Cortical connectivity in the face of congenital structural changes—A case of homozygous LAMC3 mutation

Abstract The homozygous LAMC3 gene mutation is associated with severe bilateral smoothening and thickening of the lateral occipital cortex . Despite this and further significant changes in gray matter structure, a patient harboring this mutation exhibited a range of remarkably intact perceptual abilities . One possible explanation of this perceptual sparing could be that the white matter structural integrity and functional connectivity in relevant pathways remained intact. To test this idea, we used diffusion tensor and functional magnetic resonance imaging to investigate functional connectivity in resting‐state networks in major structural pathways involved in object perception and visual attention and corresponding microstructural integrity in a patient with homozygous LAMC3 mutation and sex, age, education, and socioeconomically matched healthy control group. White matter microstructural integrity results indicated widespread disruptions in both intra‐ and interhemispheric structural connections except inferior longitudinal fasciculus. With a few exceptions, the functional connectivity between the patient's adjacent gray matter regions of major white matter tracts of interest was conserved. In addition, functional localizers for face, object, and place areas showed similar results with a representative control, providing an explanation for the patient's intact face, place, and object recognition abilities. To generalize this finding, we also compared functional connectivity between early visual areas and face, place, and object category‐selective areas, and we found that the functional connectivity of the patient was not different from the control group. Overall, our results provided complementary information about the effects of LAMC3 gene mutation on the human brain including intact temporo‐occipital structural and functional connectivity that are compatible with preserved perceptual abilities.

Calcarine hemisphere between the patient and controls. Colors correspond to t statistics, blue indicates that the patient's connectivity values were significantly lower than those of the controls, red indicates that the patient's connectivity values were significantly higher than those of the controls. Non-significant differences are plotted in light gray. ROIs within inferior fronto occipital fasciculus (red), inferior longitudinal fasciculus (blue), superior longitudinal fasciculus (purple) were represented with rectangles.

Supplementary Figure 4. Graphical overview of coherence comparisons of ROIs in the left (R)
hemisphere between the patient and controls. Colors correspond to t statistics, blue indicates that the patient's connectivity values were significantly lower than those of the controls, red indicates that the patient's connectivity values were significantly higher than those of the controls. Non-significant differences are plotted in light gray. ROIs within inferior fronto occipital fasciculus (red), inferior longitudinal fasciculus (blue), superior longitudinal fasciculus (purple) were represented with rectangles. ROIs within both calcarine and inferior fronto-occipital fasciculus were represented with green rectangles. results with corresponding 99% confidence intervals that are derived from nonparametric bootstrapping procedure of healthy participants as well as the patient's raw coherence score in left (L) and right (R) hemispheres. Probability outcomes of each test were adjusted via false discovery rate (FDR; Benjamini and Hochberg, 1995) procedures and resulting P FDR values were reevaluated at a criterion of 0.05 (*), 0.01 (**) and 0.001 (***) for statistical significance. Results are shown in t test score, [confidence intervals], patient's raw score format.  Table 4. Resting state fMRI connectivity comparisons in the Superior Longitudinal Fasciculus (SLF). The table summarizes comparison of coherence scores between healthy participants and the patient for each ROI pairs along the SLF. Given are the standard null hypothesis test (one -sample t-test) results with corresponding 99% confidence intervals that are derived from nonparametric bootstrapping procedure of healthy participants as well as the patient's raw coherence score in left (L) and right (R) hemispheres. Probability outcomes of each test were adjusted via false discovery rate (FDR; Benjamini and Hochberg, 1995) procedures and resulting P FDR values were reevaluated at a criterion of 0.05 (*), 0.01 (**) and 0.001 (***) for statistical significance. Results are shown in t test score, [confidence intervals], patient's raw score format.

Middle Temporal
Supplementary Table 6. Resting state fMRI connectivity comparisons in the calcarine. The table summarizes comparison of coherence scores between healthy participants and the patient for each ROI pairs along calcarine tracts. Given are the standard null hypothesis test (one -sample t-test) results with corresponding 99% confidence intervals that are derived from nonparametric bootstrapping procedure of healthy participants as well as the patient's raw coherence score in left (L) and right (R) hemispheres. Probability outcomes of each test were adjusted via false discovery rate (FDR;Benjamini and Hochberg, 1995) procedures and resulting P FDR values were reevaluated at a criterion of 0.05 (*), 0.01 (**) and 0.001 (***) for statistical significance. Results are shown in t test score, [confidence intervals], patient's raw score format.  Table 7. Resting state fMRI connectivity comparisons in the cingulate. The table summarizes comparison of coherence scores between healthy participants and the patient for each ROI pairs along the cingulate tracts. Given are the standard null hypothesis test (one -sample t-test) results with corresponding 99% confidence intervals that are derived from nonparametric bootstrapping procedure of healthy participants as well as the patient's raw coherence score in left (L) and right (R) hemispheres. Probability outcomes of each test were adjusted via false discovery rate (FDR; Benjamini and Hochberg, 1995) procedures and resulting P FDR values were reevaluated at a criterion of 0.05 (*), 0.01 (**) and 0.001 (***) for statistical significance. Results are shown in t test score, [confidence intervals], patient's raw score format.  Given are minimum and maximum boundaries of raw coherence scores in controls and raw coherence scores of the patient for each ROI pairs along adjacent gray matter regions of major white matter tracts, namely ILF in left (L) and right (R) hemispheres. Significantly differences are written in bold.

ILF Entorhinal
Fusiform Parahippocampal G. Supramarginal G. Pericalcarine Superior Temporal Supplementary Table 9d. Raw coherence scores of the participants that are used for functional connectivity comparison in Supplementary Table 6. Given are minimum and maximum boundaries of raw coherence scores in controls and raw coherence scores of the patient for each ROI pairs along adjacent gray matter regions of major white matter tracts, namely calcarine in left (L) and right (R) hemispheres. Significantly differences are written in bold.
Mean diffusivity along left IFOF and left rostral middle frontal-lateral orbitofrontal functional connectivity r(26)=0.8448, p=0.0021was positively correlated. Radial diffusivity along left IFOF and rostral middle frontal-lateral orbitofrontal r(26)=0.7458, p=0.0133, left precuneus-medial orbitofrontal r(26)=0.6334, p=0.0493 were positively correlated. Fractional anisotropy along the right IFOF and right caudal middle frontal-lateral orbitofrontal functional connectivity r(26)=0.6329, p=0.0495 were marginally correlated. Radial diffusivity along the right IFOF and pericalcarine-lateral orbitofrontal r(26)=-0.6467, p=0.0433 was negatively correlated. In addition, axial diffusion along tapetum and the left and right cuneus functional connectivity r(26)=-0.6457, p=0.0437 was negatively correlated. Figure 5. Comparison of functional and structural connectivity between the patient and controls. Pearson's correlation coefficient was calculated between diffusion tensor scalars of white matter tracts of interests and functional connectivity of both intra-and interhemispheric region-of-interest pairs. Warm colors represent positive correlation coefficients whereas cold colors represent negative correlation coefficients. Statistical comparisons that correspond p<0.05 were indicated with asterisk. We found a significant positive correlation between functional and structural connectivity in the right ILF.