The influence of monetary incentives on context processing in younger and older adults: an event-related potential study.

Recent evidence has indicated that neuronal activity related to reward anticipation benefits subsequent stimulus processing, but the effect of penalties remains largely unknown. Since the dual-mechanisms-of-control theory (DMC; Braver & Barch, Neuroscience and Biobehavioral Reviews, 26, 809-81, 2002) assumes that temporal differences in context updating underlie age differences in cognitive control, in this study we investigated whether motivational cues (signaling the chance to win or the risk to lose money, relative to neutral cues) preceding context information in a modified AX-CPT paradigm influence the temporal stages of context processing in younger and older adults. In the behavioral data, younger adults benefited from gain cues, evident in their enhanced context updating, whereas older adults exhibited slowed responding after motivational cues, irrespective of valence. Event-related potentials (ERPs) revealed that the enhanced processing of motivational cues in the P2 and P3b was mainly age-invariant, whereas age-differential effects were found for the ERP correlates of context processing. Younger adults showed improved context maintenance (i.e., a larger negative-going CNV), as well as increased conflict detection (larger N450) and resolution (indicated by a sustained positivity), whenever incorrect responding would lead to a monetary loss. In contrast, motivationally salient cues benefited context representations (in cue-locked P3b amplitudes), but increased working memory demands during response preparation (via a temporally prolonged P3b) in older adults. In sum, motivational valence and salience effects differentially modulated the temporal stages of context processing in younger and older adults. These results are discussed in terms of the DMC theory, recent findings of emotion regulation in old age, and the relationship between cognitive and affective processing.

Age-differential effects on updating cue information: evidence from event-related potentials.

Recent models on cognitive aging consider the ability to maintain and update context information to be a key source of age-related impairments in various cognitive tasks (Braver & Barch in Neuroscience & Biobehavioral Reviews, 26: 809-817, 2002). Context updating has been investigated with a modified AX-continuous-performance task by comparing performance and brain activity between context-dependent trials (i.e., correct responses require updating of the preceding cue information) and context-independent trials (i.e., correct responses are independent of cue information). We used an event-related potential (ERP) approach to identify sources of age differences in context processing in the early and late processing of cue information. Our behavioral data showed longer latencies and higher error rates on context-dependent than on context-independent trials for older than for younger adults, suggesting age-related impairments in context updating. The ERP data revealed larger P3b amplitudes for context-dependent than for context-independent trials only in younger adults. In contrast, in older adults, P3b amplitudes were more evenly distributed across the scalp and did not differ between context conditions. Interestingly, older but not younger adults were sensitive to changes of cue identity, as indicated by larger P3b amplitudes on cue-change than on cue-repeat trials, irrespective of the actual context condition. We also found a larger CNV on context-dependent than on context-independent trials, reflecting active maintenance of context information and response preparation. The age-differential effects in the P3b suggest that both younger and older adults were engaged in updating task-relevant information, but relied on different information: Whereas younger participants indeed relied on context cues to update and reconfigure the task settings, older adults relied on changes in cue identity, irrespective of context information.

ECHO+: An Innovative Technology-Enabled Collaborative Learning and Quality Improvement Program Strengthening Rural Primary Care in Arkansas, West Virginia, and Oklahoma.

In this paper, we describe the Project Extension for Community Healthcare Outcomes+ (ECHO+) model and evaluation plan for incorporating changes to primary care delivery, improving patient and clinician outcomes, and making long-term system improvements.

Rho-associated coiled-coil-containing kinase 2 deficiency in bone marrow-derived cells leads to increased cholesterol efflux and decreased atherosclerosis.

