Age-related differences in structural and resting-state functional brain network organization across the adult lifespan: A cross-sectional study.

We investigated age-related trends in the topology and hierarchical organization of brain structural and functional networks using diffusion-weighted imaging and resting-state fMRI data from a large cohort of healthy aging adults. At the cross-modal level, we explored age-related patterns in the RC involvement of different functional subsystems using a high-resolution functional parcellation. We further assessed age-related differences in the structure-function coupling as well as the network vulnerability to damage to rich club connectivity. Regardless of age, the structural and functional brain networks exhibited a rich club organization and small-world topology. In older individuals, we observed reduced integration and segregation within the frontal-occipital regions and the cerebellum along the brain's medial axis. Additionally, functional brain networks displayed decreased integration and increased segregation in the prefrontal, centrotemporal, and occipital regions, and the cerebellum. In older subjects, structural networks also exhibited decreased within-network and increased between-network RC connectivity. Furthermore, both within-network and between-network RC connectivity decreased in functional networks with age. An age-related decline in structure-function coupling was observed within sensory-motor, cognitive, and subcortical networks. The structural network exhibited greater vulnerability to damage to RC connectivity within the language-auditory, visual, and subcortical networks. Similarly, for functional networks, increased vulnerability was observed with damage to RC connectivity in the cerebellum, language-auditory, and sensory-motor networks. Overall, the network vulnerability decreased significantly in subjects older than 70 in both networks. Our findings underscore significant age-related differences in both brain functional and structural RC connectivity, with distinct patterns observed across the adult lifespan.

Prism adaptation therapy in spatial neglect: The importance of connectional anatomy.

The meta-analysis conducted by Székely et al. described the lack of beneficial effect of prism adaptation in neglect patients. The authors concluded that the results did "not support the routine use of prism adaptation as a therapy for spatial neglect". However, a possible nuance to this conclusion could be that the response (or lack thereof) of neglect patients to prism adaptation may actually depend on the connectional anatomy of their lesion. We develop this idea in our commentary, in order to offer a more balanced perspective on the implications of the findings obtained by Székely et al.

Dual-task versus single-task gait rehabilitation after stroke: the protocol of the cognitive-motor synergy multicenter, randomized, controlled superiority trial (SYNCOMOT).

BACKGROUND: Gait disorders and cognitive impairments are prime causes of disability and institutionalization after stroke. We hypothesized that relative to single-task gait rehabilitation (ST GR), cognitive-motor dual-task (DT) GR initiated at the subacute stage would be associated with greater improvements in ST and DT gait, balance, and cognitive performance, personal autonomy, disability, and quality of life in the short, medium and long terms after stroke. METHODS: This multicenter (n=12), two-arm, parallel-group, randomized (1:1), controlled clinical study is a superiority trial. With p<0.05, a power of 80%, and an expected loss to follow-up rate of 10%, the inclusion of 300 patients will be required to evidence a 0.1-m.s-1 gain in gait speed. Trial will include adult patients (18-90 years) in the subacute phase (0 to 6 months after a hemispheric stroke) and who are able to walk for 10 m (with or without a technical aid). Registered physiotherapists will deliver a standardized GR program (30 min three times a week, for 4 weeks). The GR program will comprise various DTs (phasic, executive function, praxis, memory, and spatial cognition tasks during gait) in the DT (experimental) group and gait exercises only in the ST (control) group. The primary outcome measure is gait speed 6 months after inclusion. The secondary outcomes are post-stroke impairments (National Institutes of Health Stroke Scale and the motor part of the Fugl-Meyer Assessment of the lower extremity), gait speed (10-m walking test), mobility and dynamic balance (timed up-and-go test), ST and DT cognitive function (the French adaptation of the harmonization standards neuropsychological battery, and eight cognitive-motor DTs), personal autonomy (functional independence measure), restrictions in participation (structured interview and the modified Rankin score), and health-related quality of life (on a visual analog scale). These variables will be assessed immediately after the end of the protocol (probing the short-term effect), 1 month thereafter (the medium-term effect), and 5 months thereafter (the long-term effect). DISCUSSION: The main study limitation is the open design. The trial will focus on a new GR program applicable at various stages after stroke and during neurological disease. TRIAL REGISTRATION: NCT03009773 . Registered on January 4, 2017.

Same, Same but Different? A Multi-Method Review of the Processes Underlying Executive Control.

