NHE3 inhibitor tenapanor maintains intestinal barrier function, decreases visceral hypersensitivity, and attenuates TRPV1 signaling in colonic sensory neurons.

The pathogenesis of irritable bowel syndrome (IBS) is multifactorial, characterized in part by increased intestinal permeability, and visceral hypersensitivity. Increased permeability is associated with IBS severity and abdominal pain. Tenapanor is FDA-approved for the treatment of IBS with constipation (IBS-C) and has demonstrated improvements in bowel motility and a reduction in IBS-related pain; however, the mechanism by which tenapanor mediates these functions remains unclear. Here, the effects of tenapanor on colonic pain signaling and intestinal permeability were assessed through behavioral, electrophysiological, and cell culture experiments. Intestinal motility studies in rats and humans demonstrated that tenapanor increased luminal sodium and water retention and gastrointestinal transit versus placebo. A significantly reduced visceral motor reflex (VMR) to colonic distension was observed with tenapanor treatment versus vehicle in two rat models of visceral hypersensitivity (neonatal acetic acid sensitization and partial restraint stress; both P < 0.05), returning VMR responses to that of nonsensitized controls. Whole cell voltage patch-clamp recordings of retrogradely labeled colonic dorsal root ganglia (DRG) neurons from sensitized rats found that tenapanor significantly reduced DRG neuron hyperexcitability to capsaicin versus vehicle (P < 0.05), an effect not mediated by epithelial cell secretions. Tenapanor also attenuated increases in intestinal permeability in human colon monolayer cultures caused by incubation with proinflammatory cytokines (P < 0.001) or fecal supernatants from patients with IBS-C (P < 0.005). These results support a model in which tenapanor reduces IBS-related pain by strengthening the intestinal barrier, thereby decreasing permeability to macromolecules and antigens and reducing DRG-mediated pain signaling.NEW & NOTEWORTHY A series of nonclinical experiments support the theory that tenapanor inhibits IBS-C-related pain by strengthening the intestinal barrier. Tenapanor treatment reduced visceral motor responses to nonsensitized levels in two rat models of hypersensitivity and reduced responses to capsaicin in sensitized colonic nociceptive dorsal root ganglia neurons. Intestinal permeability experiments in human colon monolayer cultures found that tenapanor attenuates increases in permeability induced by either inflammatory cytokines or fecal supernatants from patients with IBS-C.

Abdominal Symptom Improvement During Clinical Trials of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis.

INTRODUCTION: This post hoc analysis evaluated the efficacy of tenapanor on abdominal symptoms in patients with irritable bowel syndrome with constipation. Abdominal symptoms assessed included pain, discomfort, bloating, cramping, and fullness. METHODS: The abdominal symptom data were pooled from 3 randomized controlled trials (NCT01923428, T3MPO-1 [NCT02621892], and T3MPO-2 [NCT02686138]). Weekly scores were calculated for each abdominal symptom, and the Abdominal Score (AS) was derived as the average of weekly scores for abdominal pain, discomfort, and bloating. The overall change from baseline during the 12 weeks was assessed for each symptom weekly score and the AS. The AS 6/12-week and 9/12-week response rates (AS improvement of ≥2 points for ≥6/12- or ≥9/12-week) were also evaluated. The association of weekly AS response status (reduction of ≥30%) with weekly complete spontaneous bowel movement (CSBM) status (=0 and >0) was assessed. RESULTS: Among 1,372 patients (684 tenapanor [50 mg twice a day] and 688 placebo), the least squares mean change from baseline in AS was -2.66 for tenapanor vs -2.09 for placebo ( P < 0.0001). The 6/12-week AS response rate was 44.4% for tenapanor vs 32.4% for placebo ( P < 0.0001), and for 9/12-week AS, 30.6% for tenapanor vs 20.5% for placebo ( P < 0.0001). A significant association between weekly CSBM status and weekly AS response status was observed each week ( P < 0.0001), with a greater proportion achieving an AS reduction in patients with >0 CSBMs in a week. DISCUSSION: Tenapanor significantly reduced abdominal symptoms in patients with irritable bowel syndrome with constipation, particularly pain, discomfort, and bloating measured by AS, compared with placebo.

Carrying groceries: More items in early trips than in later trips or the reverse? Implications for pre-crastination.