BACKGROUND: Macrophages play a central role in the development of atherosclerosis. However, the signaling pathways that regulate their function are not well understood. The Rho-associated coiled-coil-containing kinases (ROCK1 and ROCK2) are serine-threonine protein kinases that are involved in the regulation of the actin cytoskeleton. Recent studies suggest that ROCK1 in macrophages and bone marrow-derived cells mediates atherogenesis. However, a similar role for ROCK2 in the pathogenesis of atherosclerosis has not been determined. METHODS AND RESULTS: The bone marrows from wild-type, ROCK2(+/-), and ROCK2(-/-) mice were transplanted into irradiated recipient low-density lipoprotein receptor(-/-) mice, and atherosclerosis was induced with a 16-week high-cholesterol diet. Compared with wild-type bone marrow-transplanted mice, ROCK2(+/-) bone marrow-transplanted and ROCK2(-/-) bone marrow-transplanted mice showed substantially less lipid accumulation in the aorta (8.46±1.42% and 9.80±2.34% versus 15.64±1.89%; P<0.01 for both) and decreased atherosclerotic lesions in the subaortic sinus (158.1±44.4 and 330.1±109.5×10(3)µm(2) versus 520.2±125.7×10(3)µm(2); P<0.01 for both). These findings correlated with decreased foam cell formation (2.27±0.57 versus 4.10±0.3; P<0.01) and increased cholesterol efflux (17.65±0.6 versus 9.75±0.8; P<0.05) in ROCK2-deficient mice that are mediated, in part, through the peroxisome proliferator-activated receptor-γ/liver X receptor/ATP-binding cassette transporter A1 pathway in macrophages. CONCLUSIONS: ROCK2 contributes to atherosclerosis, in part, by inhibiting peroxisome proliferator-activated receptor-γ-mediated reverse cholesterol transport in macrophages, which contributes to foam cell formation. These findings suggest that inhibition of ROCK2 in macrophages may have therapeutic benefits in preventing the development of atherosclerosis.

Platelet Bone Morphogenetic Protein-4 Mediates Vascular Inflammation and Neointima Formation after Arterial Injury.

The purpose of this study is to investigate the role of platelet bone morphogenetic proteins (BMP)-4 during vascular inflammation and remodeling in a mouse model of carotid wire injury. Transgenic mice with a platelet-specific deletion of BMP-4 (BMP4Plt-/-) were generated. Intravital microscopy was performed to evaluate leukocyte adhesion to the vessel wall. Expression of adhesion molecules and chemokines were analyzed. Platelet-leukocyte aggregates (PLAs) were evaluated using flow cytometry. For carotid wire injury, BMP4Plt-/- mice were further crossed with LDLr-/- mice (BMP4Plt-/-/LDLr-/-) and fed with a high cholesterol diet for 2-weeks. Carotid wire injury was performed, and re-endothelialization and neointimal formation were evaluated. In comparison to the control mice, stimulation with TNFα resulted in fewer rolling and adherent leukocytes to the vessel wall in the BMP4Plt-/- mice. mRNA and protein expression of P-selectin and adhesion molecules were reduced in the aorta of the BMP4Plt-/- mice. In platelets from the BMP4Plt-/- mice, the expression of P-selectin was reduced, and fewer PLA formations were measured than in the control mice. Loss of platelet BMP-4 further prevented neointima formation after carotid wire injury. Endothelial regeneration after injury was decelerated in the BMP4Plt-/- mice, and confirmed in-vitro, where the deletion of platelet BMP-4 inhibited endothelial cell proliferation and migration. We demonstrate for the first time that platelet BMP-4 is involved during vascular inflammation and remodeling. This is partially mediated by the inhibition of platelet activation, reduced expression of adhesion molecules and inflammatory responses. Our findings identify platelet BMP-4 as a mediator of vascular inflammation in early atherosclerosis and restenosis.

The Influence of Different Kinds of Incentives on Decision-Making and Cognitive Control in Adolescent Development: A Review of Behavioral and Neuroscientific Studies.

