BACKGROUND:Little is known about the mechanisms underlying the link between violence-related distress and asthma, particularly for asthma endotypes. METHODS:Cross-sectional analysis of violence-related distress in the previous 6 months (assessed using the Checklist of Children's Distress Symptoms [CCDS] scale) and nasal epithelial gene expression in 3 studies of youth with asthma aged 8-20 years: Stress and Treatment Response in Puerto Rican and African American Children with Asthma (STAR, n = 128), Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR, n = 228), and Vitamin D Kids Asthma (VDKA, n = 47). We then tested for the association between expression of CCDS-related genes and nasal epithelial transcriptomic profiles corresponding to T2-high and T17-high asthma endotypes. RESULTS:In a meta-analysis of the CCDS score in the three cohorts, we identified 12 differentially expressed genes (DEGs) with false discovery rate-adjusted p value (FDR-P) < 0.05 and the same direction of association as in the discovery cohort (EVA-PR) in at least one replication cohort. Of these 12 DEGs, 9 (S100A7A, CCL2, CCL8, CXCL9-11, COL15A1, CD300E, and LILRB1) were upregulated and significantly associated with T17-high asthma in a meta-analysis of the three cohorts. Two genes belong to the CC Motif Chemokine Ligand family (CCL2, CCL8) and 3 belong to the CXC Motif Chemokine Ligand family (CXCL9, CXCL10, and CXCL11). CONCLUSION:Nine novel genes were associated with violence-related distress and T17-high asthma in three cohorts of predominantly minoritized youth with asthma. Our findings may help uncover biologic processes underlying the violence-asthma link and could represent novel therapeutic targets for T17-high asthma.

Allostatic load measures the physiological consequences of stress and is associated with disease outcomes. Clinical use of allostatic load is limited, in part, because its calculation requires biomarkers not routinely measured in clinical care. Presently, we evaluated associations between high allostatic load and depression as co-occurring consequences of stress among a cohort representing population subgroups largely excluded from existing literature. We emphasize clinical implementation potential by employing both an established and a recent consensus streamlined allostatic load score. Data arise from a nested case–control study within the Southern Community Cohort Study (N = 982); 72

Mind–body interventions such as mindfulness-based stress reduction (MBSR) may improve well-being by increasing awareness and regulation of physiological and cognitive states. However, it is unclear how practice may alter long-term, baseline physiological processes, and whether these changes reflect improved well-being. Using respiration rate (RR), which can be sensitive to effects of meditation, and 3 aspects of self-reported well-being (psychological well-being [PWB], distress, and medical symptoms), we tested pre-registered hypotheses that: (1) Lower baseline RR (in a resting, non-meditative state) would be a physiological marker associated with well-being, (2) MBSR would decrease RR, and (3) Training-related decreases in RR would be associated with improved well-being. We recruited 245 adults (age range = 18–65, M = 42.4): experienced meditators (n = 42), and meditation-naïve participants randomized to MBSR (n = 72), active control (n = 41), or waitlist control (n = 66). Data were collected at pre-randomization, post-intervention (or waiting), and long-term follow-up. Lower baseline RR was associated with lower psychological distress among long-term meditators (p* = 0.03, b = 0.02, 95% CI [0.01, 0.03]), though not in non-meditators prior to training. MBSR decreased RR compared to waitlist (p = 0.02, Cohen’s d = − 0.41, 95% CI [− 0.78, − 0.06]), but not the active control. Decreased RR related to decreased medical symptoms, across all participants (p* = 0.02, b = 0.57, 95% CI [0.15, 0.98]). Post-training, lower RR was associated with higher PWB across training groups compared to waitlist (p* = 0.01, b = 0.06, 95% CI [0.02, 0.10]), though there were no significant differences in change in PWB between groups. This physiological marker may indicate higher physical and/or psychological well-being in those who engage in wellness practices.

