Parasympathetic cardiac control during attentional focus and worry in major depressive disorder.

Worry, which refers to uncontrollable chains of thoughts and images with negative affective load, is a transdiagnostic symptom of various mental disorders including major depressive disorder (MDD). Current theories relate excessive worry to deficient top-down control of automatically occurring perseverative thinking. This study investigated parasympathetic cardiac control in MDD in the context of worry and cognitive control. Heart rate variability (HRV) was recorded, in the high frequency (HF) and low frequency (LF) bands, in 36 MDD patients and 36 healthy controls while they performed a breathing focus task. The task included two phases during which participants' ability to concentrate on their breathing was assessed before and after an instructed worry phase. In addition to higher self-reported worry, MDD patients exhibited lower HF and LF HRV at rest, and lower LF HRV during the task than controls. MDD was also associated with impaired breathing concentration ability, more negative and neutral thought intrusions, more negative mood during breathing focus and increased stress during instructed worry. In the total sample, LF HRV correlated negatively with self-reported worry and negative thought intrusions, and positively with mood ratings. The reduction of HRV confirms the notion of low parasympathetic cardiac control in MDD. Moreover, low HRV represents a correlate of blunted prefrontal activity and impaired cognitive control that characterize the disorder. Impaired cognitive control may exacerbate worry, which is in turn involved in the genesis of aversive emotional states and maintenance of MDD.

Do More of What Makes You Happy? The Applicability of Signature Character Strengths and Future Physicians' Well-Being and Health Over Time.

Research on applying signature character strengths demonstrated positive effects on well-being, health and work behavior. Future health care professionals represent a group at risk for impaired well-being due to high study demands. This study investigates potential long-term protective effects on well-being. In total, 504 medical students participated in a longitudinal online study, with at least 96 providing complete data at all three time points (time lag: 1 year). Data on individual signature character strengths and their applicability, thriving (subjective and psychological well-being), work engagement, burnout, mental and physical health were collected. Longitudinal relations of signature character strengths' applicability and well-being, mental and physical health were tested with cross-lagged panel analyses. Moreover, indirect longitudinal mediation effects via work engagement and emotional exhaustion were considered. Cross-lagged panel analyses demonstrated significant positive effects of thriving on signature character strengths' applicability at later time points (ß = 0.20 to 0.27) indicating that higher levels of well-being might be mandatory first to have access to one's own signature character strengths in a naturalistic setting. Disentangling thriving, the effect was only significant for psychological well-being (t1-t2: ß = 0.23; t2-t3: ß = 0.27). Across all three time points, significant indirect effects via work engagement on the relation of the applicability of signature character strengths and well-being were identified (r = 0.15), whereas significant indirect effects on mental and physical health were only evident at t2 (both: r = 0.06) and t3 (mental health: r = 0.11). A longitudinal mediation analysis via work engagement revealed a significant indirect effect (a∗b = 0.13). These results call for further research as previous studies showed that the applicability of signature character strengths affected well-being, not vice versa. The 'broaden-and-build' theory (positive emotions broaden one's consciousness and hereupon individuals build new enduring resources and skills) and the assumption of well-being in a "top-down" model (trait-like predisposition to interpret life experiences in positive ways coloring one's evaluation of satisfaction in various domains accordingly) could possibly explain these novel results.

Parasympathetic cardiac control and attentional focus in trait worry.

Trait worry refers to a tendency toward increased vigilance to threat and reduced tolerance of uncertainty. While it has been established as a risk factor of general morbidity, knowledge about autonomic regulation in trait worry remains scarce. This study investigated parasympathetic cardiac control in trait worry, in the context of attentional focus. Healthy groups with high and low worry were selected using the Penn State Worry Questionnaire (n = 40 per group). Heart rate variability (HRV) was recorded in the high frequency (HF) and low frequency (LF) bands while participants performed a breathing focus task. The task included a phase of instructed worry and two phases during which participants´ ability to concentrate on their breathing was assessed. As compared to the low worry group, the high worry group exhibited lower HRV in the LF band during both breathing focus phases and smaller reduction of LF HRV during instructed worry. HF HRV did not differ between groups. High worry was associated with impaired ability to concentrate on breathing and more intrusive thoughts. In the total sample, negative intrusions correlated negatively with LF HRV during the first breathing focus phase and LF HRV reactivity. Instructed worry led to greater perceived stress and deterioration of mood in high worry participants. Reduced LF HRV reflects blunted parasympathetic cardiac control in trait worry, associated with elevated risk of poor health outcomes. In addition, it might represent a psychophysiological correlate of reduced cognitive inhibition, which interferes with attentional focus and impedes control of threat processing and perseverative thinking.

