Beyond cortical localization in clinico-anatomical correlation

Last year was the 150th anniversary of Paul Broca's landmark case report on speech disorder that paved the way for subsequent studies of cortical localization of higher cognitive functions. However, many complex functions rely on the activity of distributed networks rather than single cortical areas. Hence, it is important to understand how brain regions are linked within large-scale networks and to map lesions onto connecting white matter tracts. To facilitate this network approach we provide a synopsis of classical neurological syndromes associated with frontal, parietal, occipital, temporal and limbic lesions. A review of tractography studies in a variety of neuropsychiatric disorders is also included. The synopsis is accompanied by a new atlas of the human white matter connections based on diffusion tensor tractography freely downloadable on http://www.natbrainlab.com. Clinicians can use the maps to accurately identify the tract affected by lesions visible on conventional CT or MRI. The atlas will also assist researchers to interpret their group analysis results. We hope that the synopsis and the atlas by allowing a precise localization of white matter lesions and associated symptoms will facilitate future work on the functional correlates of human neural networks as derived from the study of clinical populations. Our goal is to stimulate clinicians to develop a critical approach to clinico-anatomical correlative studies and broaden their view of clinical anatomy beyond the cortical surface in order to encompass the dysfunction related to connecting pathways.     

Game theoretical mapping of white matter contributions to visuospatial attention in stroke patients with hemineglect

White matter bundles linking gray matter nodes are key anatomical players to fully characterize associations between brain systems and cognitive functions. Here we used a multivariate lesion inference approach grounded in coalitional game theory (multiperturbation Shapley value analysis, MSA) to infer causal contributions of white matter bundles to visuospatial orienting of attention. Our work is based on the characterization of the lesion patterns of 25 right hemisphere stroke patients and the causal analysis of their impact on three neuropsychological tasks: line bisection, letter cancellation, and bells cancellation. We report that, out of the 11 white matter bundles included in our MSA coalitions, the optic radiations, the inferior fronto‐occipital fasciculus and the anterior cingulum were the only tracts to display task‐invariant contributions (positive, positive, and negative, respectively) to the tasks. We also report task‐dependent influences for the branches of the superior longitudinal fasciculus and the posterior cingulum. By extending prior findings to white matter tracts linking key gray matter nodes, we further characterize from a network perspective the anatomical basis of visual and attentional orienting processes. The knowledge about interactions patterns mediated by white matter tracts linking cortical nodes of attention orienting networks, consolidated by further studies, may help develop and customize brain stimulation approaches for the rehabilitation of visuospatial neglect.     

Approximation to pain‐signaling network in humans by means of migraine

Nociceptive signals are processed within a pain‐related network of the brain. Migraine is a rather specific model to gain insight into this system. Brain networks may be described by white matter tracts interconnecting functionally defined gray matter regions. Here, we present an overview of the migraine‐related pain network revealed by this strategy. Based on diffusion tensor imaging data from subjects in the Human Connectome Project (HCP) database, we used a global tractography approach to reconstruct white matter tracts connecting brain regions that are known to be involved in migraine‐related pain signaling. This network includes an ascending nociceptive pathway, a descending modulatory pathway, a cortical processing system, and a connection between pain‐processing and modulatory areas. The insular cortex emerged as the central interface of this network. Direct connections to visual and auditory cortical association fields suggest a potential neural basis of phono‐ or photophobia and aura phenomena. The intra‐axonal volume (V_intra) as a measure of fiber integrity based on diffusion microstructure was extracted using an innovative supervised machine learning approach in form of a Bayesian estimator. Self‐reported pain levels of HCP subjects were positively correlated with tract integrity in subcortical tracts. No correlation with pain was found for the cortical processing systems.     

Test–retest reproducibility of white matter parcellation using diffusion MRI tractography fiber clustering