Attention, working memory, and executive control are commonly considered distinct cognitive functions with important reciprocal interactions. Yet, longstanding evidence from lesion studies has demonstrated both overlap and dissociation in their behavioural expression and anatomical underpinnings, suggesting that a lower dimensional framework could be employed to further identify processes supporting goal-directed behaviour. Here, we describe the anatomical and functional correspondence between attention, working memory, and executive control by providing an overview of cognitive models, as well as recent data from lesion studies, invasive and non-invasive multimodal neuroimaging and brain stimulation. We emphasize the benefits of considering converging evidence from multiple methodologies centred on the identification of brain mechanisms supporting goal-driven behaviour. We propose that expanding on this approach should enable the construction of a comprehensive anatomo-functional framework with testable new hypotheses, and aid clinical neuroscience to intervene on impairments of executive functions.

Poststroke action slowing: Motor and attentional impairments and their imaging determinants. Evidence from lesion-symptom mapping, disconnection and fMRI activation studies.

BACKGROUND AND OBJECTIVES: Although action slowing is the main cognitive impairment in stroke survivors, its mechanisms and determinants are still poorly understood. The objectives of the present study were to determine the mechanisms of post-stroke action slowing (using validated, highly specific simple reaction time (SRT) and tapping tests) and identify its imaging determinants (using multivariate lesion-symptom mapping (mLSM)). METHODS: Action speed in the GRECogVASC cohort was assessed using finger tapping and SRT tests performed with both hands and analyzed using previously validated indices. Imaging determinants were identified using validated mLSM analyses and disconnection analysis and compared to those of an fMRI activation meta-analytic database. RESULTS: Both the tapping time and SRT were 10.7% slower for the 394 patients (p = 0.0001) than for the 786 controls, without a group × test interaction (p = 0.2). The intra-individual distribution curve was characterized by a rightward shift with an unaltered attentional peak. The mLSM analyses showed tapping to be associated with lesions in the frontostriatal tract (p = 0.0007). The SRT was associated with lesions in the frontostriatal tract (p = 0.04) and the orbital part of F3 (p = 0.0001). The SRT-tapping index was associated with lesions in the orbital part of F3 (p = 0.0001). All lesions were located in the right hemisphere only and were responsible for the disconnection of several structures involved in motor preparation, initiation, and speed. A comparison with fMRI activation meta-analytic data highlighted mostly the same regions, including the orbital part of F3, the ventral and dorsal parts of F1, and the premotor and cingulate regions in the right hemisphere. DISCUSSION: Our results confirm the marked impairment of action speed in stroke and show that the primary mechanism is motor slowing and that it is related to lesions in the right frontostriatal tract. A deficit in sustained alertness accounted for action slowing in the subgroup with lesions in the right orbital part of F3. Our SRT and mLSM results were in accordance with the fMRI activation data. Thus, stroke induces slowing in the broad network associated with SRT tasks by disrupting the frontostriatal tract and, to a lesser extent, other sites involved in attention.

Right-side spatial neglect and white matter disconnection after left-hemisphere strokes.

Spatial neglect usually concerns left-sided events after right-hemisphere damage. Its anatomical correlates are debated, with evidence suggesting an important role for fronto-parietal white matter disconnections in the right hemisphere. Here, we describe the less frequent occurrence of neglect for right-sided events, observed in three right-handed patients after a focal stroke in the left hemisphere. Patients were tested 1 month and 3 months after stroke. They performed a standardized paper-and-pencil neglect battery and underwent brain MRI with both structural and diffusion tensor (DT) sequences, in order to assess both grey matter and white matter tracts metrics. Lesions were manually reconstructed for each patient. Patients presented signs of mild right-sided neglect during visual search and line bisection. One patient also showed pathological performance in everyday life. Structural MRI demonstrated left parietal strokes in two patients, in the region extending from the postcentral gyrus to the temporo-parietal junction. One of these two patients also had had a previous occipital stroke. The remaining patient had a left frontal stroke, affecting the precentral, the postcentral gyri and the basal ganglia. DT MRI tractography showed disconnections in the fronto-parietal regions, concerning principally the superior longitudinal fasciculus (SLF). These results suggest an important role for left SLF disconnection in right-side neglect, which complements analogous evidence for right SLF disconnection in left-side neglect.

Quantitative Assessment of Motor Neglect.

