Disability reduction following a lumbar stabilization exercise program for low back pain: large vs. small improvement subgroup analyses of physical and psychological variables.

BACKGROUND: Little is known about why patients with low back pain (LBP) respond differently to treatment, and more specifically, to a lumbar stabilization exercise program. As a first step toward answering this question, the present study evaluates how subgroups of patients who demonstrate large and small clinical improvements differ in terms of physical and psychological changes during treatment. METHODS: Participants (n = 110) performed the exercise program (clinical sessions and home exercises) over eight weeks, with 100 retained at six-month follow-up. Physical measures (lumbar segmental instability, motor control impairments, range of motion, trunk muscle endurance and physical performance tests) were collected twice (baseline, end of treatment), while psychological measures (fear-avoidance beliefs, pain catastrophizing, psychological distress, illness perceptions, outcome expectations) were collected at four time points (baseline, mid-treatment, end of treatment, follow-up). The participants were divided into three subgroups (large, moderate and small clinical improvements) based on the change of perceived disability scores. ANOVA for repeated measure compared well-contrasted subgroups (large vs. small improvement) at different times to test for SUBGROUP × TIME interactions. RESULTS: Statistically significant interactions were observed for several physical and psychological measures. In all these interactions, the large- and small-improvement subgroups were equivalent at baseline, but the large-improvement subgroup showed more improvements over time compared to the small-improvement subgroup. For psychological measures only (fear-avoidance beliefs, pain catastrophizing, illness perceptions), between-group differences reached moderate to strong effect sizes, at the end of treatment and follow-up. CONCLUSIONS: The large-improvement subgroup showed more improvement than the small-improvement subgroup with regard to physical factors typically targeted by this specific exercise program as well as for psychological factors that are known to influence clinical outcomes.

The RELIVE consortium for relapsed or refractory pediatric hepatoblastoma and hepatocellular carcinoma: a scoping review of the problem and a proposed solution.

Liver tumors account for approximately 2% of all pediatric malignancies. Children with advanced stages of hepatoblastoma (HB) are cured only 50-70% of the time while children with advanced hepatocellular carcinoma (HCC) have a <20% 5-year overall survival. This scoping review was performed to highlight the paucity of rigorous, reliable data guiding the management of relapsed pediatric HB or HCC. When these patients are enrolled on prospective trials, the trials are often histology-agnostic, exclude patients less than a year of age, lack a liquid formulary of the drug under study, exclude recipients of a solid organ transplant, and enroll only 1-2 patients limiting the ability to deduce efficacious regimens for current use or future study. We highlight the creation of a global pediatric consortium intended to source retrospective relapse data from over 100 institutions spanning 4 continents. The data collected from this effort will inform future relapse trials.

Pain Catastrophizing: Controversies, Misconceptions and Future Directions.

Recent reports have pointed to problems with the term "pain catastrophizing." Critiques of the term pain catastrophizing have come from several sources including individuals with chronic pain, advocates for individuals with chronic pain, and pain scholars. Reports indicate that the term has been used to dismiss the medical basis of pain complaints, to question the authenticity of pain complaints, and to blame individuals with pain for their pain condition. In this paper, we advance the position that the problems prompting calls to rename the construct of pain catastrophizing have little to do with the term, and as such, changing the term will do little to solve these problems. We argue that continued calls for changing or deleting the term pain catastrophizing will only divert attention away from some fundamental flaws in how individuals with pain conditions are assessed and treated. Some of these fundamental flaws have their roots in the inadequate training of health and allied health professionals in evidence-based models of pain, in the use of psychological assessment and intervention tools for the clinical management of pain, and in gender equity and antiracism. Critiques that pain scholars have leveled against the defining, operational, and conceptual bases of pain catastrophizing are also addressed. Arguments for reconceptualizing pain catastrophizing as a worry-related construct are discussed. Recommendations are made for remediation of the problems that have contributed to calls to rename the term pain catastrophizing. PERSPECTIVE: The issues prompting calls to rename the construct of pain catastrophizing have their roots in fundamental flaws in how individuals with pain are assessed and treated. Efforts to address these problems will require more than a simple change in terminology.

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.

Temporal Relations Between Pain Catastrophizing and Adverse Health and Mental Health Outcomes After Whiplash Injury.