Features of autonomic cardiovascular control during cognition in major depressive disorder.

Previous research has suggested reduced parasympathetic cardiac regulation during cognitive activity in major depressive disorder (MDD). However, little is known about possible abnormalities in sympathetic control and cardiovascular reactivity. This study aimed to provide a comprehensive analysis of autonomic cardiovascular control in the context of executive functions in MDD. Thirty six MDD patients and 39 healthy controls participated. Parameters of sympathetic (pre-ejection period, PEP) and parasympathetic control (high and low frequency heart rate variability, HF HRV, LF HRV; and baroreflex sensitivity, BRS) as well as RR interval were obtained at rest and during performance of executive function tasks (number-letter task, n-back task, continuous performance test, and Stroop task). Patients, as compared to controls, exhibited lower HF HRV and LF HRV during task execution and smaller shortenings in PEP and RR interval between baseline and tasks. They displayed longer reaction times during all conditions of the tasks and more omission errors and false alarms on the continuous performance test. In the total sample, on-task HF HRV, LF HRV and BRS, and reactivity in HF HRV, LF HRV, and PEP, were positively associated with task performance. As performance reduction arose independent of executive function load of the tasks, the behavioral results reflect impairments in attention and processing speed rather than executive dysfunctions in MDD. Abnormalities in cardiovascular control during cognition in MDD appear to involve both divisions of the autonomic nervous system. Low tonic parasympathetic control and blunted sympathetic reactivity imply reduced physiological adjustment resources and, by extension, provide suboptimal conditions for cognitive performance.

Dispositional empathy is associated with experimental pain reduction during provision of social support by romantic partners.

Background and aims While social interactions like verbal support and physical touch have repeatedly been shown to reduce experimental pain, analgesic effects of passive social support, i.e. the sole physical presence of a supportive other, remain unclear. Moreover, little is known about individual factors influencing the extent of pain attenuation during social support. This study investigated analgesic effects of passive support by a romantic partner and the role of partner empathy therein. Methods In 48 heterosexual couples, sensitivity to pressure pain was assessed; each participant was tested alone and in the passive presence of his/her partner. Dispositional empathy was quantified by a questionnaire. Results In the presence, as compared to absence, of their partners men and women exhibited higher pain threshold and tolerance, as well as lower sensory and affective pain ratings on constant pressure stimuli. Partner empathy was positively associated with pain tolerance and inversely associated with sensory pain experience. Conclusions The results confirm the analgesic effects of social support, which may even occur without verbal or physical contact. Partner empathy may buffer affective distress during pain exposure, thereby reducing pain sensitivity and promoting pain coping. These processes may occur solely due to a partner's physical presence and do not necessarily require direct empathetic feedback.

Cerebral blood flow modulations during antisaccade preparation in chronic hypotension.

In addition to symptoms including fatigue, dizziness, reduced drive, or mood disturbance, individuals with chronic low blood pressure (hypotension) frequently report cognitive complaints. While attentional deficits have been empirically confirmed, it is still unknown whether the impairments also encompass executive functions. This study investigated cerebral blood flow modulations in hypotension during a precued antisaccade/prosaccade task requiring the executive function of proactive inhibition in addition to preparatory attention. Using functional transcranial Doppler sonography, bilateral blood flow velocities in the middle cerebral arteries (MCA) were recorded in 39 hypotensive and 40 normotensive participants. In the task, a stimulus appeared left or right of a fixation point 5 s after a cuing stimulus; subjects had to move their gaze to the mirror image position of the stimulus (antisaccade) or toward it (prosaccade control condition). Video-based eye tracking was used for ocular recording. A right dominant MCA blood flow increase arose during task preparation, which was smaller in hypotensive than normotensive participants. In addition, hypotensive participants exhibited lower peak velocity of the saccadic response. The extent of the reductions in blood flow and task performance in hypotension did not differ between antisaccade and prosaccade conditions. The smaller MCA flow increase may reflect reduced activity in the dorsolateral prefrontal and inferior parietal cortices during proactive inhibition and preparatory attention in hypotension. Given that group differences in blood flow and performance arose independent of task complexity and executive function load, hypotension may be characterized by basic attentional impairments rather than particular executive function deficits.

