Optimization of cardiopulmonary bypass prime fluid to preserve microcirculatory perfusion during on-pump coronary artery bypass graft surgery: PRIME study protocol for a double-blind randomized trial.

BACKGROUND: Acute microcirculatory perfusion disturbances and organ edema are important factors leading to organ dysfunction during cardiac surgery with cardiopulmonary bypass (CPB). Priming of the CPB system with crystalloid or colloid fluids, which inevitably leads to hemodilution, could contribute to this effect. However, there is yet no optimal evidence-based strategy for this type of priming. Hence, we will investigate different priming strategies to reduce hemodilution and preserve microcirculatory perfusion. METHODS: The PRIME study is a single-center double-blind randomized trial. Patients undergoing elective coronary artery bypass graft surgery with CPB will be randomized into three groups of prime fluid strategy: (1) gelofusine with crystalloid, (2) albumin with crystalloid, or (3) crystalloid and retrograde autologous priming. We aim to include 30 patients, 10 patients in each arm. The primary outcome is the change in microcirculatory perfusion. Secondary outcomes include colloid oncotic pressure; albumin; hematocrit; electrolytes; fluid balance and requirements; transfusion rates; and endothelial-, glycocalyx-, inflammatory- and renal injury markers. Sublingual microcirculatory perfusion will be measured using non-invasive sidestream dark field video microscopy. Microcirculatory and blood measurements will be performed at five consecutive time points during surgery up to 24 h after admission to the intensive care unit. DISCUSSION: PRIME is the first study to assess the effect of different prime fluid strategies on microcirculatory perfusion in cardiac surgery with CPB. If the results suggest that a specific crystalloid or colloid prime fluid strategy better preserves microcirculatory perfusion during on-pump cardiac surgery, the current study may help to find the optimal pump priming in cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT05647057. Registered on 04/25/2023. CLINICALTRIALS: gov PRS: Record Summary NCT05647057, all items can be found in the protocol.

Methylphenidate undermines or enhances divergent creativity depending on baseline dopamine synthesis capacity.

Catecholamine-enhancing psychostimulants, such as methylphenidate have long been argued to undermine creative thinking. However, prior evidence for this is weak or contradictory, stemming from studies with small sample sizes that do not consider the well-established large variability in psychostimulant effects across different individuals and task demands. We aimed to definitively establish the link between psychostimulants and creative thinking by measuring effects of methylphenidate in 90 healthy participants on distinct creative tasks that measure convergent and divergent thinking, as a function of individuals' baseline dopamine synthesis capacity, indexed with 18F-FDOPA PET imaging. In a double-blind, within-subject design, participants were administered methylphenidate, placebo or selective D2 receptor antagonist sulpiride. The results showed that striatal dopamine synthesis capacity and/or methylphenidate administration did not affect divergent and convergent thinking. However, exploratory analysis demonstrated a baseline dopamine-dependent effect of methylphenidate on a measure of response divergence, a creativity measure that measures response variability. Response divergence was reduced by methylphenidate in participants with low dopamine synthesis capacity but enhanced in those with high dopamine synthesis capacity. No evidence of any effect of sulpiride was found. These results show that methylphenidate can undermine certain forms of divergent creativity but only in individuals with low baseline dopamine levels.

Evidence for absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity.

Individual differences in striatal dopamine synthesis capacity have been associated with working memory capacity, trait impulsivity, and spontaneous eye-blink rate (sEBR), as measured with readily available and easily administered, 'off-the-shelf' tests. Such findings have raised the suggestion that individual variation in dopamine synthesis capacity, estimated with expensive and invasive brain positron emission tomography (PET) scans, can be approximated with simple, more pragmatic tests. However, direct evidence for the relationship between these simple trait measures and striatal dopamine synthesis capacity has been limited and inconclusive. We measured striatal dopamine synthesis capacity using [18F]-FDOPA PET in a large sample of healthy volunteers (N = 94) and assessed the correlation with simple, short tests of working memory capacity, trait impulsivity, and sEBR. We additionally explored the relationship with an index of subjective reward sensitivity. None of these trait measures correlated significantly with striatal dopamine synthesis capacity, nor did they have out-of-sample predictive power. Bayes factor analyses indicated the evidence was in favour of absence of correlations for all but subjective reward sensitivity. These results warrant caution for using these off-the-shelf trait measures as proxies of striatal dopamine synthesis capacity.

