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Previous studies have linked global burden of age-related white matter hyperintensities (WMHs) to cognitive impairment. We aimed to determine how WMHs in individual white matter connections relate to measures of cognitive function relative to measures of connectivity which do not take WMHs into account. Brain connectivity and WMH-related disconnectivity were derived from 3714 participants of the population-based Rotterdam Study. Connectivity was represented by the structural connectome, which was defined using diffusion tensor data, whereas the disconnectome represented disconnectivity due to WMH. The relationship between (dis)connectivity and cognitive measures was estimated using linear regression. We found that lower disconnectivity and higher connectivity corresponded to better cognitive function. There were many more significant associations with cognitive function in the disconnectome than in the connectome. Most connectome associations attenuated when disconnection was included in the model. WMH-related disconnectivity was especially related to worse executive functioning. Better cognitive speed corresponded to higher connectivity in specific connections independent of WMH presence. We conclude that WMH-related disconnectivity explains more variation in cognitive function than does connectivity. Efficient wiring in specific connections is important to information processing speed independent of WMH presence. •Higher structural brain connectivity is associated with better cognitive function.•White matter lesion-related disconnectivity is associated with worse cognition.•The disconnectome has many more associations with cognition than the connectome.•Lesions explain most location-specific associations of connectivity with cognition.

Motricity is the most commonly affected ability after a stroke. While many clinical studies attempt to predict motor symptoms at different chronic time points after a stroke, longitudinal acute-to-chronic studies remain scarce. Taking advantage of recent advances in mapping brain disconnections, we predict motor outcomes in 62 patients assessed longitudinally two weeks, three months, and one year after their stroke. Results indicate that brain disconnection patterns accurately predict motor impairments. However, disconnection patterns leading to impairment differ between the three-time points and between left and right motor impairments. These results were cross-validated using resampling techniques. In sum, we demonstrated that while some neuroplasticity mechanisms exist changing the structure–function relationship, disconnection patterns prevail when predicting motor impairment at different time points after stroke.

•Leftward PA improved reaching with contralesional hand in ipsilesional space.•Post-treatment reorganization showed LH asymmetry in parietal and motor areas.•LH network segregation and intra-hemispheric dispersion increased post-treatment.•Inter-hemispheric connectivity decreased, suggesting rehab-related improvements.•Dynamic entropy linked to direct, static changes tied to indirect disconnections. Prismatic adaptation (PA) is a visuomotor procedure using prismatic lenses to induce a temporary shift of visuomotor coordinates. It relies on a brain network which includes the anterior and posterior cerebellum and parietal regions, such as the intraparietal sulcus and the posterior parietal cortex. Lesions in these parietal areas are often associated with the presence of Optic Ataxia (OA), a disorder of visually guided reaching movements. Studies report contrasting results concerning the effects of PA in OA patients, whereby some fail in adapting to prisms and others show preserved adaptation. Here, we describe behavioural and neurofunctional changes in a left hemisphere stroke patient with OA who completed ten sessions of leftward PA as part of her cognitive rehabilitation. After the treatment, reaching improved with the contralesional hand in the ipsilesional hemifield. Moreover, resting-state fMRI measures of network dispersion applied to low-dimensional functional gradients revealed marked hemispheric asymmetry, with greater reorganization in the left hemisphere involving an increase in network segregation in left attentional and somatosensory networks, alongside higher intra-hemispheric network dispersion. Conversely, inter-hemispheric dispersion decreased, particularly between attentive and somatosensory-motor networks. Dynamic edge-centric analysis showed reduced entropy in the visual network and increased entropy in the dorsal attention and control networks. These entropy shifts, reflective of nodal diversity in functional co-fluctuations, correlated with direct structural disconnections. Conversely, static gradient-based reorganization was significantly associated with indirect structural disconnection profiles. To our knowledge, this is the first study exploring changes at the behavioural and neurofunctional level in an OA patient following repetitive sessions of PA, highlighting complementary contributions of static and dynamic functional neuroimaging features in capturing possible mechanisms of functional reorganization. [Display omitted]