Substantial knowledge about asthma has accumulated in past decades from biomedical and psychobiological research. This white paper reports on synergistic perspectives for these fields discussed at the first Annual Disease-A-Year Symposium of the American Psychosomatic Society. Progress has been made in identifying mechanical, cellular and molecular mechanisms of asthma and influences of psychosocial factors on development, pathophysiology, and management have been demonstrated. However, much remains to be learned about mechanisms of asthma development, in particular the role of genes and the microbiome, and their interaction with psychosocial factors. Additional psychobiological analysis of immunobiological pathways and pathophysiological features is also needed, as well as integration with asthma phenotypes. Although traditionally viewed as a peripheral disease of the airways, its effect on the central nervous system and cognition has begun to garner attention due to neuroscientific and technological advances. Brain-body interaction is also the focus of airway interoception research, with practical consequences for the management of overperception and underperception of airway obstruction. An integrative perspective on asthma recognizes societal factors that worsen and consolidate disparities in asthma outcomes and explores mechanisms of building resilience in patients from disadvantaged communities. Biomedical treatment with novel monoclonal antibodies promises a personalized medicine approach, while improvements to asthma management trainings have increased disease control and quality of life. Psychobiological and mind-body interventions, such as exercise, breathing training, cognitive behavioral therapy, or meditation techniques, require further exploration in large-scale multicenter trials. Close interdisciplinary collaboration will bring the field closer to the ideal of a holistic biopsychosocial treatment of asthma.

Background: Asthma and depression frequently co-occur, potentially worsening each other’s symptoms. The salience network (SN) may play a key role in this link, but the roles of the default mode network (DMN) and frontoparietal network (FPN), as outlined in the triple network theory, remain unclear in the asthma-depression connection. This longitudinal study investigated pre-post changes in graph-theory metrics within and between the 3 networks in individuals with asthma and how these relate to depressive symptoms. Methods: Twenty-four individuals with asthma underwent functional magnetic resonance imaging scans pre- and postsegmental allergen challenge. Depressive symptoms were assessed at baseline using the Beck Depression Inventory. Changes in graph-theory metrics were analyzed using region-of-interest (ROI)-to-ROI analyses, controlling for sex. Results: Allergen challenge led to changes in network properties. Within-network analyses showed decreased degree centrality (β = 0.50, false discovery rate–corrected p [pFDR] = .004) and betweenness centrality (β = 0.10, pFDR = .025) of the posterior cingulate cortex (DMN) and reduced degree centrality of the anterior cingulate cortex (SN), which correlated with depressive symptoms (β = 0.05, pFDR = .017). Between-network analyses showed reduced closeness centrality in the bilateral lateral parietal during SN-DMN interactions (right: β = 0.23, pFDR = .010; left: β = 0.23, pFDR = .013) and increased degree centrality in the left posterior parietal cortex during SN-FPN interactions (β = −0.10, pFDR = .038), which correlated with depressive symptoms. Conclusions: Allergen challenge alters graph-theory metrics within and between resting-state networks, with changes linked to depression symptoms. Findings highlight the SN’s critical role in network switching and its vulnerability to inflammation in asthma-depression connection.

Trait mindfulness refers to one's disposition or tendency to pay attention to their experiences in the present moment, in a non-judgmental and accepting way. Trait mindfulness has been robustly associated with positive mental health outcomes, but its neural underpinnings are poorly understood. Prior resting-state fMRI studies have associated trait mindfulness with within- and between-network connectivity of the default-mode (DMN), fronto-parietal (FPN), and salience networks. However, it is unclear how generalizable the findings are, how they relate to different components of trait mindfulness, and how other networks and brain areas may be involved. To address these gaps, we conducted the largest resting-state fMRI study of trait mindfulness to-date, consisting of a pre-registered connectome-based predictive modeling analysis in 367 meditation-naïve adults across three samples collected at different sites. In the model-training dataset, we did not find connections that predicted overall trait mindfulness, but we identified neural models of two mindfulness subscales, Acting with Awareness and Non-judging. Models included both positive networks (sets of pairwise connections that positively predicted mindfulness with increasing connectivity) and negative networks, which showed the inverse relationship. The Acting with Awareness and Non-judging positive network models showed distinct network representations involving FPN and DMN, respectively. The negative network models, which overlapped significantly across subscales, involved connections across the whole brain with prominent involvement of somatomotor, visual and DMN networks. Only the negative networks generalized to predict subscale scores out-of-sample, and not across both test datasets. Predictions from both models were also negatively correlated with predictions from a well-established mind-wandering connectome model. We present preliminary neural evidence for a generalizable connectivity models of trait mindfulness based on specific affective and cognitive facets. However, the incomplete generalization of the models across all sites and scanners, limited stability of the models, as well as the substantial overlap between the models, underscores the difficulty of finding robust brain markers of mindfulness facets.

