Network analysis of neuropsychiatric, cognitive, and functional complications of stroke: implications for novel treatment targets.

AIM: Recovery from stroke is adversely affected by neuropsychiatric complications, cognitive impairment, and functional disability. Better knowledge of their mutual relationships is required to inform effective interventions. Network theory enables the conceptualization of symptoms and impairments as dynamic and mutually interacting systems. We aimed to identify interactions of poststroke complications using network analysis in diverse stroke samples. METHODS: Data from 2185 patients were sourced from member studies of STROKOG (Stroke and Cognition Consortium), an international collaboration of stroke studies. Networks were generated for each cohort, whereby nodes represented neuropsychiatric symptoms, cognitive deficits, and disabilities on activities of daily living. Edges characterized associations between them. Centrality measures were used to identify hub items. RESULTS: Across cohorts, a single network of interrelated poststroke complications emerged. Networks exhibited dissociable depression, apathy, fatigue, cognitive impairment, and functional disability modules. Worry was the most central symptom across cohorts, irrespective of the depression scale used. Items relating to activities of daily living were also highly central nodes. Follow-up analysis in two studies revealed that individuals who worried had more densely connected networks than those free of worry (CASPER [Cognition and Affect after Stroke: Prospective Evaluation of Risks] study: S = 9.72, P = 0.038; SSS [Sydney Stroke Study]: S = 13.56, P = 0.069). CONCLUSION: Neuropsychiatric symptoms are highly interconnected with cognitive deficits and functional disabilities resulting from stroke. Given their central position and high level of connectedness, worry and activities of daily living have the potential to drive multimorbidity and mutual reinforcement between domains of poststroke complications. Targeting these factors early after stroke may have benefits that extend to other complications, leading to better stroke outcomes.

Rhinovirus infection induces secretion of endothelin-1 from airway epithelial cells in both in vitro and in vivo models.

BACKGROUND: Rhinovirus (RV) infection of airway epithelial cells triggers asthma exacerbations, during which airway smooth muscle (ASM) excessively contracts. Due to ASM contraction, airway epithelial cells become mechanically compressed. We previously reported that compressed human bronchial epithelial (HBE) cells are a source of endothelin-1 (ET-1) that causes ASM contraction. Here, we hypothesized that epithelial sensing of RV by TLR3 and epithelial compression induce ET-1 secretion through a TGF-ß receptor (TGFßR)-dependent mechanism. METHODS: To test this, we used primary HBE cells well-differentiated in air-liquid interface culture and two mouse models (ovalbumin and house dust mite) of allergic airway disease (AAD). HBE cells were infected with RV-A16, treated with a TLR3 agonist (poly(I:C)), or exposed to compression. Thereafter, EDN1 (ET-1 protein-encoding gene) mRNA expression and secreted ET-1 protein were measured. We examined the role of TGFßR in ET-1 secretion using either a pharmacologic inhibitor of TGFßR or recombinant TGF-ß1 protein. In the AAD mouse models, allergen-sensitized and allergen-challenged mice were subsequently infected with RV. We then measured ET-1 in bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness (AHR) following methacholine challenge. RESULTS: Our data reveal that RV infection induced EDN1 expression and ET-1 secretion in HBE cells, potentially mediated by TLR3. TGFßR activation was partially required for ET-1 secretion, which was induced by RV, poly(I:C), or compression. TGFßR activation alone was sufficient to increase ET-1 secretion. In AAD mouse models, RV induced ET-1 secretion in BALF, which positively correlated with AHR. CONCLUSIONS: Our data provide evidence that RV infection increased epithelial-cell ET-1 secretion through a TGFßR-dependent mechanism, which contributes to bronchoconstriction during RV-induced asthma exacerbations.

Quantification of basal stem cell elongation and stress fiber accumulation in the pseudostratified airway epithelium during the unjamming transition.

