Power in Voxel-based Lesion–Symptom Mapping

Lesion analysis in brain-injured populations complements what can be learned from functional neuroimaging. Voxelbased approaches to mapping lesion–behavior correlations in brain-injured populations are increasingly popular, and have the potential to leverage image analysis methods drawn from functional magnetic resonance imaging. However, power is a major concern for these studies, and is likely to vary regionally due to the distribution of lesion locations. Here, we outline general considerations for voxel-based methods, characterize the use of a nonparametric permutation test adapted from functional neuroimaging, and present methods for regional power analysis in lesion studies

Bayesian lesion-deficit inference with Bayes factor mapping: key advantages, limitations, and a toolbox.

Statistical lesion-symptom mapping is largely dominated by frequentist approaches with null hypothesis significance testing. They are popular for mapping functional brain anatomy but are accompanied by some challenges and limitations. The typical analysis design and the structure of clinical lesion data are linked to the multiple comparison problem, an association problem, limitations to statistical power, and a lack of insights into evidence for the null hypothesis. Bayesian lesion deficit inference (BLDI) could be an improvement as it collects evidence for the null hypothesis, i.e. the absence of effects, and does not accumulate α-errors with repeated testing. We implemented BLDI by Bayes factor mapping with Bayesian t-tests and general linear models and evaluated its performance in comparison to frequentist lesion-symptom mapping with a permutation-based family-wise error correction. We mapped the voxel-wise neural correlates of simulated deficits in an in-silico-study with 300 stroke patients, and the voxel-wise and disconnection-wise neural correlates of phonemic verbal fluency and constructive ability in 137 stroke patients. Both the performance of frequentist and Bayesian lesion-deficit inference varied largely across analyses. In general, BLDI could find areas with evidence for the null hypothesis and was statistically more liberal in providing evidence for the alternative hypothesis, i.e. the identification of lesion-deficit associations. BLDI performed better in situations in which the frequentist method is typically strongly limited, for example with on average small lesions and in situations with low power, where BLDI also provided unprecedented transparency in terms of the informative value of the data. On the other hand, BLDI suffered more from the association problem, which led to a pronounced overshoot of lesion-deficit associations in analyses with high statistical power. We further implemented a new approach to lesion size control, adaptive lesion size control, that, in many situations, was able to counter the limitations imposed by the association problem, and increased true evidence both for the null and the alternative hypothesis. In summary, our results suggest that BLDI is a valuable addition to the method portfolio of lesion-deficit inference with some specific and exclusive advantages: it deals better with smaller lesions and low statistical power (i.e. small samples and effect sizes) and identifies regions with absent lesion-deficit associations. However, it is not superior to established frequentist approaches in all respects and therefore not to be seen as a general replacement. To make Bayesian lesion-deficit inference widely accessible, we published an R toolkit for the analysis of voxel-wise and disconnection-wise data

Strategic lesions in the anterior thalamic radiation and apathy in early Alzheimer's disease

BACKGROUND Behavioural disorders and psychological symptoms of Dementia (BPSD) are commonly observed in Alzheimer's disease (AD), and strongly contribute to increasing patients' disability. Using voxel-lesion-symptom mapping (VLSM), we investigated the impact of white matter lesions (WMLs) on the severity of BPSD in patients with amnestic mild cognitive impairment (a-MCI). METHODS Thirty-one a-MCI patients (with a conversion rate to AD of 32% at 2 year follow-up) and 26 healthy controls underwent magnetic resonance imaging (MRI) examination at 3T, including T2-weighted and fluid-attenuated-inversion-recovery images, and T1-weighted volumes. In the patient group, BPSD was assessed using the Neuropsychiatric Inventory-12. After quantitative definition of WMLs, their distribution was investigated, without an a priori anatomical hypothesis, against patients' behavioural symptoms. Unbiased regional grey matter volumetrics was also used to assess the contribution of grey matter atrophy to BPSD. RESULTS Apathy, irritability, depression/dysphoria, anxiety and agitation were shown to be the most common symptoms in the patient sample. Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD. CONCLUSIONS This study indicates that damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI. Disconnection between the prefrontal cortex and the mediodorsal and anterior thalamic nuclei might represent the pathophysiological substrate for apathy, which is one of the most common psychopathological symptoms observed in dementia

False Discovery Rate Control for Lesion-Symptom Mapping with Heterogeneous data via Weighted P-values

Lesion-symptom mapping studies provide insight into what areas of the brain are involved in different aspects of cognition. This is commonly done via behavioral testing in patients with a naturally occurring brain injury or lesions (e.g., strokes or brain tumors). This results in high-dimensional observational data where lesion status (present/absent) is non-uniformly distributed with some voxels having lesions in very few (or no) subjects. In this situation, mass univariate hypothesis tests have severe power heterogeneity where many tests are known a priori to have little to no power. Recent advancements in multiple testing methodologies allow researchers to weigh hypotheses according to side-information (e.g., information on power heterogeneity). In this paper, we propose the use of p-value weighting for voxel-based lesion-symptom mapping (VLSM) studies. The weights are created using the distribution of lesion status and spatial information to estimate different non-null prior probabilities for each hypothesis test through some common approaches. We provide a monotone minimum weight criterion which requires minimum a priori power information. Our methods are demonstrated on dependent simulated data and an aphasia study investigating which regions of the brain are associated with the severity of language impairment among stroke survivors. The results demonstrate that the proposed methods have robust error control and can increase power. Further, we showcase how weights can be used to identify regions that are inconclusive due to lack of power

