J. Matthijs Biesbroek

Association between Subcortical Vascular Lesion Location and Cognition: A Voxel-Based and Tract-Based Lesion-Symptom Mapping Study. The SMART-MR Study

Introduction Lacunar lesions (LLs) and white matter lesions (WMLs) affect cognition. We assessed whether lesions located in specific white matter tracts were associated with cognitive performance taking into account total lesion burden. Methods Within the Second Manifestations of ARTerial disease Magnetic Resonance (SMART-MR) study, cross-sectional analyses were performed on 516 patients with manifest arterial disease. We applied an assumption-free voxel-based lesion-symptom mapping approach to investigate the relation between LL and WML locations on 1.5 Tesla brain MRI and compound scores of executive functioning, memory and processing speed. Secondly, a multivariable linear regression model was used to relate the regional volume of LLs and WMLs within specific white matter tracts to cognitive functioning. Results Voxel-based lesion-symptom mapping identified several clusters of voxels with a significant correlation between WMLs and executive functioning, mostly located within the superior longitudinal fasciculus and anterior thalamic radiation. In the multivariable linear regression model, a statistically significant association was found between regional LL volume within the superior longitudinal fasciculus and anterior thalamic radiation and executive functioning after adjustment for total LL and WML burden. Conclusion These findings identify the superior longitudinal fasciculus and anterior thalamic radiation as key anatomical structures in executive functioning and emphasize the role of strategically located vascular lesions in vascular cognitive impairment.

A Novel Imaging Marker for Small Vessel Disease Based on Skeletonization of White Matter Tracts and Diffusion Histograms

To establish a fully automated, robust imaging marker for cerebral small vessel disease (SVD) and related cognitive impairment that is easy to implement, reflects disease burden, and is strongly associated with processing speed, the predominantly affected cognitive domain in SVD.

The anatomy of visuospatial construction revealed by lesion-symptom mapping.

Visuospatial construction is a complex cognitive operation that is composed of a purely constructional component (visuoconstruction proper), and visuoperceptive, attentional, and decision-making components. The anatomical correlates of visuospatial construction and its cognitive subcomponents are poorly understood. The purpose of the present study was to determine the anatomical correlates of visuospatial construction by applying lesion-symptom mapping in a cohort of 111 patients with first-ever ischemic stroke. We employed the Rey-Osterrieth Complex Figure (ROCF) copy test and the Judgment of Line Orientation (JLO); both tests measure visuoperception, while only the ROCF has a constructional component. We first performed assumption-free voxel-based lesion-symptom mapping, which revealed large shared right hemispheric correlates for the ROCF and JLO in the frontal lobe, superior temporal lobe, and supramarginal gyrus. These shared anatomical correlates reflect the visuoperceptive component of the ROCF and JLO. Anatomical correlates were discordant in the right superior parietal lobule, and angular and middle occipital gyri: lesions in these regions were associated with poor performance on the ROCF, but not the JLO. Secondly, these findings were reproduced with a region of interest-based analysis that yielded a statistically significant correlation between infarct volume in the right inferior and superior parietal, angular and middle occipital cortices, and poor performance on the ROCF, but not the JLO. This discordance in anatomical correlates of the ROCF and JLO reflects the visuoconstructive component of the ROCF. These findings provide new insights in the anatomical correlates of the visuoperceptive and visuoconstructive components of the ROCF and provide evidence for a crucial role of the right inferior and superior parietal, angular and middle occipital gyri in visuoconstruction proper.