Returning home from the grocery store with a car full of groceries requires decisions about how many bags to carry when. If the decisions exemplify procrastination, people should carry more bags per trip in late trips than in early trips (putting the hard work off until later), but if the decisions exemplify the recently discovered phenomenon of pre-crastination (Rosenbaum et al. in Psychol Sci 25: 1487-1496, 2014), people should carry more bags per trip in early trips than in late trips (doing the hard work early). To distinguish between these possibilities, we asked university students to carry 5 or 11 dodgeballs from one bin to another 4, 8, 12, or 16 feet away in as many trips as they wished. A random half of the subjects did the tasks with an additional requirement to memorize and then recall 7 digits after carrying all the balls from the home to the target bin. Consistent with pre-crastination, participants carried the most balls per trip in early trips, and consistent with the hypothesis that pre-crastination relates to memory load, the number of balls carried per trip was affected by the presence of a memory load. The results add to the growing evidence for the generality of pre-crastination.

The Cognition/Metacognition Trade-Off.

Integration to boundary is an optimal decision algorithm that accumulates evidence until the posterior reaches a decision boundary, resulting in the fastest decisions for a target accuracy. Here, we demonstrated that this advantage incurs a cost in metacognitive accuracy (confidence), generating a cognition/metacognition trade-off. Using computational modeling, we found that integration to a fixed boundary results in less variability in evidence integration and thus reduces metacognitive accuracy, compared with a collapsing-boundary or a random-timer strategy. We examined how decision strategy affects metacognitive accuracy in three cross-domain experiments, in which 102 university students completed a free-response session (evidence terminated by the participant's response) and an interrogation session (fixed number of evidence samples controlled by the experimenter). In both sessions, participants observed a sequence of evidence and reported their choice and confidence. As predicted, the interrogation protocol (preventing integration to boundary) enhanced metacognitive accuracy. We also found that in the free-response sessions, participants integrated evidence to a collapsing boundary-a strategy that achieves an efficient compromise between optimizing choice and metacognitive accuracy.

The effects of hypnotherapy compared to cognitive behavioral therapy in depression: a NIRS-study using an emotional gait paradigm.

Hypnotherapy (HT) is a promising approach to treating depression, but so far, no data are available on the neuronal mechanisms of functional reorganization after HT for depressed patients. Here, 75 patients with mild to moderate depression, who received either HT or Cognitive Behavioral Therapy (CBT), were measured before and after therapy using functional near-infrared spectroscopy. We investigated the patients' cerebral activation during an emotional human gait paradigm. Further, rumination was included as predictor. Our results showed a decrease of functional connectivity (FC) between two regions that are crucial to emotional processing, the Extrastriate Body Area (EBA) and the Superior Temporal Sulcus (STS). This FC decrease was traced back to an activation change throughout therapy in the right STS, not the EBA and was only found in the HT group, depending on rumination: less ruminating HT patients showed a decrease in right STS activation, while highly ruminating patients showed an increase. We carefully propose that this activation change is due to the promotion of emotional experiences during HT, while in CBT a focus lay on activating behavior and changing negative cognitions. HT seemed to have had differential effects on the patients, depending on their rumination style: The increase of right STS activation in highly ruminating patients might mirror the improvement of impaired emotional processing, whilst the decrease of activation in low ruminating patients might reflect a dismissal of an over-compensation, associated with a hyperactivity before therapy. We conclude that HT affects emotional processing and this effect is moderated by rumination.

What matters in making demand-based decisions: Time alone or difficulty too?

Which task is easier, doing arithmetic problems of specified form for some specified duration, or carrying a bucket of specified weight over some specified distance? If it is possible to choose between the "more cognitive" task and the "more physical" task, how are the difficulty levels of the tasks compared? We conducted two experiments in which participants chose the easier of two tasks, one that involved solving addition or multiplication problems (Experiment 1) or addition problems with different numbers of addends (Experiment 2) for varying amounts of time (in both experiments), and one that involved carrying a bucket of different weights over a fixed distance (in both experiments). We found that the probability of choosing to do the bucket task was higher when the bucket was empty than when it was weighted, and increased when the cognitive task was harder and its duration grew. We could account for the choice probabilities by mapping the independent variables onto one abstract variable, Φ. The functional identity of Φ remains to be determined. It could be interpreted as an inferred effort variable, subjective duration, or an abstract, amodal common code for difficulty.