Background and Purpose: We used differential actigraphy as a novel, objective method to quantify motor neglect (a clinical condition whereby patients mimic hemiplegia even in the absence of sensorimotor deficits), whose diagnosis is at present highly subjective, based on the clinical observation of patients' spontaneous motor behavior. Methods: Patients wear wristwatch-like accelerometers, which record spontaneous motor activity of their upper limbs during 24 hours. Asymmetries of motor behavior are then automatically computed offline. On the basis of normal participants' performance, we calculated cutoff scores of left/right motor asymmetry. Results: Differential actigraphy showed contralesional motor neglect in 9 of 35 patients with unilateral strokes, consistent with clinical assessment. An additional patient with clinical signs of motor neglect obtained a borderline asymmetry score. Lesion location in a subgroup of 25 patients was highly variable, suggesting that motor neglect is a heterogenous condition. Conclusions: Differential actigraphy provides an ecological measure of spontaneous motor behavior, and can assess upper limb motricity in an objective and quantitative manner. It thus offers a convenient, cost-effective, and relatively automatized procedure for following-up motor behavior in neurological patients and to assess the effects of rehabilitation.

"I do not feel my hand where I see it": causal mapping of visuo-proprioceptive integration network in a surgical glioma patient.

A recent tasked-based fMRI study unveiled a network of areas implicated in the process of visuo-proprioceptive integration of the right hand. In this study, we report a case of a patient operated on in awake conditions for a glioblastoma of the left superior parietal lobule. When stimulating a white matter site in the anterior wall of the cavity, the patient spontaneously reported a discrepancy between the visual and proprioceptive perceptions of her right hand. Using several multimodal approaches (axono-cortical evoked potentials, tractography, resting-state functional connectivity), we demonstrated converging support for the hypothesis that tumor-induced plasticity redistributed the left-lateralized network of right-hand visuo-proprioceptive integration towards its right-lateralized homolog.

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.

Perturbation-driven paradoxical facilitation of visuo-spatial function: Revisiting the 'Sprague effect'.

The 'Sprague Effect' described in the seminal paper of James Sprague (Science 153:1544-1547, 1966a) is an unexpected paradoxical effect in which a second brain lesion reversed functional deficits induced by an earlier lesion. It was observed initially in the cat where severe and permanent contralateral visually guided attentional deficits generated by the ablation of large areas of the visual cortex were reversed by the subsequent removal of the superior colliculus (SC) opposite to the cortical lesion or by the splitting of the collicular commissure. Physiologically, this effect has been explained in several ways-most notably by the reduction of the functional inhibition of the ipsilateral SC by the contralateral SC, and the restoration of normal interactions between cortical and midbrain structures after ablation. In the present review, we aim at reappraising the 'Sprague Effect' by critically analyzing studies that have been conducted in the feline and human brain. Moreover, we assess applications of the 'Sprague Effect' in the rehabilitation of visually guided attentional impairments by using non-invasive therapeutic approaches such as transcranial magnetic stimulation (TMS) and transcranial direct-current stimulation (tDCS). We also review theoretical models of the effect that emphasize the inhibition and balancing between the two hemispheres and show implications for lesion inference approaches. Last, we critically review whether the resulting inter-hemispheric rivalry theories lead toward an efficient rehabilitation of stroke in humans. We conclude by emphasizing key challenges in the field of 'Sprague Effect' applications in order to design better therapies for brain-damaged patients.

Revisiting 'brain modes' in a new computational era: approaches for the characterization of brain-behavioural associations.

The study of brain-function relationships is undergoing a conceptual and methodological transformation due to the emergence of network neuroscience and the development of multivariate methods for lesion-deficit inferences. Anticipating this process, in 1998 Godefroy and co-workers conceptualized the potential of four elementary typologies of brain-behaviour relationships named 'brain modes' (unicity, equivalence, association, summation) as building blocks able to describe the association between intact or lesioned brain regions and cognitive processes or neurological deficits. In the light of new multivariate lesion inference and network approaches, we critically revisit and update the original theoretical notion of brain modes, and provide real-life clinical examples that support their existence. To improve the characterization of elementary units of brain-behavioural relationships further, we extend such conceptualization with a fifth brain mode (mutual inhibition/masking summation). We critically assess the ability of these five brain modes to account for any type of brain-function relationship, and discuss past versus future contributions in redefining the anatomical basis of human cognition. We also address the potential of brain modes for predicting the behavioural consequences of lesions and their future role in the design of cognitive neurorehabilitation therapies.

Is VLSM a valid tool for determining the functional anatomy of the brain? Usefulness of additional Bayesian network analysis.

