The human brain is asymmetric. The main features of this so-called torque are (i) forward displacement of the right compared to the left hemisphere which produces frontal and occipital petalia, and (ii) a tendency for the left hemisphere to cross the midline posteriorly (i.e. so-called rightward occipital bending). However, the torque is subtle. For example, while being a good description on average and being wholly present in some individuals, in others the torque may be only partially present, not present at all, partially reversed or completely reversed. In subjects with situs inversus totalis (SI) the internal organs of the body are transposed raising the question of whether brain torque is also reversed. There have been two previous studies to address this question using Magnetic Resonance Imaging (MRI). In the first, three SI subjects were reported to have reversed petalia and leftward occipital bending, but retained left hemisphere dominance for language. In the second study, three SI subjects were again reported to have reversed petalia and 1 out of three subjects was reported to have retained left hemisphere dominance for language. Thus while there is evidence for reversed structural brain asymmetry and normal functional brain lateralisation in SI it remains of interest to know whether this will be confirmed by studies of a larger cohort. We thus recruited 16 subjects with SI and 16 age, sex and education matched controls (SS) and applied state of the art image analysis techniques to investigate the extent to which brain asymmetry is reversed on 3D MR images in these subjects.3D T1-weighted MR images were obtained using a 3 tesla MRI system at the University of Ghent. The images were segmented using the standard pipeline in FreeSurfer software (https://surfer.nmr.mgh.harvard.edu/) and this allowed measurement of total cerebral hemisphere volume, grey and white matter volume. Also a so-called bounding box was fitted to each cerebral hemisphere aligned in Talairach space and the length width and height of each cerebral hemisphere and the corresponding displacements representing the frontal and occipital petalia were calculated. Furthermore, we used the procedure described by Greve et al. [3] to determine the correspondence between vertex points on the surface of the brain in the right and left cerebral hemisphere and, using the method described in Li et al. [4], produced separate 3D images of the vertex-wise positional asymmetry in left-right (L-R), anterior-posterior (A-P) and superior-inferior (S-I) directions.

Analysis has so far been completed for 16 SI subjects and 11 SS controls. The magnitude and direction of the frontal and occipital petalia as measured by the bounding-box analysis are plotted in Figure 1 where the majority of data points for SS subjects lie in the lower left quadrant reflecting normal petalia as indicated by the schematic diagram with blue rectangles representing the cerebral hemispheres. However, as predicted there are a significant number of subjects for which data plots in other quadrants. The majority of SI subjects plot in the upper right quadrant and possess reversed petalia, however a significant number possess normal or other petalia. The t-test showed significant group difference of frontal (p=0.0497) and occipital (p=0.0186) petalia between SI and SS groups. However, within each group, only the occipital petalia in controls was found to be significant (p=0.0037).

For all three components of brain asymmetry presented in Column 5 there is a significant difference in SI compared to SS in the region of the occipital but not the frontal pole, whereas on the plots of the average values of anterior-posterior asymmetry (Row 2, Columns 1 and 6) both SI and SS subjects show a posterior displacement of the left hemisphere, this is only significant in the SS subjects. Both cohorts show leftward asymmetry of the insula (Watkins et al. [5]) but this is significantly greater in the SI subjects. On the other hand rightward asymmetry of the Superior Temporal Sulcus (STS) (Leroy et al. [6]) is only significant in the SS subjects.

Rigorous analysis has confirmed previous reports of reversed brain asymmetry in SI, although this is not the case for all individuals with SI. Furthermore, there is evidence that on average SI subjects shown the same pattern of asymmetries of individual brain structures as SS but on occasions these may be significantly diminished (e.g. STS) or significantly increased (e.g. insula) in SI. Future analyses will investigate the relationship between global and structural brain asymmetry and differences in brain function (fMRI), connectivity (DTI) and genetics (genome sequencing) in these cohorts.