A Randomized Trial of Tenapanor and Phosphate Binders as a Dual-Mechanism Treatment for Hyperphosphatemia in Patients on Maintenance Dialysis (AMPLIFY).

BACKGROUND: Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of action-tenapanor, an inhibitor of paracellular phosphate absorption, and phosphate binders-is safe and effective for the management of hyperphosphatemia in patients receiving maintenance dialysis. METHODS: This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperphosphatemia (defined in this trial as serum phosphorus 5.5-10 mg/dl inclusive) despite receiving phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4. RESULTS: Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (-0.84 versus -0.19 mg/dl, P<0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively. CONCLUSIONS: A dual-mechanism treatment using both tenapanor and phosphate binders improved control of hyperphosphatemia in patients undergoing maintenance dialysis compared with phosphate binders alone. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: AMPLIFY, NCT03824587.

Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats.

The majority of patients with chronic kidney disease (CKD) receiving dialysis do not achieve target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a nonbinder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This preclinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-h urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer [0-3% (wt/wt)]. We also evaluated the effect of the addition of tenapanor or vehicle on 24-h urinary phosphorus excretion to rats on a stable dose of sevelamer [1.5% (wt/wt)]. When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose [1.5% (wt/wt)] reduced mean ± SE urinary phosphorus excretion by 42 ± 3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37 ± 6% (P < 0.05). Although both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.

Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2).

INTRODUCTION: Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the long-term efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). METHODS: In this randomized double-blind study (ClinicalTrials.gov identifier: NCT02686138), patients with IBS-C received tenapanor 50 mg b.i.d. or placebo b.i.d. for 26 weeks. The primary endpoint was the proportion of patients who had a reduction of ≥30.0% in average weekly worst abdominal pain and an increase of ≥1 weekly complete spontaneous bowel movement from baseline, both in the same week, for ≥6 of the first 12 treatment weeks (6/12-week combined responder). RESULTS: Of the 620 randomized patients with IBS-C, 593 (95.6%) were included in the intention-to-treat analysis set (tenapanor: n = 293; placebo: n = 300) and 481 patients (77.6%) completed the 26-week treatment period. In the intention-to-treat analysis set (mean age: 45.4 years; 82.1% women), a significantly greater proportion of patients treated with tenapanor were 6/12-week combined responders than those treated with placebo (36.5% vs 23.7%; P < 0.001). Abdominal symptoms and global symptoms of IBS were significantly improved with tenapanor compared with placebo. Diarrhea, the most common adverse event, was typically transient and mild to moderate in severity. Diarrhea led to study drug discontinuation for 19 (6.5%) and 2 patients (0.7%) receiving tenapanor and placebo, respectively. DISCUSSION: Tenapanor 50 mg b.i.d. improved IBS-C symptoms over 26 weeks and was generally well tolerated, offering a potential new long-term treatment option for patients with IBS-C (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B797).

Small Intestinal Phosphate Absorption: Novel Therapeutic Implications.

BACKGROUND: Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention and, eventually, hyperphosphatemia. As hyperphosphatemia is associated with numerous adverse outcomes, including increased cardiovascular mortality, reduction in phosphorus concentrations is a guideline-recommended, established clinical practice. Dietary phosphate restriction, dialysis, and phosphate binders are currently the only options for phosphate management. However, many patients with hyperphosphatemia have phosphorus concentrations >5.5 mg/dL, despite treatment. SUMMARY: This review pre-sents recent advances in the understanding of intestinal phosphate absorption and therapeutic implications. Dietary phosphate is absorbed in the intestine through two distinct pathways, paracellular absorption and transcellular transport. Recent evidence indicates that the paracellular route accounts for 65-80% of total phosphate absorbed. Thus, the paracellular pathway is the dominant mechanism of phosphate absorption. Tenapanor is a first-in-class, non-phosphate binder that inhibits the sodium-hydrogen exchanger 3 or solute carrier family 9 member 3 (SLC9A3) encoded by the SLC9A3 gene, and blocks paracellular phosphate absorption. Key Messages: Targeted inhibition of sodium-hydrogen exchanger 3 effectively reduces paracellular permeability of phosphate. Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease.

