Multivariate pattern analysis reveals subtle brain anomalies relevant to the cognitive phenotype in neurofibromatosis type 1

Abstract

Neurofibromatosis Type 1 (NF1) is a common genetic condition associated with cognitive dysfunction. However, the pathophysiology of the NF1 cognitive deficits is not well understood. Abnormal brain structure, including increased total brain volume, white matter (WM) and grey matter (GM) abnormalities have been reported in the NF1 brain. These previous studies employed univariate model-driven methods preventing detection of subtle and spatially distributed differences in brain anatomy. Multivariate pattern analysis allows the combination of information from multiple spatial locations yielding a discriminative power beyond that of single voxels. Here we investigated for the first time subtle anomalies in the NF1 brain, using a multivariate data-driven classification approach. We used support vector machines (SVM) to classify whole-brain GM and WM segments of structural T1 -weighted MRI scans from 39 participants with NF1 and 60 non-affected individuals, divided in children/adolescents and adults groups. We also employed voxel-based morphometry (VBM) as a univariate gold standard to study brain structural differences. SVM classifiers correctly classified 94% of cases (sensitivity 92%; specificity 96%) revealing the existence of brain structural anomalies that discriminate NF1 individuals from controls. Accordingly, VBM analysis revealed structural differences in agreement with the SVM weight maps representing the most relevant brain regions for group discrimination. These included the hippocampus, basal ganglia, thalamus, and visual cortex. This multivariate data-driven analysis thus identified subtle anomalies in brain structure in the absence of visible pathology. Our results provide further insight into the neuroanatomical correlates of known features of the cognitive phenotype of NF1.

Keywords: MRI; brain structure; multivariate pattern classification; neurofibromatosis type 1; neuroimaging; support vector machine (SVM).

Figure 1

Whole‐brain representation of the discriminative map for WM relative volume classification in children/adolescents. The weight vectors are displayed from a leave‐two‐out linear SVM using 150,000 voxels. Positively weighted voxels in NF1 vs. controls are displayed in red/yellow, while negatively weighted voxels are displayed in blue/green. Regions with relatively stronger classification absolute weights are identified. The map is overlayed on the group WM template from all subjects. The z‐coordinate for each axial slice in the standard MNI space is given.

Figure 2

Whole‐brain representation of the discriminative map for WM relative volume classification in adults. The weight vectors are displayed from a leave‐two‐out linear SVM using 150,000 voxels. Positively weighted voxels in NF1 vs. controls are displayed in red/yellow, while negatively weighted voxels are displayed in blue/green. Regions with relatively stronger classification absolute weights are identified. The map is overlayed on the group WM template from all subjects. The z‐coordinate for each axial slice in the standard MNI space is given.

Figure 3

Whole‐brain representation of the discriminative map for GM relative volume classification in children/adolescents. The weight vectors are displayed from a leave‐two‐out linear SVM using 150,000 voxels. Positively weighted voxels in NF1 vs. controls are displayed in red/yellow, while negatively weighted voxels are displayed in blue/green. Regions with relatively stronger classification absolute weights are identified. The map is overlayed on the group GM template from all subjects. The z‐coordinate for each axial slice in the standard MNI space is given.

Figure 4

Whole‐brain representation of the discriminative map for GM relative volume classification in adults. The weight vectors are displayed from a leave‐two‐out linear SVM using 150,000 GM voxels. Positively weighted voxels in NF1 vs. controls are displayed in red/yellow, while negatively weighted voxels are displayed in blue/green. Regions with relatively stronger classification absolute weights are identified. The map is overlayed on the group GM template from all subjects. The z‐coordinate for each axial slice in the standard MNI space is given.

Figure 5

Results of VBM analysis of WM in children/adolescents. Results are presented at a voxel‐level P‐value < 0.05, corrected for FWE and non‐stationary smoothness. Voxels showing significant WM relative volume differences are overlaid on group‐customized WM template.

Figure 6

Results of VBM analysis of WM in adults. Results are presented at a voxel‐level P‐value < 0.05, corrected for FWE and non‐stationary smoothness. Voxels showing significant WM relative volume differences are overlaid on group‐customized WM template.