OBJECTIVES: The ability of voxel-based lesion-symptom mapping (VLSM) to define the functional anatomy of the human brain has not been fully assessed. With a view to assessing VLSM's validity, the present study analyzed the technique's ability to determine the known clinical-anatomic correlates of hemiparesis in stroke patients. DESIGN: Lesions (damaged in at least 5 patients) associated with transformed limb motor score (after adjustment on lesion volume) at 6 months were examined in 272 patients using VLSM. The value of additional multivariable linear, logistic and Bayesian analyses was examined. RESULTS: We first checked that motor hemiparesis was fully accounted for by corticospinal tract (CST) lesions (sensitivity = 100%; p = 0.0001). Conventional VLSM analysis flagged up 2 regions corresponding to the CST, but also 8 regions located outside the CST. All 10 brain regions achieving statistical significance in the VLSM analysis were submitted to 3 additional analyses. The backward linear regression analysis selected 5 regions, one only corresponding to the CST (R2: 0.03, p = 0.0008). The logistic regression analysis selected correctly the CST (OR: 2.39, 95%CI: 1.44-3.96; 0.001). The Bayesian network analysis selected regions including the CST (in 92% of 3000 bootstrap replications) and identified the source of multicollinearity. These lesions evaluated by structural equation modeling resulted in an excellent fit (p-value = 0.228, chi/df = 1.19, RMSEA = 0.032, CFI = 0.999). Analyses of confusion factors showed that conventional VLSM analyses were strongly influenced by lesion frequency (R2 = 0.377; p = 0.0001) and multicollinearity. CONCLUSIONS: Conventional VLSM analyses are sensitive but weakened by a type I error due to the combined effects of multicollinearity and lesion frequency. We demonstrate that the addition of a Bayesian network analysis, and to a lesser extent of logistic regression, controlled for this type I error and constituted a reliable means of defining the functional anatomy of the motor system in stroke patients.

Common brain networks for distinct deficits in visual neglect. A combined structural and tractography MRI approach.

Visual neglect is a heterogeneous, multi-component syndrome resulting from right hemisphere damage. Neglect patients do not pay attention to events occurring on their left side, and have a poor functional outcome. The intra-hemispheric location of lesions producing neglect is debated, because studies using different methods reported different locations in the grey matter and in the white matter of the right hemisphere. These reported locations show various patterns of overlapping with the fronto-parietal attention networks demonstrated by functional neuroimaging. We explored the anatomical correlates of neglect patients' performance on distinct tests of neglect. For the first time in neglect anatomy studies, we individually assessed 25 patients with subacute strokes in the right hemisphere, by using a combined structural and diffusion tensor deterministic tractography approach, with separate analyses for each neglect test. The results revealed that lesions in nodes of the ventral attention network (angular and supramarginal gyri) were selectively associated with deficits in performance on all the tests used; damage to other structures correlated with impaired performance on specific tests, such as the bells test (middle and inferior frontal gyri), or the reading test (temporal regions). Importantly, however, white matter damage proved crucial in producing neglect-related deficits. Voxel-based lesion-symptom mapping (VLSM) and tractography consistently revealed that damage to the ventral branch of the superior longitudinal fasciculus (SLF III) and to the inferior fronto-occipital fasciculus (IFOF) predicted pathological scores on line bisection/drawing copy and on the bells test, respectively. Moreover, damage to distinct sectors of SLF III, or combined SLF/IFOF damage, gave rise to different performance profiles. Our results indicate that both grey and white matter lesion analysis must be taken into account to determine the neural correlates of neglect-related deficits. They also suggest that damage to distinct portions of white matter tracts may give rise to distinct clinical signs of neglect, presumably by inducing dysfunction of partly overlapping, but distinct networks.

Component deficits of visual neglect: "Magnetic" attraction of attention vs. impaired spatial working memory.

Visual neglect is a disabling consequence of right hemisphere damage, whereby patients fail to detect left-sided objects. Its precise mechanisms are debated, but there is some consensus that distinct component deficits may variously associate and interact in different patients. Here we used a touch-screen based procedure to study two putative component deficits of neglect, rightward "magnetic" attraction of attention and impaired spatial working memory, in a group of 47 right brain-damaged patients, of whom 33 had signs of left neglect. Patients performed a visual search task on three distinct conditions, whereby touched targets could (1) be tagged, (2) disappear or (3) show no change. Magnetic attraction of attention was defined as more left neglect on the tag condition than on the disappear condition, where right-sided disappeared targets could not capture patients' attention. Impaired spatial working memory should instead produce more neglect on the no change condition, where no external cue indicated that a target had already been explored, than on the tag condition. Using a specifically developed analysis algorithm, we identified significant differences of performance between the critical conditions. Neglect patients as a group performed better on the disappear condition than on the no change condition and also better in the tag condition comparing with the no change condition. No difference was found between the tag condition and the disappear condition. Some of our neglect patients had dissociated patterns of performance, with predominant magnetic attraction or impaired spatial working memory. Anatomical results issued from both grey matter analysis and fiber tracking were consistent with the typical patterns of fronto-parietal and occipito-frontal disconnection in neglect, but did not identify lesional patterns specifically associated with one or another deficit, thus suggesting the possible co-localization of attentional and working memory processes in fronto-parietal networks. These findings give support to the hypothesis of the co-occurrence of distinct cognitive deficits in visual neglect and stress the necessity of multi-component models of visuospatial disorders.