Effort avoidance is not simply error avoidance.

Little is known about how effort is represented for different kinds of tasks. Recently, we suggested that it would help to establish empirical benchmarks for this problem. Accordingly, Feghhi and Rosenbaum (Journal of Experimental Psychology: Human Perception and Performance, 45:983-994, 2019) estimated how many additional digits to be memorized corresponded to navigating through a narrow gap versus a wide gap. The estimates were based on a study in which participants chose between walking paths with associated memory demands. We found that participants were equally willing to choose to walk through a narrow gap as to walk through a wide gap when the narrow-gap walk required memorization of 0.55 fewer digits on average than the wide-gap walk. In the present experiment, we sought to replicate and extend this previous finding in two ways: (1) by presenting the memory digits in auditory rather than visual form to test the hypothesis that participants used phonological recoding of the visually presented digits; and (2) by providing a new metric of the relative difficulty of navigation errors compared to recall errors. We provided 36 university students with two action/memorization options per trial and asked them to choose the easier option. Each option had varying degrees of physical demand (walking through a wide or narrow gap) and mental demand (memorizing 6, 7, or 8 digits). We expected performance to be comparable to what we observed earlier with visually presented digits to be memorized, and this prediction was confirmed. We also used a new metric to show that navigation errors were implicitly judged to be 17% more costly than recall errors. The fact that this percentage was not 0 indicates that reducing percent error was not the only basis for reducing effort.

Does attention solve the "apples-and-oranges" problems of judging task difficulty and task order?

How do we compare the difficulty of different kinds of tasks, and how we do sequence tasks of different kinds when the basis for the ordering is the tasks' difficulty levels? The ability to do these things requires a common currency, but the identity of that currency, if it exists, is unknown. We hypothesized that people may believe that the time that attention is paid to tasks enables people to compare and sequence tasks of different kinds. To evaluate this hypothesis, we tested three groups of participants. One group estimated the proportion of time that performance of a task requires attention-what we called attention time proportions or ATPs. We obtained ATPs for tasks that were "more intellectual" (counting) and others that were "more physical" (locomotion). Two additional groups made 2-alternative-forced-choice decisions about the relative ease and preferred sequencing of all possible pairs of tasks for which ATPs were independently obtained. We found that ATPs predicted judgments of task difficulty and preferred task order.

Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 12-Week, Placebo-Controlled Phase 3 Trial (T3MPO-1).

OBJECTIVES: Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with constipation-predominant irritable bowel syndrome (IBS-C). METHODS: In this phase 3, double-blind study (ClinicalTrials.gov identifier NCT02621892), patients with IBS-C were randomized to tenapanor 50 mg b.i.d. or placebo b.i.d. for 12 weeks followed by a 4-week randomized withdrawal period. The primary efficacy variable was the proportion of patients who reported a reduction in average weekly worst abdominal pain of ≥30.0% and an increase of ≥1 complete spontaneous bowel movement from baseline, both in the same week, for ≥6 weeks of the 12-week treatment period. RESULTS: Of the 629 randomized patients with IBS-C, 606 (96.3%) were included in the intention-to-treat analysis set (tenapanor: n = 307; placebo: n = 299) and 533 (84.7%) completed the 12-week treatment period. In the intention-to-treat analysis set (mean age 45 years, 81.4% women), a significantly greater proportion of patients treated with tenapanor met the primary endpoint than patients treated with placebo (27.0% vs 18.7%, P = 0.020). Abdominal symptoms and global symptoms of IBS also improved with tenapanor (P < 0.05 vs placebo). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in 6.5% and 0.7% of patients receiving tenapanor and placebo, respectively, during the 12-week treatment period. DISCUSSION: Tenapanor 50 mg b.i.d. improved IBS-C symptoms and was generally well tolerated, offering a potential new treatment option for patients with IBS-C.

Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial.

BACKGROUND: Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport. METHODS: In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group. RESULTS: Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action. CONCLUSIONS: Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.

The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia.

