White-matter bottleneck in small vessel disease: A lesion-symptom mapping study of executive-language functions


Cerebral small vessel disease (CSVD), characterized by the presence of white matter lesions (WML), is among the main causes of vascular cognitive impairment. The most well-studied cognitive domains showing impairment in CSVD are executive functioning and processing speed, which are correlated with total WML volume. By contrast, the domain of language has received much less attention. Recent studies indicate that WML location might be more informative than total WML volume in explaining the cognitive profile of CSVD. However, these studies only investigated tasks of executive function and processing speed, whereas other brain functions that might be more dependent on WML location, such as language, have remained understudied. In addition, these studies used global compound scores of executive function and processing speed with and without language involvement, precluding inferences regarding whether there is a core network underlying executive and language tasks. The present study investigates whether WML location is associated with poorer performance in executive-language tasks, as analyzed at a single task level.
This study included a cohort of 445 CSVD patients without dementia, with varying burden of WML. WML were defined as hyperintense lesions on FLAIR MRI without corresponding cerebrospinal fluid-like hypointense lesions on the T1 weighted image. The WML were segmented on FLAIR images and transformed into Montreal Neurological Institute 152 (MNI) standard space. The Stroop (word reading, color naming, and color-word naming) and the verbal fluency tests were used as measures of language production with varying degrees of executive demands. The digit symbol modality (DSMT) was used as a control task as it does not require verbal abilities.
A voxel-based lesion symptom mapping (VLSM) approach was used. In this approach, a t-test is performed at every voxel, comparing test scores (verbal fluency, each of the three tasks of the Stroop test and DSMT) in individuals with and without a WML in each voxel. Analyses were limited to those voxels where at least 4% (N= 18) of the individuals had a lesion with the goal of minimizing biased parameter estimates. To correct for multiple comparison, permutation testing was used. The cut-off for a significant cluster size was determined based on 6000 iterations, with a voxel-wise threshold set at an alpha level of 0.05 10. All VLSM analyses were corrected for age, gender, education, and lesion size. Additionally, to control for the processing speed component in language-related tasks, all VLSM analyses (verbal fluency, color-word naming and DSMT) were further corrected by a “processing speed” score. This was obtained by averaging the score of word reading and color naming of the Stroop test. Then, we divided the scores of verbal fluency, color-word naming test and DSTM by the processing speed score.
The VLSM analyses revealed statistically significant clusters for verbal fluency, and Stroop word reading, color naming and color-word naming, but not for DSMT. Worse scores in all tests were associated with WML predominantly in the forceps minor, bilateral thalamic radiations and the caudate nuclei. This set of brain areas was similar across all tests. The lesion-symptom associations remained the same once the scores of the verbal fluency and Stroop color-word naming tests were corrected for processing speed.
A relationship was found between WML in a core fronto-striatal network and executive-language functioning in CSVD independent of lesion size. This circuitry formed by the caudate nuclei, forceps minor and thalamic radiations, seems to underlie executive-language functioning beyond the role of general processing speed and it might constitute a bottleneck area in CSVD. Finally, the contribution of this circuitry seems to be stronger for tasks requiring language functioning.

Poster and oral presentation at SNL 2019 and SoA 2019
Ileana Camerino
Ileana Camerino
PhD candidate