There are two popular approaches for automated white matter parcellation using diffusion MRI tractography, including fiber clustering strategies that group white matter fibers according to their geometric trajectories and cortical‐parcellation‐based strategies that focus on the structural connectivity among different brain regions of interest. While multiple studies have assessed test–retest reproducibility of automated white matter parcellations using cortical‐parcellation‐based strategies, there are no existing studies of test–retest reproducibility of fiber clustering parcellation. In this work, we perform what we believe is the first study of fiber clustering white matter parcellation test–retest reproducibility. The assessment is performed on three test–retest diffusion MRI datasets including a total of 255 subjects across genders, a broad age range (5–82 years), health conditions (autism, Parkinson's disease and healthy subjects), and imaging acquisition protocols (three different sites). A comprehensive evaluation is conducted for a fiber clustering method that leverages an anatomically curated fiber clustering white matter atlas, with comparison to a popular cortical‐parcellation‐based method. The two methods are compared for the two main white matter parcellation applications of dividing the entire white matter into parcels (i.e., whole brain white matter parcellation) and identifying particular anatomical fiber tracts (i.e., anatomical fiber tract parcellation). Test–retest reproducibility is measured using both geometric and diffusion features, including volumetric overlap (wDice) and relative difference of fractional anisotropy. Our experimental results in general indicate that the fiber clustering method produced more reproducible white matter parcellations than the cortical‐parcellation‐based method.     

Grey matter pathology in multiple sclerosis

Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions are known to occur in grey matter. Recent immunohistochemical studies have demonstrated extensive grey matter demyelination in chronic MS. The most common lesion type consists of purely cortical lesions extending inward from the surface of the brain, this lesion subgroup is grossly underestimated by standard histochemical myelin staining methods. Some MS patients have subpial demyelination in all cortical areas of the brain; this pattern has been termed 'general cortical subpial demyelination'. Extensive cortical demyelination is associated with the progressive phases of disease, as less cortical demyelination has been detected in relapsing-remitting MS. The pathology of grey matter lesions differs from that of white matter lesions; grey matter lesions are less inflammatory, with less macrophage and lymphocyte infiltration. In purely cortical lesions there is no significant increase in lymphocytes compared with non-demyelinated adjacent cortical areas in MS patients or cerebral cortex in control patients. Significant axonal transection and neuronal loss have been demonstrated in grey matter MS lesions. Current magnetic resonance imaging (MRI) methods are not sensitive for purely cortical MS lesions. The clinical significance of cortical MS lesions may not be characterised until more sensitive MRI methods are developed.     

Morphological spectrum, distribution and clinical correlation of white matter lesions in AIDS brains

This paper analyses the histopathological characteristics and the topographical distribution of 'pure' HIV-associated white matter lesions of the brain in 18 AIDS patients at autopsy; it includes a time-controlled correlation of neuropathology to clinical staging of the AIDS dementia complex. Three distinct lesion types can be delineated: 1 Vacuolar myelin damage (n = 15) in the hemispheric and interhemispheric white matter, in projection fibre tracts, and in intracerebral segments of cranial nerves III, VII, and VIII; 2 Angiocentric foci (n = 14), disseminated randomly in the white matter; 3 HIV leukoencephalopathy (n = 14), as previously defined, seen predominantly in the hemispheric white matter. As a sole lesion type, HIV leukoencephalopathy is found in two cases, while vacuolar myelin damage and angiocentric foci always occur in combination with one or both other types of pathology. Patients with advanced AIDS-dementia complex consistently show severe and combined white matter pathologies at autopsy. We conclude that, in addition to the previously defined features of diffuse HIV leukoencephalopathy, vacuolar myelin damage and angiocentric foci are significant and frequent components of white matter pathology in AIDS autopsies. This reflects the multitude of pathogenetic factors which co-operate in damaging the brain in AIDS. The advanced AIDS dementia complex correlates with the combined and severe white matter lesions.     

Coordinated brain development: exploring the synchrony between changes in grey and white matter during childhood maturation

Brain development during childhood and early adolescence is characterized by global changes in brain architecture. Neuroimaging studies have revealed overall decreases in cortical thickness (CT) and increases in fractional anisotropy (FA). Furthermore, previous studies have shown that certain cortical regions display coordinated growth during development. However, there is significant heterogeneity in the timing and speed of these developmental transformations, and it is still unclear whether white and grey matter changes are co-localized. In this multimodal neuroimaging study, we investigated the relationship between grey and white matter developmental changes and asynchronous maturation within brain regions in 249 normally developing children between the ages 7–14. We used structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to analyze CT and FA, respectively, as well as their covariance across development. Consistent with previous studies, we observed overall cortical thinning with age, which was accompanied by increased FA. We then compared the coordinated development of grey and white matter as indexed by covariance measures. Covariance between grey matter regions and the microstructure of white matter tracts connecting those regions were highly similar, suggesting that coordinated changes in the cortex were mirrored by coordinated changes in their respective tracts. Examining within-brain divergent trajectories, we found significant structural decoupling (decreased covariance) between several brain regions and tracts in the 9- to 11-year-old group, particularly involving the forceps minor and the regions that it connects to. We argue that this decoupling could reflect a developmental pattern within the prefrontal region in 9- and 11-year-old children, possibly related to the significant changes in cognitive control observed at this age.     