Under homeostatic conditions, epithelial cells remain non-migratory. However, during embryonic development and pathological conditions, they become migratory. The mechanism underlying the transition of the epithelial layer between non-migratory and migratory phases is a fundamental question in biology. Using well-differentiated primary human bronchial epithelial cells that form a pseudostratified epithelium, we have previously identified that a confluent epithelial layer can transition from a non-migratory to migratory phase through an unjamming transition (UJT). We previously defined collective cellular migration and apical cell elongation as hallmarks of UJT. However, other cell-type-specific changes have not been previously studied in the pseudostratified airway epithelium, which consists of multiple cell types. Here, we focused on the quantifying morphological changes in basal stem cells during the UJT. Our data demonstrate that during the UJT, airway basal stem cells elongated and enlarged, and their stress fibers elongated and aligned. These morphological changes observed in basal stem cells correlated to the previously defined hallmarks of the UJT. Moreover, basal cell and stress fiber elongation were observed prior to apical cell elongation. Together, these morphological changes indicate that basal stem cells in pseudostratified airway epithelium are actively remodeling, presumably through accumulation of stress fibers during the UJT.

White matter microstructure is associated with the precision of visual working memory.

Visual working memory is critical for goal-directed behavior as it maintains continuity between previous and current visual input. Functional neuroimaging studies have shown that visual working memory relies on communication between distributed brain regions, which implies an important role for long-range white matter connections in visual working memory performance. Here, we characterized the relationship between the microstructure of white matter association tracts and the precision of visual working memory representations. To that purpose, we devised a delayed estimation task which required participants to reproduce visual features along a continuous scale. A sample of 80 healthy adults performed the task and underwent diffusion-weighted MRI. We applied mixture distribution modelling to quantify the precision of working memory representations, swap errors, and guess rates, all of which contribute to observed responses. Latent components of microstructural properties in sets of anatomical tracts were identified by principal component analysis. We found an interdependency between fibre coherence in the bilateral superior longitudinal fasciculus (SLF) I, SLF II, and SLF III, on one hand, and the bilateral inferior fronto-occipital fasciculus (IFOF), on the other, in mediating the precision of visual working memory in a functionally specific manner. We also found that individual differences in axonal density in a network comprising the bilateral inferior longitudinal fasciculus (ILF) and SLF III and right SLF II, in combination with a supporting network located elsewhere in the brain, form a common system for visual working memory to modulate response precision, swap errors, and random guess rates.

Cognitive Recovery After Stroke: Memory.

Memory impairment occurs in over a third of patients after symptomatic stroke. Memory deficits rarely occur in isolation but are an important component of the poststroke cognitive syndrome because of the strong relationship with the risk of poststroke dementia. In this review, we summarize available data on impairment of episodic memory, with a particular emphasis on the natural history of memory impairment after stroke and the factors influencing trajectory informed by an updated systematic review. We next discuss the pathophysiology of memory impairment and mechanisms of both decline and recovery of function. We then turn to the practical issue of measurement of memory deficits after stroke, emerging biomarkers, and therapeutic approaches. Our review identifies critical gaps, particularly in studies of the natural history that properly map the long-term trajectory of memory and the associations with factors that modulate prognosis. Few studies have used advanced neuroimaging and this, in conjunction with other biomarker approaches, has the potential to provide a much richer understanding of the mechanisms at play and promising therapeutic avenues.

Hyperconnectivity and altered interactions of a nucleus accumbens network in post-stroke depression.