OBJECTIVES: Pain catastrophizing has been shown to be a prognostic indicator for pain severity and the co-occurrence of mental health conditions such as depression and post-traumatic stress disorder after whiplash injury. However, the pattern of available findings is limited in its implications for the possible "antecedent" or "causal" role of pain catastrophizing. The purpose of the present study was to examine the temporal relations between pain catastrophizing, pain severity, depressive symptoms, and post-traumatic stress symptoms (PTSS) in individuals receiving treatment for whiplash injury. MATERIALS AND METHODS: The sample consisted of 388 individuals enrolled in a multidisciplinary program for whiplash injury. Participants completed self-report measures of pain catastrophizing, pain severity, depressive symptoms, and PTSS at the time of admission, mid-treatment (4 week), and treatment completion (7 week). A cross-lagged panel analysis was used to examine the temporal relations between pain catastrophizing, pain severity, depressive symptoms, and PTSS across all 3 timepoints. RESULTS: Model fit was acceptable after the inclusion of modification indices. Pain catastrophizing at the time of admission predicted all other variables at 4 weeks. Pain catastrophizing at 4 weeks also predicted all other variables at 7 weeks. In addition, some bidirectional relations were present, particularly for variables assessed at week 4 and week 7. DISCUSSION: Findings support the view that pain catastrophizing might play a transdiagnostic role in the onset and maintenance of health and mental health conditions. The findings call for greater emphasis on the development of treatment techniques that target pain catastrophizing in intervention programs for whiplash injury.

Qualitative Examination of the Experience of Perceived Injustice Following Disabling Occupational Injury.

PURPOSE: The primary objective of this study was to explore individuals' perspectives on the factors, situations or events that contributed to their perceptions of injustice following occupational injury. MATERIALS AND METHODS: The study sample consisted of 30 participants (18 women, 12 men) who had submitted a time-loss claim for a work-related musculoskeletal injury. Participants with elevated scores on a measure of perceived injustice were interviewed about the factors that contributed to their sense of injustice. A thematic analysis was conducted to identify the broad classes of situations or events that participants experienced as unjust in the weeks following occupational injury. RESULTS: Three dominant themes emerged from the interviews: (1) Invalidation, (2) Undeserved suffering and (3) Blame. Inductively derived subthemes reflected specific dimensions of post-injury experiences that contributed to participants' sense of injustice. CONCLUSIONS: Given that suffering and invalidating communication are potentially modifiable factors, there are grounds for optimism that intervention approaches can be developed to prevent or reduce perceptions of injustice in the aftermath of debilitating injury. The development of intervention approaches that are effective in preventing or reducing perceptions of injustice holds promise of contributing to more positive recovery outcomes in individuals who have sustained debilitating work injuries.

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.

Establishing the Reliability, Validity, and Prognostic Utility of the Momentary Pain Catastrophizing Scale for Use in Ecological Momentary Assessment Research.

Despite the marked increase in ecological momentary assessment research, few reliable and valid measures of momentary experiences have been established. The goal of this preregistered study was to establish the reliability, validity, and prognostic utility of the momentary Pain Catastrophizing Scale (mPCS), a 3-item measure developed to assess situational pain catastrophizing. Participants in 2 studies of postsurgical pain outcomes completed the mPCS 3 to 5 times per day prior to surgery (N = 494, T = 20,271 total assessments). The mPCS showed good psychometric properties, including multilevel reliability and factor invariance across time. Participant-level average mPCS was strongly positively correlated with dispositional pain catastrophizing as assessed by the Pain Catastrophizing Scale (r = .55 and .69 in study 1 and study 2, respectively). To establish prognostic utility, we then examined whether the mPCS improved prediction of postsurgical pain outcomes above and beyond one-time assessment of dispositional pain catastrophizing. Indeed, greater variability in momentary pain catastrophizing prior to surgery was uniquely associated with increased pain immediately after surgery (b = .58, P = .005), after controlling for preoperative pain levels and dispositional pain catastrophizing. Greater average mPCS score prior to surgery was also uniquely associated with lesser day-to-day improvement in postsurgical pain (b = .01, P = .003), whereas dispositional pain catastrophizing was not (b = -.007, P = .099). These results show that the mPCS is a reliable and valid tool for ecological momentary assessment research and highlight its potential utility over and above retrospective measures of pain catastrophizing. PERSPECTIVE: This article presents the psychometric properties and prognostic utility of a new measure to assess momentary pain catastrophizing. This brief, 3-item measure will allow researchers and clinicians to assess fluctuations in pain catastrophizing during individuals' daily lives, as well as dynamic relationships between catastrophizing, pain, and related factors.

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.

Positive, but not negative, treatment outcome expectancies mediate the relation between depressive symptoms and treatment-related pain reduction.