Background: Elevated serum fibroblast growth factor 23 (FGF23) is strongly associated with cardiovascular risk and mortality. Tenapanor, an inhibitor of gastrointestinal sodium/hydrogen exchanger isoform 3, decreased serum phosphate in a randomized, double-blind, placebo-controlled Phase 2 trial (ClinicalTrials.gov identifier NCT02081534) of patients receiving hemodialysis with hyperphosphatemia. Here, we report a secondary analysis of effects on serum FGF23 during that study. Methods: After 1-3 weeks of washout of phosphate binders, 162 patients were randomized to receive 4 weeks of treatment with placebo or one of six tenapanor regimens (3 or 30 mg once daily, or 1, 3, 10 or 30 mg twice daily). Intact FGF23 concentrations were determined from serum samples collected at screening, post-washout and end of treatment, assayed in duplicate in a single batch at the end of the study. Results: After phosphate-binder washout, serum FGF23 concentrations increased in all groups [range of geometric means: 1430-2605 pg/mL before, to 2601-6294 pg/mL after washout (P < 0.001 for all patients analyzed as a single group)]. Serum FGF23 concentrations subsequently decreased in tenapanor-treated patients (2030-3563 pg/mL), whereas they increased further in placebo-treated patients (6930 pg/mL). In an analysis of covariance, FGF23 decreased by 9.1-27.9% in tenapanor-treated patients and increased by 21.9% in placebo-treated patients (P ≤ 0.001-0.04). Conclusions: Following a marked increase in serum FGF23 in response to withdrawal of phosphate binders, tenapanor significantly decreased serum FGF23 in patients receiving hemodialysis with hyperphosphatemia. Further studies are required to explore the long-term effects of controlling FGF23 with tenapanor.

Polyvascular subclinical atherosclerosis in familial hypercholesterolemia: The role of cholesterol burden and gender.

BACKGROUND AND AIM: Heterozygous familial hypercholesterolemia (HeFH) is a genetic disease characterized by a heterogeneous phenotype. The assessment of cardiovascular (CV) risk is challenging for HeFH. Cholesterol burden (CB) allows to estimate the lifelong exposure to high levels of cholesterol. The aim of this study was to analyze the distribution of subclinical atherosclerosis and the relationship between atherosclerosis and the CB in a sample of HeFH patients, focusing on sex-related differences. METHODS AND RESULTS: 154 asymptomatic HeFH subjects underwent coronary-artery-calcium score (CACs) and Doppler ultrasound of carotid and femoral arteries. Yearly lipid profiles and HeHF history were obtained from patients' files in order to calculate total CB. Atherosclerotic burden was defined by the presence of CACs > 0 or by the presence of carotid or femoral plaque. Study population was stratified according to gender. The prevalence of CAC, carotid and femoral atherosclerosis was of 62%, 55% and 56%, respectively. Coronary district was the least involved in women, who had a higher prevalence in carotid atherosclerosis. When two vascular districts were affected, women had an increased prevalence of femoral and carotid atherosclerosis whereas men had a higher prevalence of coronary and femoral atherosclerosis. CB correlated to the presence of atherosclerosis in any of the three vascular districts with a significant increasing trend depending on the number of affected areas. CONCLUSIONS: A polyvascular atherosclerotic burden is found in asymptomatic HeFH patients. Gender differences in the territory distribution were observed. The early and lasting exposure to high cholesterol, as expressed by CB, is a major determinant of atherosclerotic burden.

End-state comfort meets pre-crastination.

Research on motor planning has revealed two seemingly contradictory phenomena. One is the end-state comfort effect, the tendency to grasp objects in physically awkward ways for the sake of comfortable or easy-to-control final postures (Rosenbaum et al., Attention and Performance XIII: Motor representation and control, Lawrence Erlbaum Associates, Hillsdale, New Jersey, 1990). The other is pre-crastination, the tendency to hasten the completion of tasks even at the expense of extra physical effort (Rosenbaum et al., Psychol Sci 25:1487-1496, 2014). End-state comfort seems to reflect emphasis on final states, whereas pre-crastination seems to reflect emphasis on initial states. How can both effects exist? We sought to resolve this seeming conflict by noting, first, that the effects have been tested in different contexts. End-state comfort has been tested with grasping, whereas pre-crastination has been tested with walking plus grasping. Second, both effects may reflect planning that aids aiming, as already demonstrated for end-state comfort but not yet tested for pre-crastination. We tested the two effects in a single walk-and-grasp task and found that demands on aiming influenced both effects, although precrastination was not fully influenced by changes in the demands of aiming. We conclude that end-state comfort and precrastination are both aiming-related, but that precrastination also reflects a desire to hasten early task completion.