Post-stroke depression is a common complication of stroke. To date, no consistent locus of injury is associated with this complication. Here, we probed network dynamics and structural alterations in post-stroke depression in four functional circuits linked to major depressive disorder and a visual network, which served as a control network. Forty-four participants with recent stroke (mean age = 69.03, standard deviation age = 8.59, age range = 51-86 and gender: female = 10) and 16 healthy volunteers (mean age = 71.53, standard deviation age = 10.62, age range = 51-84 and gender: female = 11) were imaged with 3-Tesla structural, diffusion and resting-state functional MRI. The Geriatric Depression Scale was administered to measure depression severity. Associations between depression severity and functional connectivity were investigated within networks seeded from nucleus accumbens, amygdala, dorsolateral prefrontal cortex and primary visual cortex. In addition, the default mode network was identified by connectivity with medial prefrontal cortex and posterior cingulate cortex. Circuits that exhibited altered activity associated with depression severity were further investigated by extracting within-network volumetric and microstructural measures from structural images. In the stroke group, functional connectivity within the nucleus accumbens-seeded network (left hemisphere: P = 0.001; and right hemisphere: P = 0.004) and default mode network (cluster one: P < 0.001; and cluster two: P < 0.001) correlated positively with depressive symptoms. Normal anticorrelations between these two networks were absent in patients with post-stroke depression. Grey matter volume of the right posterior cingulate cortex (Pearson correlation coefficient = -0.286, P = 0.03), as well as microstructural measures in the posterior cingulate cortex (right: Pearson correlation coefficient = 0.4, P = 0.024; and left: Pearson correlation coefficient = 0.3, P = 0.048), right medial prefrontal cortex (Pearson correlation coefficient = 0.312, P = 0.039) and the medial forebrain bundle (Pearson correlation coefficient = 0.450, P = 0.003), a major projection pathway interconnecting the nucleus accumbens-seeded network and linking to medial prefrontal cortex, were associated with depression severity. Depression after stroke is marked by reduced mutual inhibition between functional circuits involving nucleus accumbens and default mode network as well as volumetric and microstructural changes within these networks. Aberrant network dynamics present in patients with post-stroke depression are therefore likely to be influenced by secondary, pervasive alterations in grey and white matter, remote from the site of injury.

Delay activity during visual working memory: A meta-analysis of 30 fMRI experiments.

Visual working memory refers to the temporary maintenance and manipulation of task-related visual information. Recent debate on the underlying neural substrates of visual working memory has focused on the delay period of relevant tasks. Persistent neural activity throughout the delay period has been recognized as a correlate of working memory, yet regions demonstrating sustained hemodynamic responses show inconsistency across individual studies. To develop a more precise understanding of delay-period activations during visual working memory, we conducted a coordinate-based meta-analysis on 30 fMRI experiments involving 515 healthy adults with a mean age of 25.65 years. The main analysis revealed a widespread frontoparietal network associated with delay-period activity, as well as activation in the right inferior temporal cortex. These findings were replicated using different meta-analytical algorithms and were shown to be robust against between-study heterogeneity and publication bias. Further meta-analyses on different subgroups of experiments with specific task demands and stimulus types revealed similar delay-period networks, with activations distributed across the frontal and parietal cortices. The roles of prefrontal regions, posterior parietal regions, and inferior temporal areas are reviewed and discussed in the context of content-specific storage. We conclude that cognitive operations that occur during the unfilled delay period in visual working memory tasks can be flexibly expressed across a frontoparietal-temporal network depending on experimental parameters.

Cholinergic and hippocampal systems facilitate cross-domain cognitive recovery after stroke.

Spontaneous recovery of motor and cognitive function occurs in many individuals after stroke. The mechanisms are incompletely understood, but may involve neurotransmitter systems that support neural plasticity, networks that are involved in learning and regions of the brain that are able to flexibly adapt to demand (such as the 'multiple-demand system'). Forty-two patients with first symptomatic ischaemic stroke were enrolled in a longitudinal cohort study of cognitive function after stroke. High-resolution volumetric, diffusion MRI and neuropsychological assessment were performed at a mean of 70 ± 18 days after stroke. Cognitive assessment was repeated 1 year after stroke, using parallel test versions to avoid learning effects, and change scores were computed for long-term episodic, short-term and working memory. Structural MRI features that predicted change in cognitive scores were identified by a two-stage analysis: a discovery phase used whole-brain approaches in a hypothesis-free unbiased way; and an independent focused phase, where measurements were derived from regions identified in the discovery phase, using targeted volumetric measurements or tractography. Evaluation of the cholinergic basal forebrain, based on a validated atlas-based approach, was included given prior evidence of a role in neural plasticity. The status of the fornix, cholinergic basal forebrain and a set of hippocampal subfields were found to predict improvement in long-term memory performance. In contrast to prior expectation, the same pattern was found for short-term and working memory, suggesting that these regions are part of a common infrastructure that supports recovery across cognitive domains. Associations between cholinergic basal forebrain volume and cognitive recovery were found primarily in subregions associated with the nucleus basalis of Meynert, suggesting that it is the cholinergic outflow to the neocortex that enables recovery. Support vector regression models derived from baseline measurements of fornix, cholinergic basal forebrain and hippocampal subfields were able to explain 62% of change in long-term episodic and 41% of change in working memory performance over the subsequent 9 months. The results suggest that the cholinergic system and extended hippocampal network play key roles in cognitive recovery after stroke. Evaluation of these systems early after stroke may inform personalized therapeutic strategies to enhance recovery.