Cerebral blood flow modulations during proactive control in chronic hypotension.

In addition to complaints including fatigue, mood disturbance, dizziness or cold limbs, chronic low blood pressure (hypotension) is associated with reduced cognitive performance. Deficiencies in cerebral blood flow regulation may contribute to this impairment. This study investigated cerebral blood flow modulations during proactive control in hypotension. Proactive control refers to cognitive processes during anticipation of a behaviourally relevant event that allow optimization of readiness to react. Using functional transcranial Doppler sonography, bilateral blood flow velocities in the middle cerebral arteries were recorded in 40 hypotensive and 40 normotensive participants during a precued Stroop task. Hypotensive participants exhibited smaller bilateral blood flow increases during response preparation and longer response time. The group differences in blood flow and response time did not vary by executive function load, i.e. congruent vs. incongruent trials. Over the total sample, the flow increase correlated negatively with response time in trials with a higher executive function load. The findings indicate reduced cerebral blood flow adjustment during both the basic and more complex requirements of proactive control in hypotension. They also suggest a general deficit in attentional function and processing speed due to low blood pressure and cerebral hemodynamic dysregulations rather than particular impairments in executive functions.

The nuclear membrane leukotriene synthetic complex is a signal integrator and transducer.

Leukotrienes (LTs) are lipid-signaling molecules derived from arachidonic acid (AA) that initiate and amplify inflammation. To initiate LT formation, the 5-lipoxygenase (5-LO) enzyme translocates to nuclear membranes, where it associates with its scaffold protein, 5-lipoxygenase-activating protein (FLAP), to form the core of the multiprotein LT synthetic complex. FLAP is considered to function by binding free AA and facilitating its use as a substrate by 5-LO to form the initial LT, LTA(4). We used a combination of fluorescence lifetime imaging microscopy, cell biology, and biochemistry to identify discrete AA-dependent and AA-independent steps that occur on nuclear membranes to control the assembly of the LT synthetic complex in polymorphonuclear leukocytes. The association of AA with FLAP changes the configuration of the scaffold protein, enhances recruitment of membrane-associated 5-LO to form complexes with FLAP, and controls the closeness of this association. Granulocyte monocyte colony-stimulating factor provides a second AA-independent signal that controls the closeness of 5-LO and FLAP within complexes but not the number of complexes that are assembled. Our results demonstrate that the LT synthetic complex is a signal integrator that transduces extracellular signals to modulate the interaction of 5-LO and FLAP.

Ly6G ligation blocks recruitment of neutrophils via a ß2-integrin-dependent mechanism.

Ly6G is a glycosylphosphatidylinositol (GPI)-anchored protein of unknown function that is commonly targeted to induce experimental neutrophil depletion in mice. In the present study, we found that doses of anti-Ly6G Abs too low to produce sustained neutropenia remained capable of inhibiting experimental arthritis, leaving joint tissues free of infiltrating neutrophils. Thioglycollate-stimulated peritonitis was also attenuated. No alteration in neutrophil apoptosis was observed, implicating impaired recruitment. Indeed, Ly6G ligation abrogated neutrophil migration toward LTB(4) and other chemoattractants in a transwell system. Exploring the basis for this blockade, we identified colocalization of Ly6G and ß2-integrins by confocal microscopy and confirmed close association by both coimmunoprecipitation and fluorescence lifetime imaging microscopy. Anti-Ly6G Ab impaired surface expression of ß2-integrins in LTB(4)-stimulated neutrophils and mimicked CD11a blockade in inhibiting both ICAM-1 binding and firm adhesion to activated endothelium under flow conditions. Correspondingly, migration of ß2-integrin-deficient neutrophils was no longer inhibited by anti-Ly6G. These results demonstrate that experimental targeting of Ly6G has functional effects on the neutrophil population and identify a previously unappreciated role for Ly6G as a modulator of neutrophil migration to sites of inflammation via a ß2-integrin-dependent mechanism.