BACKGROUND:Asthma, a highly prevalent chronic inflammatory disease of the airways, results in an average of 10 deaths per day in the U.S., and psychological stress hinders its effective management. Threat-sensitive neurocircuitry, active during psychological stress, may intensify airway inflammatory responses and contribute to poor clinical outcomes. However, the neural mechanisms and descending pathways connecting acute stress and inflammatory responses to allergen exposure remain poorly understood. We hypothesized that stress-induced engagement of the salience network would prime Th17 immune pathways and potentiate airway inflammation. METHODS:We measured brain glucose metabolism during the Trier Social Stress Test (TSST) and a non-stressful control task using [18F]fluorodeoxyglucose positron emission tomography (PET) in 28 adults (18F) with asthma. Salivary cortisol was collected to quantify physiological stress responses. Before and after airway provocation with a whole-lung allergen challenge (WL-AG), airway inflammation was assessed using fraction of exhaled nitric oxide (FeNO), sputum % eosinophils, and expression of Th17-related cytokine mRNA in the airway. RESULTS:As expected, the WL-AG increased all inflammatory biomarkers. Acute stress significantly increased salivary cortisol (t(27.3) = -27.3, p < 0.01), but did not significantly affect airway inflammation overall. Instead, more robust cortisol responses to stress predicted increased glucose metabolism in the amygdala, insula, and dorsal anterior cingulate cortex, key nodes in the salience network, as well as increased IL-23A mRNA expression (t(22.1) = 2.38, p = 0.026) and FeNO (t(21.5) = 2.17, p = 0.041). Moreover, differential increases in amygdala and dACC glucose metabolism predicted differential increases IL-23A mRNA expression following WL-AG. In addition, compared to low chronic stress, high chronic stress was associated with enhanced IL-17A mRNA expression in response to acute stress and WL-AG. CONCLUSIONS:Individual differences in salience network and cortisol responses to acute stress predict enhanced allergen challenge-provoked Th17-related responses, advancing our understanding of the efferent arm of the lung-brain axis in asthma. This work underscores the importance of translational research for the development of novel interventions that target stress-sensitive brain and immune pathways.

Background: Airway inflammation plays a critical role in asthma pathogenesis and pathophysiology, but the molecular pathways contributing to airway inflammation are not fully known, particularly type 2 (T2) inflammation characterized by both eosinophilia and higher fractional exhaled nitric oxide (FENO) levels. Objective: We sought to identify genes whose level of expression in epithelial brushing samples were associated with both bronchoalveolar lavage (BAL) eosinophilia and generation of FENO. Methods: We performed segmental allergen bronchoprovocation (SBP-Ag) in participants with asthma, then RNA sequencing analyses of BAL cells and brushing samples before and 48 hours after SBP-Ag to identify regulation of eosinophil recruitment and FENO changes. Results: Allergen bronchoprovocation increased FENO levels, which correlated with eosinophilia. Thirteen genes were identified in brushing samples, whose expression changed in response to SBP-Ag and correlated with both airway eosinophilia and FENO levels after SBP-Ag. Among these 13 genes, epithelial cell product CDH26/cadherin-26 contributed to the amplification of T2 inflammation, as reflected by eosinophilia and FENO, and causal mediation analyses with pro-T2 and proeosinophilic cytokine mediators in BAL fluids. Among the genes associated with reduced eosinophilia and FENO, HEY2 is known to enhance cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition, as well as to reduce apoptosis. Conclusion: This unbiased RNA sequencing analysis in participants with allergic asthma revealed several epithelial cell genes, particularly CDH26, that may be critical for the development or augmentation of T2 inflammation in asthma. (J Allergy Clin Immunol 2025;155:1510-20.)