Structural disconnectome analyses have provided valuable insights into how a stroke lesion results in widespread network disturbances and how these relate to deficits, recovery patterns, and outcomes. Previous analyses have primarily focused on patients with relatively mild to moderate deficits. However, outcomes vary among survivors of severe strokes, and the mechanisms of recovery remain poorly understood. This study assesses the association between lesion‐induced network disconnection and outcome after severe stroke. Thirty‐eight ischaemic stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow‐up. Lesion information was integrated with normative connectome data to infer individual disconnectome profiles on a localized regional and region‐to‐region pathway level. Ordinal logistic regressions were computed to link disconnectome information to the modified Rankin Scale after 3–6 months. Disconnections of ipsilesional frontal, parietal, and temporal cortical brain areas were significantly associated with a worse motor outcome after a severe stroke, adjusted for the initial deficit, lesion volume, and age. The analysis of the underlying pathways mediating this association revealed location‐specific results: For frontal, prefrontal, and temporal brain areas, the association was primarily driven by relatively sparse intrahemispheric disconnections. In contrast, the ipsilesional primary motor cortex, the dorsal premotor cortex, and various parietal brain regions showed a remarkable involvement of either frontoparietal intrahemispheric or additionally interhemispheric disconnections. These results indicate that localized disconnection of multiple regions embedded in the structural frontoparietal network correlates with worse outcomes after severe stroke. Specifically, primary motor and parietal cortices might gain particular importance as they structurally link frontoparietal networks of both hemispheres. These data shed novel light on the significance of distinct brain networks for recovery after a severe stroke. Network disconnection was analyzed in 38 severely impaired acute stroke patients using lesion masks and normative connectome data. Logistic regression models were computed to associate region‐ and pathway‐related disconnections with the outcome. Localized structural frontoparietal network disconnections were significantly linked to a worse outcome after stroke.

•Examination of the effect of disconnectivity following stroke on multiplication.•WM between AG and superior temporal areas was associated with worse multiplication.•Disconnections in the arithmetic fact retrieval network led to worse multiplication.•White matter disconnectivity needs more examination in numerical cognition research. Arithmetic fact retrieval has been suggested to recruit a left-lateralized network comprising perisylvian language areas, parietal areas such as the angular gyrus (AG), and non-neocortical structures such as the hippocampus. However, the underlying white matter connectivity of these areas has not been evaluated systematically so far. Using simple multiplication problems, we evaluated how disconnections in parietal brain areas affected arithmetic fact retrieval following stroke. We derived disconnectivity measures by jointly considering data from n = 73 patients with acute unilateral lesions in either hemisphere and a white-matter tractography atlas (HCP-842) using the Lesion Quantification Toolbox (LQT). Whole-brain voxel-based analysis indicated a left-hemispheric cluster of white matter fibers connecting the AG and superior temporal areas to be associated with a fact retrieval deficit. Subsequent analyses of direct gray-to-gray matter disconnections revealed that disconnections of additional left-hemispheric areas (e.g., between the superior temporal gyrus and parietal areas) were significantly associated with the observed fact retrieval deficit. Results imply that disconnections of parietal areas (i.e., the AG) with language-related areas (i.e., superior and middle temporal gyri) seem specifically detrimental to arithmetic fact retrieval. This suggests that arithmetic fact retrieval recruits a widespread left-hemispheric network and emphasizes the relevance of white matter connectivity for number processing.