Shared and distinct anatomical correlates of semantic and phonemic fluency revealed by lesion-symptom mapping in patients with ischemic stroke

Semantic and phonemic fluency tasks are frequently used to test executive functioning, speed and attention, and access to the mental lexicon. In semantic fluency tasks, subjects are required to generate words belonging to a category (e.g., animals) within a limited time window, whereas in phonemic fluency tasks subjects have to generate words starting with a given letter. Anatomical correlates of semantic and phonemic fluency are currently assumed to overlap in left frontal structures, reflecting shared executive processes, and to be distinct in left temporal and right frontal structures, reflecting involvement of distinct memory processes and search strategies. Definite evidence for this assumption is lacking. To further establish the anatomical correlates of semantic and phonemic fluency, we applied assumption-free voxel-based and region-of-interest-based lesion-symptom mapping in 93 patients with ischemic stroke. Fluency was assessed by asking patients to name animals (semantic), and words starting with the letter N and A (phonemic). Our findings indicate that anatomical correlates of semantic and phonemic fluency overlap in the left inferior frontal gyrus and insula, reflecting shared underlying cognitive processes. Phonemic fluency additionally draws on the left rolandic operculum, which might reflect a search through phonological memory, and the middle frontal gyrus. Semantic fluency additionally draws on left medial temporal regions, probably reflecting a search through semantic memory, and the right inferior frontal gyrus, which might reflect the application of a visuospatial mental imagery strategy in semantic fluency. These findings establish shared and distinct anatomical correlates of semantic and phonemic fluency.

Lesion location and cognitive impact of cerebral small vessel disease

Cerebral small vessel disease (SVD) is an important cause of cognitive impairment. Important MRI manifestations of SVD include white matter hyperintensities (WMH) and lacunes. This narrative review addresses the role of anatomical lesion location in the impact of SVD on cognition, integrating findings from early autopsy studies with emerging findings from recent studies with advanced image analysis techniques. Early autopsy and imaging studies of small case series indicate that single lacunar infarcts in, for example the thalamus, caudate nucleus or internal capsule can cause marked cognitive impairment. However, the findings of such case studies may not be generalizable. Emerging location-based image analysis approaches are now being applied to large cohorts. Recent studies show that WMH burden in strategic white matter tracts, such as the forceps minor or anterior thalamic radiation (ATR), is more relevant in explaining variance in cognitive functioning than global WMH volume. These findings suggest that the future diagnostic work-up of memory clinic patients could potentially be improved by shifting from a global assessment of WMH and lacune burden towards a quantitative assessment of lesion volumes within strategic brain regions. In this review, a summary of currently known strategic regions for SVD-related cognitive impairment is provided, highlighting recent technical developments in SVD research. The potential and challenges of location-based approaches for diagnostic purposes in clinical practice are discussed, along with their potential prognostic and therapeutic applications.

The right hemisphere is dominant in organization of visual search—A study in stroke patients

Cancellation tasks are widely used for diagnosis of lateralized attentional deficits in stroke patients. A disorganized fashion of target cancellation has been hypothesized to reflect disturbed spatial exploration. In the current study we aimed to examine which lesion locations result in disorganized visual search during cancellation tasks, in order to determine which brain areas are involved in search organization. A computerized shape cancellation task was administered in 78 stroke patients. As an index for search organization, the amount of intersections of paths between consecutive crossed targets was computed (i.e., intersections rate). This measure is known to accurately depict disorganized visual search in a stroke population. Ischemic lesions were delineated on CT or MRI images. Assumption-free voxel-based lesion-symptom mapping and region of interest-based analyses were used to determine the grey and white matter anatomical correlates of the intersections rate as a continuous measure. The right lateral occipital cortex, superior parietal lobule, postcentral gyrus, superior temporal gyrus, middle temporal gyrus, supramarginal gyrus, inferior longitudinal fasciculus, first branch of the superior longitudinal fasciculus (SLF I), and the inferior fronto-occipital fasciculus, were related to search organization. To conclude, a clear right hemispheric dominance for search organization was revealed. Further, the correlates of disorganized search overlap with regions that have previously been associated with conjunctive search and spatial working memory. This suggests that disorganized visual search is caused by disturbed spatial processes, rather than deficits in high level executive function or planning, which would be expected to be more related to frontal regions.