Starting or finishing sooner? Sequencing preferences in object transfer tasks.

When tasks are performed, other tasks are postponed, at least implicitly. Little is known about how task sequencing is determined. We examined task sequencing in object transfer tasks for which either task could easily or logically come before the other. The task was to transfer ping pong balls from two buckets into a bowl. To perform the task, participants walked down a corridor, picked up one of two buckets (their choice), carried it to the end of the corridor, transferred the balls from the bucket into a bowl, carried the bucket back to the start position, and then did the same with the other remaining bucket. As in an earlier study where just one of two buckets had to be carried to the end of a corridor (Rosenbaum et al. Psychol Sci 25(7):1487-1496, 2014), participants showed a marked tendency to start with the near bucket. The near-bucket preference was modulated only to a small extent by the number of balls that could be emptied into the bowl. The relative lack of importance of the number of balls to be transferred (to finish the first task more quickly or to get closer to the end goal of transferring all balls into the bowl) was further demonstrated by the fact that the effect of the number of balls to be transferred did not depend on how the emptying was supposed to occur (by pouring the balls or placing the balls one at a time into the bowl), or by whether the instruction focused on filling the bowl or emptying the buckets. The results suggest that the near-bucket preference reflects a strong inclination to start the task (sub-goal) as soon as possible rather than complete the task (sub-goal) as soon as possible. Starting the task as soon as possible may be related to the affordance triggered by the sight of the near object or by the freedom to perform without having to inhibit a reach for a bucket when the performer is empty-handed. Starting a task sooner may free up cognitive resources for subsequent decision-making.

Forgiveness and cognitive control - Provoking revenge via theta-burst-stimulation of the DLPFC.

In order to act in a socially acceptable way, the ability to forgive is indispensable. It has been suggested that forgiveness relies on cognitive control, more specifically inhibition. In this study, we combined an ultimatum game (UG) and a dictator game (DG) with inhibitory, continuous theta-burst stimulation (cTBS; verum vs. placebo, within-subjects design) of the right dorsolateral prefrontal cortex (DLPFC) to investigate the effect of reduced cognitive control on forgiveness. To this end, participants played an UG against fair and unfair opponents, where they had to accept or reject (fair and unfair) monetary offers, and then received a cTBS prior to playing a DG against the same opponents with reversed roles. The participants now had the possibility to forgive the unfair opponents (allocation of a fair amount of money) or to take revenge whereby the cTBS effects were assessed with functional near-infrared spectroscopy. Following verum cTBS, participants allocated significantly less money to their unfair opponents than in the placebo cTBS condition. Also, reaction times (RTs) differed significantly between verum and placebo cTBS for unfair opponents (higher RTs following verum stimulation) but not for fair opponents. These results strongly indicate that cognitive control is a fundamental requirement for overcoming unwanted emotional responses.

Cortical hemodynamic changes during the Trier Social Stress Test: An fNIRS study.

The study of the stress response has been of great interest in the last decades due to its relationship to physical and mental health. Along with the technological progress in the neurosciences, different methods of stress induction have been developed for the special requirements regarding the acquisition of neuroimaging data. However, these paradigms often differ from ecologically valid stress inductions such as the Trier Social Stress Test (TSST) in substantial ways. In the study at hand, we used the rather robust optical imaging method of functional Near-infrared Spectroscopy (fNIRS) to assess brain activation during the TSST and two non-stressful control conditions. Additionally, we measured other stress parameters including the cortisol response and subjective stress ratings. As expected we found significant increases in subjective and physiological stress measures during the TSST in comparison to the baseline and control conditions. We found higher activation in parts of the cognitive control network (CCN) and dorsal attention network (DAN) - comprising the dorsolateral prefrontal cortex, the inferior frontal gyrus and superior parietal cortex - during the performance of the TSST in comparison to the control conditions. Further, calculation errors during the TSST as well as subjective and physiological stress parameters correlated significantly with the activation in the CCN. Our study confirms the validity of previous neuroimaging data obtained from adapted stress procedures by providing cortical activation data during a classical stress induction paradigm (i.e., the TSST) for the first time.