Joint tissues amplify inflammation and alter their invasive behavior via leukotriene B4 in experimental inflammatory arthritis.

Mechanisms by which mesenchymal-derived tissue lineages participate in amplifying and perpetuating synovial inflammation in arthritis have been relatively underinvestigated and are therefore poorly understood. Elucidating these processes is likely to provide new insights into the pathogenesis of multiple diseases. Leukotriene B(4) (LTB(4)) is a potent proinflammatory lipid mediator that initiates and amplifies synovial inflammation in the K/BxN model of arthritis. We sought to elucidate mechanisms by which mesenchymal-derived fibroblast-like synoviocytes (FLSs) perpetuate synovial inflammation. We focused on the abilities of FLSs to contribute to LTB(4) synthesis and to respond to LTB(4) within the joint. Using a series of bone marrow chimeras generated from 5-lipoxygenase(-/-) and leukotriene A(4) (LTA(4)) hydrolase(-/-) mice, we demonstrate that FLSs generate sufficient levels of LTB(4) production through transcellular metabolism in K/BxN serum-induced arthritis to drive inflammatory arthritis. FLSs-which comprise the predominant lineage populating the synovial lining-are competent to metabolize exogenous LTA(4) into LTB(4) ex vivo. Stimulation of FLSs with TNF increased their capacity to generate LTB(4) 3-fold without inducing the expression of LTA(4) hydrolase protein. Moreover, LTB(4) (acting via LTB(4) receptor 1) was found to modulate the migratory and invasive activity of FLSs in vitro and also promote joint erosion by pannus tissue in vivo. Our results identify novel roles for FLSs and LTB(4) in joints, placing LTB(4) regulation of FLS biology at the center of a previously unrecognized amplification loop for synovial inflammation and tissue pathology.

Ca2+ entry via TRPC channels is necessary for thrombin-induced NF-kappaB activation in endothelial cells through AMP-activated protein kinase and protein kinase Cdelta.

The transient receptor potential canonical (TRPC) family channels are proposed to be essential for store-operated Ca2+ entry in endothelial cells. Ca2+ signaling is involved in NF-kappaB activation, but the role of store-operated Ca2+ entry is unclear. Here we show that thrombin-induced Ca2+ entry and the resultant AMP-activated protein kinase (AMPK) activation targets the Ca2+-independent protein kinase Cdelta (PKCdelta) to mediate NF-kappaB activation in endothelial cells. We observed that thrombin-induced p65/RelA, AMPK, and PKCdelta activation were markedly reduced by knockdown of the TRPC isoform TRPC1 expressed in human endothelial cells and in endothelial cells obtained from Trpc4 knock-out mice. Inhibition of Ca2+/calmodulin-dependent protein kinase kinase beta downstream of the Ca2+ influx or knockdown of the downstream Ca2+/calmodulin-dependent protein kinase kinase beta target kinase, AMPK, also prevented NF-kappaB activation. Further, we observed that AMPK interacted with PKCdelta and phosphorylated Thr505 in the activation loop of PKCdelta in thrombin-stimulated endothelial cells. Expression of a PKCdelta-T505A mutant suppressed the thrombin-induced but not the TNF-alpha-induced NF-kappaB activation. These findings demonstrate a novel mechanism for TRPC channels to mediate NF-kappaB activation in endothelial cells that involves the convergence of the TRPC-regulated signaling at AMPK and PKCdelta and that may be a target of interference of the inappropriate activation of NF-kappaB associated with thrombosis.

The nuclear membrane organization of leukotriene synthesis.