Mechanical Compression of Human Airway Epithelial Cells Induces Release of Extracellular Vesicles Containing Tenascin C.

Aberrant remodeling of the asthmatic airway is not well understood but is thought to be attributable in part to mechanical compression of airway epithelial cells. Here, we examine compression-induced expression and secretion of the extracellular matrix protein tenascin C (TNC) from well-differentiated primary human bronchial epithelial (HBE) cells grown in an air-liquid interface culture. We measured TNC mRNA expression using RT-qPCR and secreted TNC protein using Western blotting and ELISA. To determine intracellular signaling pathways, we used specific inhibitors for either ERK or TGF-ß receptor, and to assess the release of extracellular vesicles (EVs) we used a commercially available kit and Western blotting. At baseline, secreted TNC protein was significantly higher in asthmatic compared to non-asthmatic cells. In response to mechanical compression, both TNC mRNA expression and secreted TNC protein was significantly increased in both non-asthmatic and asthmatic cells. TNC production depended on both the ERK and TGF-ß receptor pathways. Moreover, mechanically compressed HBE cells released EVs that contain TNC. These data reveal a novel mechanism by which mechanical compression, as is caused by bronchospasm, is sufficient to induce the production of ECM protein in the airway and potentially contribute to airway remodeling.

Transdiagnostic In Vivo Magnetic Resonance Imaging Markers of Neuroinflammation.

Accumulating evidence suggests that inflammation is not limited to archetypal inflammatory diseases such as multiple sclerosis, but instead represents an intrinsic feature of many psychiatric and neurological disorders not typically classified as neuroinflammatory. A growing body of research suggests that neuroinflammation can be observed in early and prodromal stages of these disorders and, under certain circumstances, may lead to tissue damage. Traditional methods to assess neuroinflammation include serum or cerebrospinal fluid markers and positron emission tomography. These methods require invasive procedures or radiation exposure and lack the exquisite spatial resolution of magnetic resonance imaging (MRI). There is, therefore, an increasing interest in noninvasive neuroimaging tools to evaluate neuroinflammation reliably and with high specificity. While MRI does not provide information at a cellular level, it facilitates the characterization of several biophysical tissue properties that are closely linked to neuroinflammatory processes. The purpose of this review is to evaluate the potential of MRI as a noninvasive, accessible, and cost-effective technology to image neuroinflammation across neurological and psychiatric disorders. We provide an overview of current and developing MRI methods used to study different aspects of neuroinflammation and weigh their strengths and shortcomings. Novel MRI contrast agents are increasingly able to target inflammatory processes directly, therefore offering a high degree of specificity, particularly if used in conjunction with multitissue, biophysical diffusion MRI compartment models. The capability of these methods to characterize several aspects of the neuroinflammatory milieu will likely push MRI to the forefront of neuroimaging modalities used to characterize neuroinflammation transdiagnostically.

Serum from Older Adults Increases Apoptosis and Molecular Aging Markers in Human Hippocampal Progenitor Cells.