Game theoretical mapping of causal interactions underlying visuo-spatial attention in the human brain based on stroke lesions.

Anatomical studies conducted in neurological conditions have developed our understanding of the causal relationships between brain lesions and their clinical consequences. The analysis of lesion patterns extended across brain networks has been particularly useful in offering new insights on brain-behavior relationships. Here we applied multiperturbation Shapley value Analysis (MSA), a multivariate method based on coalitional game theory inferring causal regional contributions to specific behavioral outcomes from the characteristic functional deficits after stroke lesions. We established the causal patterns of contributions and interactions of nodes of the attentional orienting network on the basis of lesion and behavioral data from 25 right hemisphere stroke patients tested in visuo-spatial attention tasks. We calculated the percentage of damaged voxels for five right hemisphere cortical regions contributing to attentional orienting, involving seven specific Brodmann Areas (BA): Frontal Eye Fields, (FEF-BA6), Intraparietal Sulcus (IPS-BA7), Inferior Frontal Gyrus (IFG-BA44/BA45), Temporo-Parietal Junction (TPJ-BA39/BA40), and Inferior Occipital Gyrus (IOG-BA19). We computed the MSA contributions of these seven BAs to three behavioral clinical tests (line bisection, bells cancellation, and letter cancelation). Our analyses indicated IPS as the main contributor to the attentional orienting and also revealed synergistic influences among IPS, TPJ, and IOG (for bells cancellation and line bisection) and between TPJ and IFG (for bells and letter cancellation tasks). The findings demonstrate the ability of the MSA approach to infer plausible causal contributions of relevant right hemisphere sites in poststroke visuo-spatial attention and awareness disorders. Hum Brain Mapp 38:3454-3471, 2017. © 2017 Wiley Periodicals, Inc.

Visual Contrast Sensitivity Improvement by Right Frontal High-Beta Activity Is Mediated by Contrast Gain Mechanisms and Influenced by Fronto-Parietal White Matter Microstructure.

Behavioral and electrophysiological studies in humans and non-human primates have correlated frontal high-beta activity with the orienting of endogenous attention and shown the ability of the latter function to modulate visual performance. We here combined rhythmic transcranial magnetic stimulation (TMS) and diffusion imaging to study the relation between frontal oscillatory activity and visual performance, and we associated these phenomena to a specific set of white matter pathways that in humans subtend attentional processes. High-beta rhythmic activity on the right frontal eye field (FEF) was induced with TMS and its causal effects on a contrast sensitivity function were recorded to explore its ability to improve visual detection performance across different stimulus contrast levels. Our results show that frequency-specific activity patterns engaged in the right FEF have the ability to induce a leftward shift of the psychometric function. This increase in visual performance across different levels of stimulus contrast is likely mediated by a contrast gain mechanism. Interestingly, microstructural measures of white matter connectivity suggest a strong implication of right fronto-parietal connectivity linking the FEF and the intraparietal sulcus in propagating high-beta rhythmic signals across brain networks and subtending top-down frontal influences on visual performance.

Visual neglect: is there a relationship between impaired spatial working memory and re-cancellation?

In visual search tasks, neglect patients tend to explore and repeatedly re-cancel stimuli on the ipsilesional side, as if they did not realize that they had previously examined the rightward locations favoured by their lateral bias. The aim of this study was to explore the hypothesis that a spatial working memory deficit explains these ipsilesional re-cancellation errors in neglect patients. For the first time, we evaluated spatial working memory and re-cancellation through separate and independent tasks in a group of patients with right hemisphere damage and a diagnosis of left neglect. Results showed impaired spatial working memory in neglect patients. Compared to the control group, neglect patients cancelled fewer targets and made more re-cancellations both on the left side and on the right side. The spatial working memory deficit appears to be related to re-cancellations, but only for some neglect patients. Alternative interpretations of re-exploration of space are discussed.