Human immunodeficiency virus‐related decreases in corpus callosal integrity and corresponding increases in functional connectivity

People living with human immunodeficiency virus (PLWH) often have neurocognitive impairment. However, findings on HIV‐related differences in brain network function underlying these impairments are inconsistent. One principle frequently absent from these reports is that brain function is largely emergent from brain structure. PLWH commonly have degraded white matter; we hypothesized that functional communities connected by degraded white matter tracts would show abnormal functional connectivity. We measured white matter integrity in 69 PLWH and 67 controls using fractional anisotropy (FA) in 24 intracerebral white matter tracts. Then, among tracts with degraded FA, we identified gray matter regions connected to these tracts and measured their functional connectivity during rest. Finally, we identified cognitive impairment related to these structural and functional connectivity systems. We found HIV‐related decreased FA in the corpus callosum body (CCb), which coordinates activity between the left and right hemispheres, and corresponding increases in functional connectivity. Finally, we found that individuals with impaired cognitive functioning have lower CCb FA and higher CCb functional connectivity. This result clarifies the functional relevance of the corpus callosum in HIV and provides a framework in which abnormal brain function can be understood in the context of abnormal brain structure, which may both contribute to cognitive impairment.     

Disconnection's renaissance takes shape: Formal incorporation in group-level lesion studies

Group-level voxelwise statistical analyses of lesion-deficit relationships have been used to implicate brain structures critical for specific aspects of human cognition and behavior. Current approaches fail to account for the role of fiber tract disruptions in causing deficit, and confound cortical damage with damage to fibers of passage. Here, we develop a framework, Generalized Lesion-Symptom Mapping (GLSM), to integrate fiber tract information from DTI-based tractographic atlases in tractwise and voxelwise lesion-deficit analyses. First, we used the geniculo-calcarine system as a validation testbed. Using logistic regressions we predicted right homonymous visual field deficits in 149 subjects with focal brain damage based on lesion location, with and without incorporating fiber tract information. A probabilistic fiber tract atlas [Wakana S, Jiang H, Nagae-Poetscher LM, Van Zijl PC, Mori S. Fiber tract-based atlas of human white matter anatomy. Radiology 2004;230:77-87] coregistered to our reference brain was used to estimate disconnection to the optic radiations and adjacent fiber tracts. When tract information was not incorporated, lesions in multiple sectors of the temporal lobe were associated with visual field defects. When the optic radiations were incorporated, this artifactual association was eliminated and the calcarine cortex was correctly isolated. Among the incorporated tracts, only the optic radiations significantly predicted visual field defects. Second, we applied the approach to impairments of higher visuoperceptual functions in 111 subjects who were administered the Hooper Visual Organization Test. We included all six association fiber tracts available in the atlas, plus the optic radiations. Tract inclusion narrowed the cortical sectors associated with impaired performance in a manner consistent with recent fMRI findings. The left cingulum and inferior longitudinal fasciculus, significantly predicted impairments. The results demonstrate the viability, validity and value of incorporating fiber tract information in lesion-deficit analyses. The enhanced analysis framework opens a new avenue for studying neural systems, with the potential to facilitate identification of both cortical sectors and fiber tracts critical for cognitive functioning.     

Brain structure in prenatal stroke: quantitative magnetic resonance imaging (MRI) analysis

Neonatal stroke outcome studies demonstrate variable findings of either relatively spared intellectual function or persistent impairments. Volumetric measurement of the brain can provide more precise data on lesion-cognition outcomes. We studied 7 children with unilateral focal lesions from prenatal stroke. Whole-brain magnetic resonance imaging scans were analyzed to produce volumes of cortical gray matter, total white matter, cerebrospinal fluid, lesion, and lesion constricted fluid, and we ascertained the relationship of morphometric variables to intellectual and clinical outcome. Children with cystic encephalomalacia plus atrophy had poorer outcomes than children with atrophy or gliosis alone. These children also demonstrated the largest lesion size, smallest gray matter volume, and greatest proportion of hyperintense white matter in the affected hemisphere. Findings suggest that the type and size of the lesion, in addition to the integrity of white matter and residual cortex, may be better predictors of intellectual functioning than either of these indices alone.