Age-related alteration in neural stem cell function is linked to neurodegenerative conditions and cognitive decline. In rodents, this can be reversed by exposure to a young systemic milieu and conversely, the old milieu can inhibit stem cell function in young rodents. In this study, we investigated the in vitro effect of the human systemic milieu on human hippocampal progenitor cells (HPCs) using human serum from early adulthood, mid-life and older age. We showed that neuroblast number following serum treatment is predictive of larger dentate gyrus, CA3, CA4 and whole hippocampus volumes and that allogeneic human serum from asymptomatic older individuals induced a two-fold increase in apoptotic cell death of HPCs compared with serum from young adults. General linear models revealed that variability in markers of proliferation and differentiation was partly attributable to use of antihypertensive medication and very mild cognitive decline among older subjects. Finally, using an endophenotype approach and whole-genome expression arrays, we showed upregulation of established and novel ageing molecular hallmarks in response to old serum. Serum from older subjects induced a wide range of cellular and molecular phenotypes, likely reflecting a lifetime of environmental exposures. Our findings support a role for the systemic enviroment in neural stem cell maintenance and are in line with others highlighting a distinction between neurobiological and chronological ageing. Finally, the herein described serum assay can be used by future studies to further analyse the effect of environmental exposures as well as to determine the role of the systemic environment in health and disease.

Genomic signatures of the unjamming transition in compressed human bronchial epithelial cells.

Epithelial tissue can transition from a jammed, solid-like, quiescent phase to an unjammed, fluid-like, migratory phase, but the underlying molecular events of the unjamming transition (UJT) remain largely unexplored. Using primary human bronchial epithelial cells (HBECs) and one well-defined trigger of the UJT, compression mimicking the mechanical effects of bronchoconstriction, here, we combine RNA sequencing data with protein-protein interaction networks to provide the first genome-wide analysis of the UJT. Our results show that compression induces an early transcriptional activation of the membrane and actomyosin network and a delayed activation of the extracellular matrix (ECM) and cell-matrix networks. This response is associated with a signaling cascade that promotes actin polymerization and cellular motility through the coordinated interplay of downstream pathways including ERK, JNK, integrin signaling, and energy metabolism. Moreover, in nonasthmatic versus asthmatic HBECs, common genomic patterns associated with ECM remodeling suggest a molecular connection between airway remodeling, bronchoconstriction, and the UJT.

White and Gray Matter Abnormalities in Australian Footballers With a History of Sports-Related Concussion: An MRI Study.

Sports-related concussion (SRC) is a form of mild traumatic brain injury that has been linked to long-term neurological abnormalities. Australian rules football is a collision sport with wide national participation and is growing in popularity worldwide. However, the chronic neurological consequences of SRC in Australian footballers remain poorly understood. This study investigated the presence of brain abnormalities in Australian footballers with a history of sports-related concussion (HoC) using multimodal MRI. Male Australian footballers with HoC (n = 26), as well as noncollision sport athletes with no HoC (n = 27), were recruited to the study. None of the footballers had sustained a concussion in the preceding 6 months, and all players were asymptomatic. Data were acquired using a 3T MRI scanner. White matter integrity was assessed using diffusion tensor imaging. Cortical thickness, subcortical volumes, and cavum septum pellucidum (CSP) were analyzed using structural MRI. Australian footballers had evidence of widespread microstructural white matter damage and cortical thinning. No significant differences were found regarding subcortical volumes or CSP. These novel findings provide evidence of persisting white and gray matter abnormalities in Australian footballers with HoC, and raise concerns related to the long-term neurological health of these athletes.

In well-differentiated primary human bronchial epithelial cells, TGF-ß1 and TGF-ß2 induce expression of furin.