Previous research has shown that depression is associated with adverse recovery outcomes following work-related musculoskeletal injury. Treatment outcome expectancies have also been shown to predict recovery trajectories following musculoskeletal injury. The present study examined the role of positive and negative treatment outcome expectancies as mediators of the relation between depressive symptoms and treatment outcome for individuals receiving physical therapy for a musculoskeletal injury. The study sample consisted of 153 individuals who had sustained a work-related musculoskeletal injury to the back or neck within 6 months of enrolment. Participants completed self-report measures of depressive symptom severity, pain severity, and treatment outcome expectancies prior to treatment; pain severity was assessed again after 4 weeks of treatment. The results of this study were consistent with previous research showing significant relations between depressive symptom severity, pain severity and treatment outcome expectancies. Bootstrapping mediation analyses separately assessed the mediating roles of positive and negative treatment outcome expectancies on the relation between depressive symptoms and pain severity. Findings revealed that positive treatment outcome expectancies mediated the relation between depressive symptoms and pain severity, whereas negative treatment outcome expectancies did not. Discussion addresses potential pathways through which positive treatment outcome expectancies might influence pain outcomes. The findings suggest that intervention techniques aimed at increasing positive treatment outcome expectancies, rather than decreasing negative treatment outcome expectancies, might contribute to better recovery outcomes for individuals experiencing pain and depressive symptoms following a work-related musculoskeletal injury.

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.

Improving well-being for individuals with persistent pain after surgery for breast cancer, lobular carcinoma in situ, or ductal carcinoma in situ: A randomized clinical trial.

>276,000 Americans will be diagnosed with invasive breast cancer, lobular carcinoma in situ, or ductal carcinoma in situ this year and most will undergo breast surgery as part of their care. Although prognosis is excellent, many patients experience persistent post-surgical pain (PSP), which has no satisfactory pharmacological treatment. The causal contributions of pain-associated psychological factors (e.g., catastrophic thoughts about pain, psychological flexibility, self-efficacy) to the continuing burden of PSP have not yet been determined and may be opportune intervention targets. The randomized trial described here will compare the benefits of three manualized behavioral interventions for individuals with PSP. Participants will receive either: 1) self-guided health education (SGHE); 2) interventionist-guided health education (IGHE); or 3) interventionist-guided pain coping skills training with elements of acceptance and commitment therapy that specially target catastrophic thoughts about pain, self-efficacy, and psychological flexibility (CST-PSP). Participants will prospectively complete validated assessments of primary outcomes (PSP severity and interference) at baseline (pre-intervention) and 3-, 6-, and 12-months later. Validated measures of emotional distress and cancer-specific distress will be assessed as secondary outcomes. To test their roles as drivers of PSP, catastrophic thoughts about pain, self-efficacy, and psychological flexibility, will be assessed and statistically analyzed as mediators of hypothesized beneficial effects. The interventions' impacts on pain sensitivity and central sensitization will be investigated to test these physiological pathways as proximal drivers of PSP. To better characterize the patient experience, additional validated measures will be explored for associations with PSP, along with demographic and clinical factors. Trial registration: https://clinicaltrials.gov/ct2/show/NCT04225585, registered January 13, 2020.

Risk-targeted behavioral activation for the management of work disability associated with comorbid pain and depression: a feasibility study.

PURPOSE: The purpose of the present study was to conduct a preliminary evaluation of the feasibility and impact of a risk-targeted behavioral activation intervention for work-disabled individuals with comorbid pain and depression. METHODS: The design of the study was a single-arm non-randomized trial. The sample consisted of 66 work-disabled individuals with comorbid pain and depression. The treatment program consisted of a 10-week standardized behavioral activation intervention supplemented by techniques to target two psychosocial risk factors for delayed recovery, namely, catastrophic thinking and perceptions of injustice. Measures of pain severity, depression, catastrophic thinking, perceived injustice, and self-reported disability were completed pre-, mid-, and post-treatment. Satisfaction with treatment was assessed at post-treatment. Return to work was assessed at 6-month follow-up. RESULTS: The drop-out rate was 18%. At treatment termination, 91% of participants indicated that they were "very" or "completely" satisfied with their involvement in the treatment program. Significant reductions in pain (Cohen's d = 0.71), depression (d = 0.86), catastrophic thinking (d = 1.1), and perceived injustice (d = 1.0) were observed through the course of treatment. In multivariate analyses, treatment-related reductions in depression, catastrophic thinking, and perceived injustice, but not pain, contributed significant unique variance to the prediction of return-to-work outcomes. CONCLUSIONS: Risk-targeted behavioral activation was found to be an acceptable and effective intervention for work-disabled individuals with comorbid pain and depression. The findings suggest that interventions targeting psychosocial risk factors for pain and depression might contribute to more positive recovery outcomes in work-disabled individuals with comorbid pain and depression. TRIAL REGISTRATION: ClinicalTrials.gov: NCT0517442 . Retrospectively registered.

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.