The development of new approaches indirectly measuring the structural disconnectome has recently led to an increase in studies investigating pairwise structural disconnections following brain damage. Previous studies jointly analyzed patients with left hemispheric and patients with right hemispheric lesions when investigating a behavior of interest. An alternative approach would be to perform analyses separated by hemisphere, which has been applied in only a minority of studies to date. The present simulation study investigated whether joint or separate analyses (or both equally) are appropriate to reveal the ground truth disconnections. In fact, both approaches resulted in very different patterns of disconnection. In contrast to analyses separated by hemisphere, joint analyses introduced a bias to the disadvantage of intra‐hemispheric disconnections. Intra‐hemispheric disconnections were statistically underpowered in the joint analysis and thus surpassed the significance threshold with more difficulty compared to inter‐hemispheric disconnections. This statistical imbalance was also shown by a greater number of significant inter‐hemispheric than significant intra‐hemispheric disconnections. This bias from joint analyses is based on mechanisms similar to those underlying the “partial injury problem.” We therefore conclude that pairwise structural disconnections in patients with unilateral left hemispheric and with unilateral right hemispheric lesions exhibiting a specific behavior (or disorder) of interest should be studied separately by hemisphere rather than in a joint analysis. We simulated pairwise structural disconnections and compared two approaches of analyzing brain damage: unilateral lesions from both hemispheres together or separated by hemisphere. In contrast to the separate analyses, the joint analysis led to biased results: intra‐hemispheric disconnections were statistically underpowered and therefore missed more often compared to inter‐hemispheric disconnections.

Mounting evidences have shown that progression of white matter hyperintensities (WMHs) with vascular origin might cause cognitive dysfunction symptoms through their effects on brain networks. However, the vulnerability of specific neural connection related to WMHs in Alzheimer's disease (AD) still remains unclear. In this study, we established an atlas‐guided computational framework based on brain disconnectome to assess the spatial–temporal patterns of WMH‐related structural disconnectivity within a longitudinal investigation. Alzheimer's Disease Neuroimaging Initiative (ADNI) database was adopted with 91, 90 and 44 subjects including in cognitive normal aging, stable and progressive mild cognitive impairment (MCI), respectively. The parcel‐wise disconnectome was computed by indirect mapping of individual WMHs onto population‐averaged tractography atlas. By performing chi‐square test, we discovered a spatial–temporal pattern of brain disconnectome along AD evolution. When applied such pattern as predictor, our models achieved highest mean accuracy of 0.82, mean sensitivity of 0.86, mean specificity of 0.82 and mean area under the receiver operating characteristic curve (AUC) of 0.91 for predicting conversion from MCI to dementia, which outperformed methods utilizing lesion volume as predictors. Our analysis suggests that brain WMH‐related structural disconnectome contributes to AD evolution mainly through attacking connections between: (1) parahippocampal gyrus and superior frontal gyrus, orbital gyrus, and lateral occipital cortex; and (2) hippocampus and cingulate gyrus, which are also vulnerable to Aβ and tau confirmed by other researches. All the results further indicate that a synergistic relationship exists between multiple contributors of AD as they attack similar brain connectivity at the prodromal stage of disease. We proposed an atlas‐guided computation framework to detect distinctive spatial‐temporal progressive WMH‐related brain disconnectome on the continuum of AD. We located the progressive disconnectome patterns within structural connectivity associated with parahippocampal gyrus and hippocampus. By developing prediction models, we further showed that brain disconnectome can be used as powerful predictor for conversion from MCI to dementia.

In rare cases, cortical infarcts lead to vertigo. We evaluated structural and functional disconnection in patients with acute vertigo due to unilateral ischemic cortical infarcts compared to infarcts without vertigo in a similar location with a focus on the connectivity of the vestibular cortex, i.e., the parieto-opercular (retro-)insular cortex (PIVC). Using lesion maps from the ten published case reports, we computed lesion–functional connectivity networks in a set of healthy individuals from the human connectome project. The probability of lesion disconnection was evaluated by white matter disconnectome mapping. In all ten cases with rotational vertigo, disconnections of interhemispheric connections via the corpus callosum were present but were spared in lesions of the PIVC without vertigo. Further, the arcuate fascicle was affected in 90% of the lesions that led to vertigo and spared in lesions that did not lead to vertigo. The lesion–functional connectivity network included vestibulo-cerebellar hubs, the vestibular nuclei, the PIVC, the retro-insular and posterior insular cortex, the multisensory vestibular ventral intraparietal area, motion-sensitive areas (temporal area MT+ and cingulate visual sulcus) as well as hubs for ocular motor control (lateral intraparietal area, cingulate and frontal eye fields). However, this was not sufficient to differentiate between lesions with and without vertigo. Disruption of interhemispheric connections of both PIVC via the corpus callosum and intra-hemispheric disconnection via the arcuate fascicle might be the distinguishing factor between vestibular cortical network lesions that manifest with vertigo compared to those without vertigo.