The COVID-19 pandemic is an ongoing threat to public health. Since the identification of COVID-19, the disease caused by SARS-CoV-2, no drugs have been developed to specifically target SARS-CoV-2. To develop effective and safe treatment options, a better understanding of cellular mechanisms underlying SARS-CoV-2 infection is required. To fill this knowledge gap, researchers require reliable experimental systems that express the host factor proteins necessary for the cellular entry of SARS-CoV-2. These proteins include the viral receptor, angiotensin-converting enzyme 2 (ACE2), and the proteases, transmembrane serine protease 2 (TMPRSS2) and furin. A number of studies have reported cell-type-specific expression of the genes encoding these molecules. However, less is known about the protein expression of these molecules. We assessed the suitability of primary human bronchial epithelial (HBE) cells maintained in an air-liquid interface (ALI) as an experimental system for studying SARS-CoV-2 infection in vitro. During cellular differentiation, we measured the expression of ACE2, TMPRSS2, and furin over progressive ALI days by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence staining. We also explored the effect of the fibrotic cytokine TGF-ß on the expression of these proteins in well-differentiated HBE cells. Like ACE2, TMPRSS2 and furin proteins are localized in differentiated ciliated cells, as confirmed by immunofluorescence staining. These data suggest that well-differentiated HBE cells maintained in ALI are a reliable in vitro system for investigating cellular mechanisms of SARS-CoV-2 infection. We further identified that the profibrotic mediators, TGF-ß1 and TGF-ß2, increase the expression of furin, which is a protease required for the cellular entry of SARS-CoV-2.

Bronchoconstriction: a potential missing link in airway remodelling.

In asthma, progressive structural changes of the airway wall are collectively termed airway remodelling. Despite its deleterious effect on lung function, airway remodelling is incompletely understood. As one of the important causes leading to airway remodelling, here we discuss the significance of mechanical forces that are produced in the narrowed airway during asthma exacerbation, as a driving force of airway remodelling. We cover in vitro, ex vivo and in vivo work in this field, and discuss up-to-date literature supporting the idea that bronchoconstriction may be the missing link in a comprehensive understanding of airway remodelling in asthma.

Patterns of Mitochondrial TSPO Binding in Cerebral Small Vessel Disease: An in vivo PET Study With Neuropathological Comparison.

Small vessel disease (SVD) is associated with cognitive impairment in older age and be implicated in vascular dementia. Post-mortem studies show proliferation of activated microglia in the affected white matter. However, the role of inflammation in SVD pathogenesis is incompletely understood and better biomarkers are needed. We hypothesized that expression of the 18 kDa translocator protein (TSPO), a marker of microglial activation, would be higher in SVD. Positron emission tomography (PET) was performed with the second-generation TSPO ligand [11C]PBR28 in 11 participants with SVD. TSPO binding was evaluated by a two-tissue compartment model, with and without a vascular binding component, in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM). In post-mortem tissue, in a separate cohort of individuals with SVD, immunohistochemistry was performed for TSPO and a pan-microglial marker Iba1. Kinetic modeling showed reduced tracer volume and blood volume fraction in WMH compared with NAWM, but a significant increase in vascular binding. Vascular [11C]PBR28 binding was also increased compared with normal-appearing white matter of healthy participants free of SVD. Immunohistochemistry showed a diffuse increase in microglial staining (with Iba1) in sampled tissue in SVD compared with control samples, but with only a subset of microglia staining positively for TSPO. Intense TSPO staining was observed in the vicinity of damaged small blood vessels, which included perivascular macrophages. The results suggest an altered phenotype of activated microglia, with reduced TSPO expression, in the areas of greatest white matter ischemia in SVD, with implications for the interpretation of TSPO PET studies in older individuals or those with vascular risk factors.

In primary airway epithelial cells, the unjamming transition is distinct from the epithelial-to-mesenchymal transition.

The epithelial-to-mesenchymal transition (EMT) and the unjamming transition (UJT) each comprises a gateway to cellular migration, plasticity and remodeling, but the extent to which these core programs are distinct, overlapping, or identical has remained undefined. Here, we triggered partial EMT (pEMT) or UJT in differentiated primary human bronchial epithelial cells. After triggering UJT, cell-cell junctions, apico-basal polarity, and barrier function remain intact, cells elongate and align into cooperative migratory packs, and mesenchymal markers of EMT remain unapparent. After triggering pEMT these and other metrics of UJT versus pEMT diverge. A computational model attributes effects of pEMT mainly to diminished junctional tension but attributes those of UJT mainly to augmented cellular propulsion. Through the actions of UJT and pEMT working independently, sequentially, or interactively, those tissues that are subject to development, injury, or disease become endowed with rich mechanisms for cellular migration, plasticity, self-repair, and regeneration.