Topological map of the body in post-stroke patients: lesional and hodological aspects

Objective: It has been repeatedly hypothesized that at least 3 distinct types of body representations do exist: body schema, a representation derived from multiple sensory and motor inputs; topological map of the body, a structural description of spatial relations among the body parts; and body semantics, a lexical-semantic representation. Although several studies have assessed neural correlates of the topological map of the body in healthy participants, a systematic investigation of neural underpinnings of the topological map of the body in brain-damaged patients is still lacking. Method: Here we investigated the neural substrates of topological map of the body in 23 brain-damaged patients, both from a topological and an hodological perspectives, using Voxel Lesion Symptom Mapping and atlas-based track-wise statistical analysis. Besides neuroimaging investigation, consisting of T1-weighted and FLAIR sequences, patients underwent the frontal body-evocation subtest (FBE) to assess the topological map of the body. Results: The present results reveal a large-scale brain network involved in the topological map of the body assessed with FBE, encompassing both regions of primary elaboration and multisensory associative areas, in the temporal, parietal, frontal, and insular cortices. Hodological analysis revealed significant association between processing of the body topological map and the disconnection of the frontomarginal tract. Conclusions: These findings suggest that the topological map of the body is built up basing on both external and internal information that comes from the body and are constantly updated and integrated. The theoretical and clinical relevance of these results is discussed

Speed-accuracy strategy regulations in prefrontal tumor patients

The ability to flexibly switch between fast and accurate decisions is crucial in everyday life. Recent neuroimaging evidence suggested that left lateral prefrontal cortex plays a role in switching from a quick response strategy to an accurate one. However, the causal role of the left prefrontal cortex in this particular, non-verbal, strategy switch has never been demonstrated. To fill this gap, we administered a perceptual decision-making task to neuro-oncological prefrontal patients, in which the requirement to be quick or accurate changed randomly on a trial-by-trial basis. To directly assess hemispheric asymmetries in speed-accuracy regulation, patients were tested a few days before and a few days after surgical excision of a brain tumor involving either the left (N=13) or the right (N=12) lateral frontal brain region. A group of age- and education-matched healthy controls was also recruited. To gain more insight on the component processes implied in the task, performance data (accuracy and speed) were not only analyzed separately but also submitted to a diffusion model analysis. The main findings indicated that the left prefrontal patients were impaired in appropriately adopting stricter response criteria in speed-to-accuracy switching trials with respect to healthy controls and right prefrontal patients, who were not impaired in this condition. This study demonstrates that the prefrontal cortex in the left hemisphere is necessary for flexible behavioral regulations, in particular when setting stricter response criteria is required in order to successfully switch from a speedy strategy to an accurate one

Damage to the right insula disrupts the perception of affective touch

© 2020 Kirsch et al. This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.Specific, peripheral C-tactile afferents contribute to the perception of tactile pleasure, but the brain areas involved in their processing remain debated. We report the first human lesion study on the perception of C-tactile touch in right hemisphere stroke patients (N = 59), revealing that right posterior and anterior insula lesions reduce tactile, contralateral and ipsilateral pleasantness sensitivity, respectively. These findings corroborate previous imaging studies regarding the role of the posterior insula in the perception of affective touch. However, our findings about the crucial role of the anterior insula for ipsilateral affective touch perception open new avenues of enquiry regarding the cortical organization of this tactile system.Peer reviewe

Does stroke location predict walk speed response to gait rehabilitation?

Objectives Recovery of independent ambulation after stroke is a major goal. However, which rehabilitation regimen best benefits each individual is unknown and decisions are currently made on a subjective basis. Predictors of response to specific therapies would guide the type of therapy most appropriate for each patient. Although lesion topography is a strong predictor of upper limb response, walking involves more distributed functions. Earlier studies that assessed the cortico-spinal tract (CST) were negative, suggesting other structures may be important. Experimental Design: The relationship between lesion topography and response of walking speed to standard rehabilitation was assessed in 50 adult-onset patients using both volumetric measurement of CST lesion load and voxel-based lesion–symptom mapping (VLSM) to assess non-CST structures. Two functional mobility scales, the functional ambulation category (FAC) and the modified rivermead mobility index (MRMI) were also administered. Performance measures were obtained both at entry into the study (3–42 days post-stroke) and at the end of a 6-week course of therapy. Baseline score, age, time since stroke onset and white matter hyperintensities score were included as nuisance covariates in regression models. Principal Observations: CST damage independently predicted response to therapy for FAC and MRMI, but not for walk speed. However, using VLSM the latter was predicted by damage to the putamen, insula, external capsule and neighbouring white matter. Conclusions Walk speed response to rehabilitation was affected by damage involving the putamen and neighbouring structures but not the CST, while the latter had modest but significant impact on everyday functions of general mobility and gait