Distinct anatomical correlates of discriminability and criterion setting in verbal recognition memory revealed by lesion-symptom mapping

Recognition memory, that is, the ability to judge whether an item has been previously encountered in a particular context, depends on two factors: discriminability and criterion setting. Discriminability draws on memory processes while criterion setting (i.e., the application of a threshold resulting in a yes/no response) is regarded as a process of cognitive control. Discriminability and criterion setting are assumed to draw on distinct anatomical structures, but definite evidence for this assumption is lacking. We applied voxel‐based and region of interest‐based lesion‐symptom mapping to 83 patients in the acute phase of ischemic stroke to determine the anatomical correlates of discriminability and criterion setting in verbal recognition memory. Recognition memory was measured with the Rey Auditory Verbal Learning Test. Signal‐detection theory was used to calculate measures for discriminability and criterion setting. Lesion‐symptom mapping revealed that discriminability draws on left medial temporal and temporo‐occipital structures, both thalami and the right hippocampus, while criterion setting draws on the right inferior frontal gyrus. Lesions in the right inferior frontal gyrus were associated with liberal response bias. These findings indicate that discriminability and criterion setting indeed depend on distinct anatomical structures and provide new insights in the anatomical correlates of these cognitive processes that underlie verbal recognition memory. Hum Brain Mapp 36:1292–1303, 2015.

Culture-negative Candida meningitis diagnosed by detection of Candida mannan antigen in CSF

We present a patient with chronic culture-negative Candida meningitis, in whom the diagnosis was made by detection of the mannan antigen (Mn) and anti-mannan antibodies (A-Mn) in the CSF.

Impact of Strategically Located White Matter Hyperintensities on Cognition in Memory Clinic Patients with Small Vessel Disease

Background and Purpose Studies on the impact of small vessel disease (SVD) on cognition generally focus on white matter hyperintensity (WMH) volume. The extent to which WMH location relates to cognitive performance has received less attention, but is likely to be functionally important. We examined the relation between WMH location and cognition in a memory clinic cohort of patients with sporadic SVD. Methods A total of 167 patients with SVD were recruited from memory clinics. Assumption-free region of interest-based analyses based on major white matter tracts and voxel-wise analyses were used to determine the association between WMH location and executive functioning, visuomotor speed and memory. Results Region of interest-based analyses showed that WMHs located particularly within the anterior thalamic radiation and forceps minor were inversely associated with both executive functioning and visuomotor speed, independent of total WMH volume. Memory was significantly associated with WMH volume in the forceps minor, independent of total WMH volume. An independent assumption-free voxel-wise analysis identified strategic voxels in these same tracts. Region of interest-based analyses showed that WMH volume within the anterior thalamic radiation explained 6.8% of variance in executive functioning, compared to 3.9% for total WMH volume; WMH volume within the forceps minor explained 4.6% of variance in visuomotor speed and 4.2% of variance in memory, compared to 1.8% and 1.3% respectively for total WMH volume. Conclusions Our findings identify the anterior thalamic radiation and forceps minor as strategic white matter tracts in which WMHs are most strongly associated with cognitive impairment in memory clinic patients with SVD. WMH volumes in individual tracts explained more variance in cognition than total WMH burden, emphasizing the importance of lesion location when addressing the functional consequences of WMHs.

Registration of Brain CT Images to an MRI Template for the Purpose of Lesion-Symptom Mapping

Lesion-symptom mapping is a valuable tool for exploring the relation between brain structure and function. In order to perform lesion-symptom mapping, lesion delineations made on different brain CT images need to be transformed to a standardized coordinate system. The preferred choice for this is the MNI152 template image that is based on T1-weighted MR images. This requires a multi-modal registration procedure to transform lesion delineations for each CT image to the MNI152 template image. A two-step registration procedure was implemented, using lesion-masking and contrast stretching to correctly align the soft tissue of the CT image to the MNI152 template image. The results were used to transform the lesion delineations to the template. The quality of the registration was assessed by an expert human observer. Of the 86 CT images, the registration was highly successful in 71 cases (83%). Slight manual adjustments of the lesion delineations in the standard coordinate system were required to make unsuccessful cases suitable for a lesion-symptom mapping study.