Leukotrienes (LTs) are signaling molecules derived from arachidonic acid that initiate and amplify innate and adaptive immunity. In turn, how their synthesis is organized on the nuclear envelope of myeloid cells in response to extracellular signals is not understood. We define the supramolecular architecture of LT synthesis by identifying the activation-dependent assembly of novel multiprotein complexes on the outer and inner nuclear membranes of mast cells. These complexes are centered on the integral membrane protein 5-Lipoxygenase-Activating Protein, which we identify as a scaffold protein for 5-Lipoxygenase, the initial enzyme of LT synthesis. We also identify these complexes in mouse neutrophils isolated from inflamed joints. Our studies reveal the macromolecular organization of LT synthesis.

Role of NF-kappaB-dependent caveolin-1 expression in the mechanism of increased endothelial permeability induced by lipopolysaccharide.

We investigated the role of NF-kappaB activation by the bacterial product lipopolysaccharide (LPS) in inducing caveolin-1 (Cav-1) expression and its consequence in contributing to the leakiness of the endothelial barrier. We observed that LPS challenge of human lung microvascular endothelial cells induced concentration- and time-dependent increases in expression of Cav-1 mRNA and protein. The NEMO (NF-kappaB essential modifier binding domain)-binding domain peptide (IkB kinase (IKK)-NEMO-binding domain (NBD) peptide), which prevents NF-kappaB activation by inhibiting the interaction of IKKgamma with the IKK complex, blocked LPS-induced Cav-1 mRNA and protein expression. Knockdown of NF-kappaB subunit p65/RelA expression with small interfering RNA also prevented LPS-induced Cav-1 expression. Caveolae open to the apical and basal plasmalemma of endothelial cells increased 2-4-fold within 4 h of LPS exposure. IKK-NBD peptide markedly reduced the LPS-induced increase in the number of caveolae as well as transendothelial albumin permeability. These observations were recapitulated in mouse studies in which IKK-NBD peptide prevented Cav-1 expression and interfered with the increase in lung microvessel permeability induced by LPS. Thus, LPS mediates NF-kappaB-dependent Cav-1 expression that results in increased caveolae number and thereby contributes to the mechanism of increased transendothelial albumin permeability.

Ca2+ influx induced by protease-activated receptor-1 activates a feed-forward mechanism of TRPC1 expression via nuclear factor-kappaB activation in endothelial cells.

Thrombin activation of protease-activated receptor-1 induces Ca(2+) influx through store-operated cation channel TRPC1 in endothelial cells. We examined the role of Ca(2+) influx induced by the depletion of Ca(2+) stores in signaling TRPC1 expression in endothelial cells. Both thrombin and a protease-activated receptor-1-specific agonist peptide induced TRPC1 expression in human umbilical vein endothelial cells, which was coupled to an augmented store-operated Ca(2+) influx and increase in endothelial permeability. To delineate the mechanisms of thrombin-induced TRPC1 expression, we transfected in endothelial cells TRPC1-promoter-luciferase (TRPC1-Pro-Luc) construct containing multiple nuclear factor-kappaB (NF-kappaB) binding sites. Co-expression of dominant negative IkappaBalpha mutant prevented the thrombin-induced increase in TRPC1 expression, indicating the key role of NF-kappaB activation in mediating the response. Using TRPC1 promoter-deletion mutant constructs, we showed that NF-kappaB binding sites located between -1623 and -871 in the TRPC1 5'-regulatory region were required for thrombin-induced TRPC1 expression. Electrophoretic mobility shift assay utilizing TRPC1 promoter-specific oligonucleotides identified that the DNA binding activities of NF-kappaB to NF-kappaB consensus sites were located in this domain. Supershift assays using NF-kappaB protein-specific antibodies demonstrated the binding of p65 homodimer to the TRPC1 promoter. Inhibition of store Ca(2+) depletion, buffering of intracellular Ca(2+), or down-regulation of protein kinase Calpha downstream of Ca(2+) influx all blocked thrombin-induced NF-kappaB activation and the resultant TRPC1 expression in endothelial cells. Thus, Ca(2+) influx via TRPC1 is a critical feed-forward pathway responsible for TRPC1 expression. The NF-kappaB-regulated TRPC1 expression may be an essential mechanism of vascular inflammation and, hence, a novel therapeutic target.