FYI. For your doctor to figure out how this will help your recovery.
Dynamic brain states in spatial neglect after stroke
Sara Spadone1, 
Francesco de Pasquale2, 
Anna Digiovanni1, 
Eleonora Grande1, 
Luigi Pavone3, 
Stefano L. Sensi1, 
Giorgia Committeri1 and 
Antonello Baldassarre1*- 1Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
- 2Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy
- 3IRCCS NEUROMED, Pozzilli, Italy
Previous studies indicated that spatial neglect is characterized by widespread alteration of resting-state functional connectivity and changes in the functional topology of large-scale brain systems. However, whether such network modulations exhibit temporal fluctuations related to spatial neglect is still largely unknown. This study investigated the association between brain states and spatial neglect after the onset of focal brain lesions. A cohort of right-hemisphere stroke patients (n = 20) underwent neuropsychological assessment of neglect as well as structural and resting-state functional MRI sessions within 2 weeks from stroke onset. Brain states were identified using dynamic functional connectivity as estimated by the sliding window approach followed by clustering of seven resting state networks. The networks included visual, dorsal attention, sensorimotor, cingulo-opercular, language, fronto-parietal, and default mode networks. The analyses on the whole cohort of patients, i.e., with and without neglect, identified two distinct brain states characterized by different degrees of brain modularity and system segregation. Compared to non-neglect patients, neglect subjects spent more time in less modular and segregated state characterized by weak intra-network coupling and sparse inter-network interactions. By contrast, patients without neglect dwelt mainly in more modular and segregated states, which displayed robust intra-network connectivity and anti-correlations among task-positive and task-negative systems. Notably, correlational analyses indicated that patients exhibiting more severe neglect spent more time and dwelt more often in the state featuring low brain modularity and system segregation and vice versa. Furthermore, separate analyses on neglect vs. non-neglect patients yielded two distinct brain states for each sub-cohort. A state featuring widespread strong connections within and between networks and low modularity and system segregation was detected only in the neglect group. Such a connectivity profile blurred the distinction among functional systems. Finally, a state exhibiting a clear separation among modules with strong positive intra-network and negative inter-network connectivity was found only in the non-neglect group. Overall, our results indicate that stroke yielding spatial attention deficits affects the time-varying properties of functional interactions among large-scale networks. These findings provide further insights into the pathophysiology of spatial neglect and its treatment.
Introduction
Spatial neglect, a neuropsychological syndrome affecting around ~20–30% of all stroke patients (Buxbaum et al., 2004; Ringman et al., 2004), is characterized by an impairment in attending, processing, and responding to targets which are presented in the side of the space and body opposed to the brain lesion, which is more frequently in the right hemisphere (Halligan et al., 1989; Verdon et al., 2010; Corbetta and Shulman, 2011). This contralesional spatial bias is also associated with non-spatial deficits of sustained attention, arousal, and vigilance (Husain and Rorden, 2003).
Albeit investigated for a long-time, the neurofunctional correlates of spatial neglect are still debated (Husain and Rorden, 2003; Corbetta and Shulman, 2011; Bartolomeo et al., 2012; Karnath and Rorden, 2012). Lesion-to-symptom mapping studies have identified several brain structures related to neglect, such as inferior frontal (Husain and Kennard, 1996; Committeri et al., 2007; Corbetta et al., 2015), insular (Karnath et al., 2009; Corbetta et al., 2015), temporo-parietal (Karnath et al., 2001, 2004; Committeri et al., 2007; Corbetta et al., 2015) and inferior parietal (Mort et al., 2003) cortex, basal ganglia (Karnath et al., 2005; Corbetta et al., 2015), thalamus (Corbetta et al., 2015) as well as underlying white matter (Doricchi and Tomaiuolo, 2003; Karnath et al., 2009; Thiebaut de Schotten et al., 2014; Corbetta et al., 2015).
In recent years, such a challenge has been attempted within the framework of the so-called “connectomal diaschisis”, a novel type of diaschisis, which posits that a focal brain injury leads to widespread changes of large-scale networks among areas that are structurally spared and distant from the lesion site (Carrera and Tononi, 2014) (for reviews on stroke, see Varsou et al., 2014; Baldassarre et al., 2016; Siegel et al., 2022). Indeed, two pioneer studies showed that the extent of the rightward bias in neglect patients is associated with a breakdown of the inter-hemispheric resting-state functional connectivity (FC) MRI among intact fronto-parietal areas of the dorsal attention network that is involved in the control of visuo-spatial attention (He et al., 2007; Carter et al., 2010). Subsequently, in our previous work (Baldassarre et al., 2014), we detected two large-scale patterns of abnormal functional connectivity associated with the severity of spatial neglect in a large cohort of acute stroke patients: reduction of inter-hemispheric FC within dorsal attention/sensory motor networks as well as loss of negative FC (i.e., anti-correlation) between these networks and the default mode network. More recently, by adopting a graph-theoretic approach, in two companion studies, we have shown that spatial neglect is characterized by widespread changes in the brain topological organization at different scales of network analysis (de Pasquale et al., 2021a; Spadone et al., 2022). At the micro-scale level, we identified two sets of neglect-relevant hubs derived using the betweenness centrality metric [i.e., the number of the shortest paths passing through a given node (Rubinov and Sporns, 2010; de Pasquale et al., 2021a)]. Specifically, one group of neglect hubs was detected in higher-order associative systems, such as the dorsal and ventral attention, frontoparietal, and default mode networks. These hubs exhibited lower centrality as well as higher shortest paths length (i.e., less efficient) associated with severe neglect. Conversely, a reverse pattern was observed in a second cohort of neglect hubs dislocated in lower-level sensory-processing systems such as the visual and motor networks. At meso-scale level, neglect was associated with a loss of system segregation, i.e., the balance between the functional specialization and dynamic integration of distinct and segregated (sub)networks (Tononi et al., 1994; Wig, 2017), involving higher-order associative networks such as dorsal attention, fronto-parietal and default mode as well as the sensorimotor network (Spadone et al., 2022).
Overall, these lines of evidence indicate that neglect is characterized by widespread alteration of resting-state networks as well topological changes in the brain, suggesting a maladaptive shift from higher-order to low-level sensory-processing systems.
However, the brain is a dynamic system characterized by transient states with different degrees of integration and segregation among multiple large-scale networks (de Pasquale et al., 2021a,b). Notably, recent functional MRI studies adopting a dynamic functional connectivity approach have identified time-varying properties of functional connections among brain networks (Calhoun et al., 2014). Clinically, several reports indicated that such brain states are affected after stroke (Bonkhoff et al., 2020, 2021a,b; Wang et al., 2020; Favaretto et al., 2022). Hence, the dynamic connectivity method can capture transient conditions of network reconfigurations as they happen after a focal brain lesion. Therefore, the goal of the current study was to investigate whether the above-described network modulations exhibit temporal variations which can be potentially related to spatial neglect. To this aim, we estimated functional connectivity dynamics (Calhoun et al., 2014) on our previously collected dataset (de Pasquale et al., 2021a; Spadone et al., 2022) to characterize the temporal fluctuations of brain states associated with spatial neglect after right hemisphere strokes. Since neglect has been associated with changes of functional connectivity in multiple large-scale networks, we expect to identify brain states characterized by widespread alterations of their functional architecture.
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