Common behavioral clusters and subcortical anatomy in stroke

Abstract

A long-held view is that stroke causes many distinct neurological syndromes due to damage of specialized cortical and subcortical centers. However, it is unknown if a syndrome-based description is helpful in characterizing behavioral deficits across a large number of patients. We studied a large prospective sample of first-time stroke patients with heterogeneous lesions at 1-2 weeks post-stroke. We measured behavior over multiple domains and lesion anatomy with structural MRI and a probabilistic atlas of white matter pathways. Multivariate methods estimated the percentage of behavioral variance explained by structural damage. A few clusters of behavioral deficits spanning multiple functions explained neurological impairment. Stroke topography was predominantly subcortical, and disconnection of white matter tracts critically contributed to behavioral deficits and their correlation. The locus of damage explained more variance for motor and language than memory or attention deficits. Our findings highlight the need for better models of white matter damage on cognition.

Figure 1. Experiments and time line

The red outline indicates the data used in this report.

Figure 2. Principal component analysis (PCA) within each domain of function

A) Factor scores for left side (blue, right hemisphere) and right side (red, left hemisphere) motor tests. Note walking in between (green). B) Scatter plot of Arm Research Action (ARA) test scores vs. right motor factor scores. Healthy controls: green dots; Left hemisphere patients: red dots; right hemisphere patients: blue dots. Note that healthy controls were not included in PCA. C) Left vs. right motor factor scores. D) Oral command vs. language factor scores. E) Language factor scores vs. lesion hemisphere. F) Boston Naming vs. Word Comprehension scores. G) Spatial span vs. Spatial memory factor scores; H) Hopkins Verbal Memory (% retained) vs. Verbal memory factor scores; I) Verbal vs. Spatial memory factor scores; J) Posner visual field accuracy vs. Attention visual field factor scores; K) Posner overall reaction time vs. Attention general performance factor scores; L) Language vs. Attention visual field bias factor scores.

Figure 3. Higher-order PCA

The diameter of each red circle corresponds to the % variance accounted for by each factor. The font size corresponds to the loading of each function onto the factor.

Figure 4. Correlation matrix of behavioral scores

The color scale indicates Pearson r-values. C1–C3 refers to factors 1–3 as described in the text. Y-axis: individual tests. X-axis: functional domains.

Figure 5. Topography of stroke

Lesion overlay map in atlas space. Color scale: number of subjects with lesions at each voxel.

Figure 6. Ridge regression maps relating behavioral deficits to anatomical damage

The color scale indicates weights (ω) determined by ridge regression for six behavioral factors, normalized to have a standard deviation of 1. Inset bar graphs show the percent of variance explained by lesion size alone (blue) or by lesion location (red). The dashed lines indicate significance thresholds determined by 10,000 random permutations of factor scores (5–6%).

Figure 7. Anatomy of correlated behavioral deficits

A) Conjunction map of ridge regression maps for seven behavioral domains (L/R motor, language, verbal memory, attention visual field bias, general performance, attention shifting). Each single domain map was corrected for multiple comparisons correction and binarized. The color scale (1–8) indicates at each voxel the number of significant ridge regression maps. B) Correlated behavior and disconnection. Lesions affecting white matter regions of high tract overlap (SLF/AF/CST/etc.) cause deficits in multiple domains (motor, language, etc). The gray-to-white overlay on the atlas-registered subject average is a conjunction of 57 white matter tracts. White indicates 1 tract and black indicates 8+ tracts overlap (at 40% tract probability) in that voxel. The yellow-to-red overlay is the conjunction of eight domain specific Logistic Regresion maps. Yellow indicates 3 behavioral domains affected and red indicates 6 or more domains affected by lesion to that voxel. Graph: as the number of domains effected by lesion to a given voxel increases, the number of WM tracts contained in that voxels increases.