispheric neuron density in the planum temporale (parts of BA 22, BA 41, and BA 42) (Buxhoeveden et al., 2001; Smiley et al., 2011) as well as greater left-hemispheric average minicolumn width. Moreover, there is a greater average distance between mini- (Buxhoeveden et al., 2001; Chance et al., 2006; Economo and Horn, 1930; Seldon, 1981a) and macrocolumns (Galuske et al., 2000) in the left hemisphere that is compensated for by greater left-hemispheric dendritic spread (Seldon, 1981a, 1981b) and dendrite density (Seldon, 1982). For the mid-posterior fusiform region (BA 37), greater right-hemispheric neuron density and greater left-hemispheric minicolumn width have been reported (Chance et al., 2013). Greater minicolumn width has also been reported for the right-hemispheric anterior fusiform cortex including BA 20 (Di Rosa et al., 2009). In the frontal lobes, Broca's area (BA 44 and 45) is characterized by a greater GLI in the right hemisphere (Amunts et al., 1999; Amunts et al., 2003). In the primary motor cortex (BA 4), right-hemispheric GLI has been found to be greater than left-hemispheric GLI (Amunts et al., 1996; Amunts et al., 1997). In the superior frontal gyrus (BA 9), greater cell density was found in the left hemisphere (Cullen et al., 2006), while no asymmetry was found in a subsequent study only investigating male brains (Smiley et al., 2011). In the occipital and parietal lobes, analysis of the primary visual cortex (V1, BA 17), V2 (BA 18), and area hOc5, an area sensitive to motion, showed a small interhemispheric asymmetry with lower GLI in the left hemisphere (Amunts et al., 2007). In the inferior parietal lobe, greater neuron density was found in the right supramarginal gyrus (BA 40) (Smiley et al., 2012). One important question is if findings from post mortem studies can be replicated in vivo. Thus, the second aim of the present study was to compare the results obtained with NODDI with findings from previous histological studies.
Section snippets
Participants
Asymmetries in gray matter microstructure were investigated in two independent samples from Germany and the US.
German sample. The German sample included 269 participants (143 female) between 18 and 39 years of age (M = 24.35, SD = 4.27). All participants were free from neurodevelopmental, neuropsychiatric, or neurological disorders. Handedness was determined using the Edinburgh handedness inventory (EHI) (Oldfield, 1971). For ten manual actions, participants chose one of five response options
Microstructural asymmetries – consistent effects in both samples
For INVF, the repeated-measures ANCOVAs revealed main effects of hemisphere for 41 cortical areas (22.78% of 180 cortical areas) that were found in both samples after correction for multiple comparisons (German sample: all F(1,267) > 14.56, US sample: all F(1,249) > 13.69, all p < .00028). Thirteen cortical areas displayed leftward asymmetries in INVF with combined partial η2 ranging from 0.09 to 0.39. Among these cortical areas were four early auditory areas (STSvp, MI, AVI, FOP5), three
Discussion
Hemispheric asymmetries in microstructure have mainly been investigated in histological post mortem studies, which are usually characterized by small samples, clearly defined cortical areas and non-conservative exclusion criteria (e.g. regarding neurological causes of death). NODDI aims to estimate neurite density and its orientation distribution in vivo (Zhang et al., 2012), thereby providing the opportunity to investigate microstructural asymmetries in large samples and across the whole
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (grant numbers Gu227/16-1, GE2777/2-1) and DFG SFB 1280 project A03 and the MERCUR foundation (grant number An-2015-0044). The US Sample was supported by the John Templeton Foundation (grant number #22156, The Neuroscience of Scientific Creativity). The authors thank Lara Schlaffke, Martijn Froeling and PHILIPS Germany (Burkhard Mädler) for their scientific support with the MRI measurements as well as Tobias Otto for his
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These authors contributed equally to this manuscript.