Microstructural changes in the reward system are associated with post-stroke depression.

BACKGROUND: Studies of lesion location have been unsuccessful in identifying mappings between single brain regions and post-stroke depression (PSD). Based on studies implicating the reward system in major depressive disorder without stroke, we investigated structural correlates within this system and their associations with PSD. METHODS: The study enrolled 16 healthy controls, 12 stroke patients with PSD and 34 stroke patients free of PSD. Participants underwent 3T structural and diffusion MRI. Graph theoretical measures were used to examine global topology and whole-brain connectome analyses were employed to assess differences in the interregional connectivity matrix between groups. Structural correlates specific to the reward system were examined from grey matter volumes and by reconstructing its main white matter pathways, namely the medial forebrain bundle and cingulum connections, using deterministic tractography. Fractional anisotropy (FA) was derived as a measure of microstructural organization, and extracellular free-water (FW) as a possible proxy of neuroinflammation. RESULTS: Subnetworks of decreased FA-weighted and increased FW-weighted connectivity were observed in patients with PSD relative to healthy controls. These networks subsumed the majority of regions constituting the reward system. Within the reward system, FA and FW of major connection pathways and grey matter volume were collectively predictive of PSD, explaining 37.8% of the variance in depression severity. CONCLUSIONS: PSD is associated with grey matter volume loss, reduced FA and increased extracellular FW in the reward system, similar to features observed in major depression without stroke. Structural characterization of the reward system is a promising biomarker of vulnerability to depression after stroke.

Irradiation Induces Epithelial Cell Unjamming.

The healthy and mature epithelial layer is ordinarily quiescent, non-migratory, solid-like, and jammed. However, in a variety of circumstances the layer transitions to a phase that is dynamic, migratory, fluid-like and unjammed. This has been demonstrated in the developing embryo, the developing avian airway, the epithelial layer reconstituted in vitro from asthmatic donors, wounding, and exposure to mechanical stress. Here we examine the extent to which ionizing radiation might similarly provoke epithelial layer unjamming. We exposed primary human bronchial epithelial (HBE) cells maintained in air-liquid interface (ALI) to sub-therapeutic doses (1 Gy) of ionizing radiation (IR). We first assessed: (1) DNA damage by measuring p-H2AX, (2) the integrity of the epithelial layer by measuring transepithelial electrical resistance (TEER), and (3) the extent of epithelial cell differentiation by detecting markers of differentiated airway epithelial cells. As expected, IR exposure induced DNA damage but, surprisingly, disrupted neither normal differentiation nor the integrity of the epithelial cell layer. We then measured cell shape and cellular migration to determine the extent of the unjamming transition (UJT). IR caused cell shape elongation and increased cellular motility, both of which are hallmarks of the UJT as previously confirmed. To understand the mechanism of IR-induced UJT, we inhibited TGF-ß receptor activity, and found that migratory responses were attenuated. Together, these observations show that IR can provoke epithelial layer unjamming in a TGF-ß receptor-dependent manner.

Network neuroscience of apathy in cerebrovascular disease.

Apathy is a reduction in motivated goal-directed behavior (GDB) that is prevalent in cerebrovascular disease, providing an important opportunity to study the mechanistic underpinnings of motivation in humans. Focal lesions, such as those seen in stroke, have been crucial in developing models of brain regions underlying motivated behavior, while studies of cerebral small vessel disease (SVD) have helped define the connections between brain regions supporting such behavior. However, current lesion-based models cannot fully explain the neurobiology of apathy in stroke and SVD. To address this, we propose a network-based model which conceptualizes apathy as the result of damage to GDB-related networks. A review of the current evidence suggests that cerebrovascular disease-related pathology can lead to network changes outside of initially damaged territories, which may propagate to regions that share structural or functional connections. The presentation and longitudinal trajectory of apathy in stroke and SVD may be the result of these network changes. Distinct subnetworks might support cognitive components of GDB, the disruption of which results in specific symptoms of apathy. This network-based model of apathy may open new approaches for investigating its underlying neurobiology, and presents novel opportunities for its diagnosis and treatment.