A number of recent hypothetical models on adolescent development take a dual-systems perspective and propose an imbalance in the maturation of neural systems underlying reward-driven and control-related behavior. In particular, such models suggest that the relative dominance of the early emerging subcortical reward system over the later emerging prefrontal-guided control system leads to higher risk-taking and sensation-seeking behavior in mid-adolescents. Here, we will review recent empirical evidence from behavioral and neuroscientific studies examining interactions between these systems and showing that empirical evidence in support for the view of a higher sensitivity to rewards in mid-adolescents is rather mixed. One possible explanation for this may be the use of different kinds and amounts of incentives across studies. We will therefore include developmental studies comparing the differential influence of primary and secondary incentives, as well as those investigating within the class of secondary incentives the effects of monetary, cognitive, or social incentives. We hypothesized that the value of receiving sweets or sours, winning or losing small or large amounts of money, and being accepted or rejected from a peer group may also changes across development, and thereby might modulate age differences in decision-making and cognitive control. Our review revealed that although developmental studies directly comparing different kinds of incentives are rather scarce, results of various studies rather consistently showed only minor age differences in the impact of incentives on the behavioral level. In tendency, adolescents were more sensitive to higher amounts of incentives and larger uncertainty of receiving them, as well as to social incentives such as the presence of peers observing them. Electrophysiological studies showed that processing efficiency was enhanced during anticipation of incentives and receiving them, irrespective of incentive type. Again, we found no strong evidence for interactions with age across studies. Finally, functional brain imaging studies revealed evidence for overlapping brain regions activated during processing of primary and secondary incentives, as well as social and non-social incentives. Adolescents recruited similar reward-related and control-related brain regions as adults did, but to a different degree. Implications for future research will be discussed.

Extracellular bone morphogenetic protein modulator BMPER and twisted gastrulation homolog 1 preserve arterial-venous specification in zebrafish blood vessel development and regulate Notch signaling in endothelial cells.

The bone morphogenetic protein (BMP) signaling pathway plays a central role during vasculature development. Mutations or dysregulation of the BMP pathway members have been linked to arteriovenous malformations. In the present study, we investigated the effect of the BMP modulators bone morphogenetic protein endothelial precursor-derived regulator (BMPER) and twisted gastrulation protein homolog 1 (TWSG1) on arteriovenous specification during zebrafish development and analyzed downstream Notch signaling pathway in human endothelial cells. Silencing of bmper and twsg1b in zebrafish embryos by morpholinos resulted in a pronounced enhancement of venous ephrinB4a marker expression and concomitant dysregulated arterial ephrinb2a marker expression detected by in situ hybridization. As arteriovenous specification was disturbed, we assessed the impact of BMPER and TWSG1 protein stimulation on the Notch signaling pathway on endothelial cells from different origin. Quantitative real-time PCR (qRT-PCR) and western blot analysis showed increased expression of Notch target gene hairy and enhancer of split, HEY1/2 and EPHRINB2. Consistently, silencing of BMPER in endothelial cells by siRNAs decreased Notch signaling and downstream effectors. BMP receptor antagonist DMH1 abolished BMPER and BMP4 induced Notch signaling pathway activation. In conclusion, we found that in endothelial cells, BMPER and TWSG1 are necessary for regular Notch signaling activity and in zebrafish embryos BMPER and TWSG1 preserve arteriovenous specification to prevent malformations.

Does the Effort of Processing Potential Incentives Influence the Adaption of Context Updating in Older Adults?

A number of aging studies suggest that older adults process positive and negative information differently. For instance, the socioemotional selectivity theory postulates that older adults preferably process positive information in service of emotional well-being (Reed and Carstensen, 2012). Moreover, recent research has started to investigate whether incentives like gains or losses can influence cognitive control in an ongoing task. In an earlier study (Schmitt et al., 2015), we examined whether incentive cues, indicating potential monetary gains, losses, or neutral outcomes for good performance in the following trial, would influence older adults' ability to exert cognitive control. Cognitive control was measured in an AX-Continuous-Performance-Task (AX-CPT) in which participants had to select their responses to probe stimuli depending on a preceding context cue. In this study, we did not find support for a positivity effect in older adults, but both gains and losses led to enhanced context processing. As the trial-wise presentation mode may be too demanding on cognitive resources for such a bias to occur, the main goal of the present study was to examine whether motivational mindsets, induced by block-wise presentation of incentives, would result in a positivity effect. For this reason, we examined 17 older participants (65-76 years) in the AX-CPT using a block-wise presentation of incentive cues and compared them to 18 older adults (69-78 years) with the trial-wise presentation mode from our earlier study (Schmitt et al., 2015). Event-related potentials were recorded to the onset of the motivational cue and during the AX-CPT. Our results show that (a) older adults initially process cues signaling potential losses more strongly, but later during the AX-CPT invest more cognitive resources in preparatory processes like context updating in conditions with potential gains, and (b) block-wise and trial-wise presentation of incentive cues differentially influenced cognitive control. When incentives were presented block-wise, the above described valence effects were consistently found. In contrast, when incentives were presented trial-wise, the effects were mixed and salience as well as valence effects can be obtained. Hence, how positive and negative incentive cues influence cognitive control in older adults is dependent on demands of cue processing.