Introduction Chronic systemic inflammation is highly prevalent and has deleterious effects on the brain, impacting both function and structure, and manifesting in elevations in psychological symptoms transdiagnostically. Asthma is a chronic inflammatory disease of the airway that affects more than 300 million people worldwide and is known to be highly comorbid with psychological and cognitive dysfunction. Though a growing corpus of work has identified functional brain abnormalities associated with asthma, limited research has investigated structural differences which may partially underlie functional changes. Identifying and characterizing asthma-related structural brain changes will shed light on the neurobiology through which asthma impacts mental function and has the potential to inform prophylaxis and treatment. Methods We examined differences in regional brain volume, cortical thickness, and surface area, in 128 individuals with asthma compared to 134 non-asthma healthy controls. Five regions of interest were examined a priori, based on their previous implication in inflammation-related functional consequences (dorsal and ventral striatum, pallidum, and insula), or previous evidence of asthma-related structural impact (hippocampus and thalamus). We supplemented our region of interest approach with a voxel-wise whole-brain analysis. Additionally, we examined the association of brain structure with depression symptoms, asthma severity, degree of inflammation, and plasma biomarkers of neuroinflammation, neurodegeneration, and Alzheimer’s disease specific pathology. Results Compared to non-asthma control participants, those with asthma had smaller nucleus accumbens volumes, thicker orbitofrontal cortices, larger middle frontal cortex surface areas, and greater diencephalon volumes. Those with more severe asthma had smaller nucleus accumbens and dorsal striatal volumes, reduced anterior cingulate cortex surface area, and greater amygdala volume compared to those with mild asthma. In untreated asthma patients, greater depressive symptoms were associated with smaller striatal volume, suggesting a potential CNS-protective effect of medications that reduce airway inflammation in asthma. In addition, a plasma marker of astrogliosis was associated with larger diencephalon, cerebellum, brainstem, and thalamus volumes, but reduced insula thickness and surface area. Conclusions Patterns of structural brain changes in participants with asthma encompass key regions of reward and salience networks, which may in part give rise to the functional alterations in these networks characteristic of chronic systemic inflammation.

BACKGROUND:Inflammation is an established contributor to the pathophysiology of depression and the prevalence of depression in those with chronic inflammatory disease is two- to four-fold higher than the general population. Yet little is known about the neurobiological changes that confer depression or resilience to depression, that occur when episodes of heightened inflammation are frequent or span many years. METHODS:We used an innovative combination of longitudinal resting state functional magnetic resonance imaging coupled to segmental bronchial provocation with allergen (SBP-Ag) to assess changes in resting state functional connectivity (rsFC) of the salience network (SN) caused by an acute inflammatory exacerbation in twenty-six adults (15 female) with asthma and varying levels of depressive symptoms. Eosinophils measured in bronchoalveolar lavage fluid and blood provided an index of allergic inflammation and the Beck Depression Inventory provided an index of depressive symptoms. RESULTS:We found that in those with the highest symptoms of depression at baseline, SN rsFC declined most from pre- to post-SBP-Ag in the context of a robust eosinophilic response to challenge, but in those with low depressive symptoms SN rsFC was maintained or increased, even in those with the most pronounced SBP-Ag response. CONCLUSIONS:Thus, the maintenance of SN rsFC during inflammation may be a biomarker of resilience to depression, perhaps via more effective orchestration of large-scale brain network dynamics by the SN. These findings advance our understanding of the functional role of the SN during inflammation and inform treatment recommendations for those with comorbid inflammatory disease and depression.

Background: The staggering morbidity associated with chronic inflammatory diseases can be reduced by psychological interventions, including Mindfulness-Based Stress Reduction (MBSR). Proposed mechanisms for MBSR's beneficial effects include changes in salience network function. Salience network perturbations are also associated with chronic inflammation, including airway inflammation in asthma, a chronic inflammatory disease affecting approximately 10% of the population. However, no studies have examined whether MBSR-related improvements in disease control are related to changes in salience network function.Methods: Adults with asthma were randomized to 8 weeks of MBSR or a waitlist control group. Resting state functional connectivity was measured using fMRI before randomization, immediately post-intervention, and 4 months post-intervention. Using key salience network regions as seeds, we calculated group differences in change in functional connectivity over time and examined whether functional connectivity changes were associated with increased mindfulness, improved asthma control, and decreased inflammatory biomarkers.Results: The MBSR group showed greater increases in functional connectivity between salience network regions relative to the waitlist group. Improvements in asthma control correlated with increased functional connectivity between the salience network and regions important for attention control and emotion regulation. Improvements in inflammatory biomarkers were related to decreased functional connectivity between the salience network and other networks.Conclusions: Increased resting salience network coherence and connectivity with networks that subserve attention and emotion regulation may contribute to the benefits of MBSR for patients with asthma. Understanding the neural underpinnings of MBSR-related benefits in patients is a critical step towards optimizing brain targeted interventions for chronic inflammatory disease management.

