The role of corpus callosum development in functional connectivity and cognitive processing

Abstract

The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8-12 Hz), beta (12-30 Hz) and gamma (30-55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified.

Figure 1. Averaged power spectral density estimates derived from MEG sensors separately for the healthy control (HC; in green), partial (pAgCC; in blue) and complete agenesis of the corpus callosum (cAgCC; in red) groups during a single resting epoch.

Figure 2. Alpha band (8–12Hz) global connectivity (GC) maps for the HC and AgCC groups and results from a direct comparison between the two samples.

In both HC (A) and AgCC (B) groups, high resting-state alpha GC is seen across the occipital, parietal and temporal lobes. In the group contrast, three regions are identified as being significantly underconnected across both hemispheres in the patient group. GC within a region of dorsolateral pre-frontal cortex bilaterally (DLPFC; in blue) is lower in the AgCC group. A cluster of voxels in posterior parietal cortex (PPC; in blue) are significantly underconnected in both hemispheres of patients with AgCC. Caudal to PPC, a region of parieto-occipital cortex (PO) was also disconnected in both hemispheres in the AgCC group. Statistical maps are thresholded (p<0.05, FWE corrected) and superimposed over a rendering of the MNI template brain.

Figure 3. Interhemispheric (across) and intrahemispheric (white bars) connections (averaged GC across all voxels in both hemispheres) for three regions of interest identified as being significantly underconnected in the group contrast, dorsolateral pre-frontal cortex (DLPFC), posterior parietal cortex (PPC) and parieto-occipital cortex (PO).

Across the three ROIs, both inter- and intrahemispheric connections are significantly lower in the AgCC group compared to healthy controls. Diamond  =  group mean, error bars  =  S.D. of mean.

Figure 4. Results from a direct comparison between HC and AgCC groups for connectivity maps split by connection type.

For both interhemispheric connections (top row) and intrahemispheric connections of voxels (bottom row), reductions in DLPFC, PPC and PO coherence are predominant bilaterally in the group comparison, similar to the spatial distribution of reduced connectivity observed in the global connectivity maps (Figure 2).

Figure 5. Planned comparison between partial AgCC (pAgCC) and complete AgCC (cAgCC) patients for interhemispheric (across) and intrahemispheric (within) connections of DLPFC, PPC and PO.

No significant differences between the pAgCC and cAgCC groups are identifiable in any of the ROIs. Conventions as in Figure 3.

Figure 6. Results of a voxel-wise correlation between global imaginary coherence (GC) at rest in the AgCC cohort (scatterplots, in black) and verbal processing speed (VPS) performance on the D-KEFS Color-Word Interference Test.

Functional connections of two regions in the left hemisphere were positively correlated (overlay, in red) with processing speed in AgCC, in the left medial temporal gyrus (MTG) and the superior temporal gyrus (STG). These same two regions were not found to be significantly correlated with processing speed in healthy controls (scatterplots, in red). No regions in the right hemisphere were correlated with verbal processing speed in any group. pAgCC  =  partial agenesis of the corpus callosum. cAgCC  =  complete agenesis of the corpus callosum. Statistical maps (Pearson's r) are thresholded (p<0.05, 1% FDR correction) and superimposed as in previous figures.

Figure 7. Results of a voxel-wise correlation between global imaginary coherence (GC) at rest in the AgCC cohort (in black) and problem solving (PS) performance on the D-KEFS Tower Test.

Functional connectivity of a region in medial pre-frontal cortex (PFC, top panel) and the left superior frontal gyrus in Brodmann's Area 8 (BA8; bottom panel) was positively correlated with Tower scores (p<0.05, 5% FDR correction) in the AgCC group. No significant relationship between performance on Tower and functional connectivity was identified in the healthy control group (in red). Conventions as in Figure 4. Statistical maps (Pearson's r) are thresholded (p<0.05, 10% FDR correction) and superimposed as in previous figures.