MnTBAP increases BMPR-II expression in endothelial cells and attenuates vascular inflammation.

AIMS: The endothelium plays an important role during vascular inflammation. Previous data have demonstrated a high expression level of manganese-superoxide dismutase (MnSOD) in endothelial cells and suggested an important role of MnSOD in several cardiovascular diseases. Manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) has been shown to mimic some of the effects of MnSOD and prevented the development of diabetes and obesity. However, its effect on vascular inflammation and the underlying mechanism is still unknown. METHODS AND RESULTS: Leukocyte adhesion was evaluated in-vivo and in-vitro using dynamic flow chamber and intravital microscopy in mice. Expression of adhesion molecules induced by TNFα and adhesion of leukocytes to the vessel wall were inhibited by MnTBAP. The anti-inflammatory effect of MnTBAP was partly mediated by up-regulation of the BMPR-II and Smad dependent pathway. Additionally, MnTBAP decelerated the turn-over of endogenous BMPR-II. CONCLUSION: Our data demonstrate that MnTBAP activates Smad signaling, preserves the turn-over of BMPR-II and elicits anti-inflammatory effects in endothelial cells, partly mediated by BMPR-II. This finding suggests a potential therapeutic impact of MnTBAP in the treatment of vascular inflammation.

Does verbal labeling influence age differences in proactive and reactive cognitive control?

The main goal of this study was to examine whether different types of verbal labeling can influence age-related changes in the dynamic control of behavior by inducing either a proactive or reactive mode of control. Proactive control is characterized by a strong engagement in maintaining task-relevant information to be optimally prepared while reactive control is characterized by a reactivation of task-related information during responding. To investigate dynamic shifts between these control modes, we applied the AX-Continuous-Performance-Task in 2 experiments that differed in the complexity of stimuli and types of labeling in children (range = 7-10 years), younger (range = 19-33 years), and older adults (range = 69-83 years). We expected that labeling the cue information would promote a shift from a reactive to a proactive control mode primarily in children and older adults, while labeling the probe information would result in a shift from a proactive to a reactive control mode primarily in younger adults. Results of both experiments indicated that children, younger, and older adults were equally engaged in cue processing and performed the task in a proactive manner. While cue labeling did not further promote performing the task proactively, probe labeling induced a shift to a reactive control mode, especially in children. In the first experiment, including younger children than in the second experiment, children had more problems than adults to reactivate cue information to overcome a strong response tendency. These findings support the view that verbal labeling can influence the regulation of behavior by selectively attracting attention to relevant information in a given task.

MnTBAP stimulates angiogenic functions in endothelial cells through mitofusin-1.

AIMS: Angiogenesis is defined as the sprouting of capillaries from pre-existing vasculature. It is a complex process that includes endothelial proliferation, migration, and tube formation. Previous data have demonstrated a high expression level of manganese-superoxide dismutase (MnSOD) in endothelial cells and suggested an important role of MnSOD in several cardiovascular diseases. In addition, manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) has been shown to mimic some of the effects of MnSOD in various tissues. However, its effect on the vasculature remains unknown. METHODS AND RESULTS: HUVECs were treated with MnTBAP. Migration, tube formation, and capillary sprouting assays were performed to evaluate the pro-angiogenic effect in vitro. Matrigel plug assay was performed to assess capillary ingrowth in vivo. Compared to control, treatment with MnTBAP revealed increased cell migration, tube formation and capillary sprouting along with more capillary ingrowth in the Matrigel plug assay. This effect was mediated through a mitofusin (Mfn)-1-dependent pathway. Expression of Tie-2, Ang-2 and VEGF mRNA was increased in muscle tissues after ligation in MnTBAP treated mice. However, revascularization in the hindlimb ischemia model was not statistically significant at day 10 in MnTBAP treated mice. CONCLUSION: In summary, our data demonstrate a strong pro-angiogenic, but less pro-arteriogenic effect of MnTBAP in HUVECs mediated by Mfn-1.