BACKGROUND:International data suggest that asthma, like other inflammatory diseases, might increase Alzheimer disease (AD) risk. OBJECTIVE:We sought to explore risk pathways and future mitigation strategies by comparing diagnostic claims-based AD incidence and prevalence among US patients with asthma with those without asthma. METHODS:This cohort study included a national Medicare 20% random sample (2013-2015). Adult patients with asthma with more than 12 months continuous Medicare were compared with subjects without asthma overall and as matched. Asthma was defined by 1 inpatient or 2 outpatient codes for asthma. The main outcomes were 2-year incident or prevalent AD defined by International Classification of Diseases, Ninth Revision code 331.0 or Tenth Revision code G30.0, G30.1, G30.8, or G30.9. RESULTS:Among 5,460,732 total beneficiaries, 678,730 patients were identified with baseline asthma and more often identified as Black or Hispanic, were Medicaid eligible, or resided in a highly disadvantaged neighborhood than those without asthma. Two-year incidence of AD was 1.4% with asthma versus 1.1% without asthma; prevalence was 7.8% versus 5.4% (both P ≤ .001). Per 100,000 patients over 2 years, 303 more incident AD diagnoses occurred in those with asthma, with 2,425 more prevalent cases (P < .001). Multivariable models showed that asthma had greater odds of 2-year AD incidence (adjusted odds ratio, 1.33 [95% CI, 1.29-1.36]; matched 1.2 [95% CI, 1.17-1.24]) and prevalence (adjusted odds ratio, 1.48 [95% CI, 1.47-1.50]; matched 1.25 [95% CI, 1.22-1.27]). CONCLUSIONS:Asthma was associated with 20% to 33% increased 2-year incidence and 25% to 48% increased prevalence of claims-based AD in this nationally representative US sample. Future research should investigate risk pathways of underlying comorbidities and social determinants as well as whether there are potential asthma treatments that may preserve brain health.

BACKGROUND:Accumulating evidence indicates that asthma has systemic effects and affects brain function. Although airway inflammation is proposed to initiate afferent communications with the brain, the signaling pathways have not been established.OBJECTIVE:We sought to identify the cellular and molecular pathways involved in afferent lung-brain communication during airway inflammation in asthma.METHODS:In 23 adults with mild asthma, segmental bronchial provocation with allergen (SBP-Ag) was used to provoke airway inflammation and retrieve bronchoalveolar lavage fluid for targeted protein analysis and RNA sequencing to determine gene expression profiles. Neural responses to emotional cues in nodes of the salience network were assessed with functional magnetic resonance imaging at baseline and 48 hours after SBP-Ag.RESULTS:Cell deconvolution and gene coexpression network analysis identified 11 cell-associated gene modules that changed in response to SBP-Ag. SBP-Ag increased bronchoalveolar lavage eosinophils and expression of an eosinophil-associated module enriched for genes related to TH17-type inflammation (eg, IL17A), as well as cell proliferation in lung and brain (eg, NOTCH1, VEGFA, and LIF). Increased expression of genes in this module, as well as several TH17-type inflammation-related proteins, was associated with an increase from baseline in salience network reactivity.CONCLUSIONS:Our results identify a specific inflammatory pathway linking asthma-related airway inflammation and emotion-related neural function. Systemically, TH17-type inflammation has been implicated in both depression and neuroinflammation, with impacts on long-term brain health. Thus, our data emphasize that inflammation in the lung in asthma may have profound effects outside of the lung that may be targetable with novel therapeutic approaches.