White matter (WM) tracts shape the brain's dynamical activity and their damage (e.g., white matter hyperintensities, WMH) yields relevant functional alterations, ultimately leading to cognitive symptoms. The mechanisms linking the structural damage caused by WMH to the arising alterations of brain dynamics is currently unknown. To estimate the impact of WMH on brain dynamics, we combine neural‐mass whole‐brain modeling with a virtual‐lesioning (disconnectome) approach informed by empirical data. We account for the heterogeneous effects of WMH either on inter‐regional communication (i.e., edges) or on dynamics (i.e., nodes) and create models of their local versus global, and edge versus nodal effects using a large fMRI dataset comprising 188 non‐demented individuals (120 cognitively normal, 68 with mild cognitive impairment) with varying degrees of WMH. We show that, although WMH mainly determine local damage to specific WM tracts, these lesions yield relevant global dynamical effects by reducing the overall synchronization of the brain through a reduction of global coupling. Alterations of local nodal dynamics through disconnections are less relevant and present only at later stages of WMH damage. Exploratory analyses suggest that education might play a beneficial role in counteracting the reduction in global coupling associated with WMH. This study provides generative models linking the structural damage caused by WMH to alterations in brain dynamics. These models might be used to evaluate the detrimental effects of WMH on brain dynamics in a subject‐specific manner. Furthermore, it validates the use of whole‐brain modeling for hypothesis‐testing of structure–function relationships in diseased states characterized by empirical disconnections. By combining whole‐brain neural mass modeling with a virtual‐lesioning approach informed by empirical WMH lesion masks, we provide evidence that WMH induce changes in brain dynamics by reducing the global coupling of the brain network. An effect is also seen on nodal intrinsic dynamics in later stages of damage. Education might play a protective role in counterbalancing the WMH‐induced reduction in global coupling.

Limb apraxia is a higher-order motor disorder often occurring post-stroke, which affects skilled actions. It is assessed through tasks involving gesture production or pantomime, recognition, meaningless gesture imitation, complex figure drawing, single and multi-object use. A two-system model for the organisation of actions hypothesizes distinct pathways mediating praxis deficits via conceptual, ‘indirect’, and perceptual ‘direct’ routes to action. Traditional lesion- symptom mapping techniques have failed to identify these distinct routes. We assessed 29 left hemisphere stroke patients to investigate white matter disconnections on deficits of praxis tasks from the Birmingham Cognitive Screening. White matter disconnection maps derived from patients’ structural T1 lesions were created using a diffusion-weighted healthy participant dataset acquired from the human connectome project (HCP). Initial group-level regression analyses revealed significant disconnection between occipital lobes via the splenium of the corpus callosum and involvement of the inferior longitudinal fasciculus in meaningless gesture imitation deficits. There was a trend of left fornix disconnection in gesture production deficits. Further, voxel-wise Bayesian Crawford single-case analyses performed on two patients with the most severe meaningless gesture imitation and meaningful gesture production deficits, respectively, confirmed distinct posterior interhemispheric disconnection, for the former, and disconnections between temporal and frontal areas via the fornix, rostrum of the corpus callosum and anterior cingulum, for the latter. Our results suggest distinct pathways associated with perceptual and conceptual deficits akin to ‘direct’ and ‘indirect’ action routes, with some patients displaying both. Larger studies are needed to validate and elaborate on these findings, advancing our understanding of limb apraxia.