Effect of striatal dopamine on Pavlovian bias. A large [¹8F]-DOPA PET study.

Interaction between Pavlovian and instrumental control systems is key for adaptive motivated behavior, but also plays an important role in various neuropsychiatric disorders, including depression, addiction, and anxiety. Here, we employed the flouorodopa positron emission tomography ([¹8F]-DOPA PET) in healthy participants (N = 100) to assess whether dopamine synthesis capacity (Ki), specifically in the ventral striatum, accounts for individual variation in Pavlovian-to-instrumental transfer (PIT). Surprisingly, this was not the case. Rather, the relationship of ventral striatal Ki with PIT depended on working memory (WM) capacity. Ventral striatal dopamine boosted the effects of Pavlovian cues on instrumental responding to a greater degree in participants with higher WM capacity. Caution is warranted to interpret this post hoc four-way interaction given the modest sample size. Nonetheless, these results chime with prior findings demonstrating that dopaminergic drugs boost Pavlovian biases to a greater degree in participants with greater WM capacity and highlight the importance of interactions between striatal dopamine and WM capacity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Striatal dopamine dissociates methylphenidate effects on value-based versus surprise-based reversal learning.

Psychostimulants such as methylphenidate are widely used for their cognitive enhancing effects, but there is large variability in the direction and extent of these effects. We tested the hypothesis that methylphenidate enhances or impairs reward/punishment-based reversal learning depending on baseline striatal dopamine levels and corticostriatal gating of reward/punishment-related representations in stimulus-specific sensory cortex. Young healthy adults (N = 100) were scanned with functional magnetic resonance imaging during a reward/punishment reversal learning task, after intake of methylphenidate or the selective D2/3-receptor antagonist sulpiride. Striatal dopamine synthesis capacity was indexed with [18F]DOPA positron emission tomography. Methylphenidate improved and sulpiride decreased overall accuracy and response speed. Both drugs boosted reward versus punishment learning signals to a greater degree in participants with higher dopamine synthesis capacity. By contrast, striatal and stimulus-specific sensory surprise signals were boosted in participants with lower dopamine synthesis. These results unravel the mechanisms by which methylphenidate gates both attention and reward learning.

Portable magnetic resonance imaging of patients indoors, outdoors and at home.

Mobile medical imaging devices are invaluable for clinical diagnostic purposes both in and outside healthcare institutions. Among the various imaging modalities, only a few are readily portable. Magnetic resonance imaging (MRI), the gold standard for numerous healthcare conditions, does not traditionally belong to this group. Recently, low-field MRI technology companies have demonstrated the first decisive steps towards portability within medical facilities and vehicles. However, these scanners' weight and dimensions are incompatible with more demanding use cases such as in remote and developing regions, sports facilities and events, medical and military camps, or home healthcare. Here we present in vivo images taken with a light, small footprint, low-field extremity MRI scanner outside the controlled environment provided by medical facilities. To demonstrate the true portability of the system and benchmark its performance in various relevant scenarios, we have acquired images of a volunteer's knee in: (i) an MRI physics laboratory; (ii) an office room; (iii) outside a campus building, connected to a nearby power outlet; (iv) in open air, powered from a small fuel-based generator; and (v) at the volunteer's home. All images have been acquired within clinically viable times, and signal-to-noise ratios and tissue contrast suffice for 2D and 3D reconstructions with diagnostic value. Furthermore, the volunteer carries a fixation metallic implant screwed to the femur, which leads to strong artifacts in standard clinical systems but appears sharp in our low-field acquisitions. Altogether, this work opens a path towards highly accessible MRI under circumstances previously unrealistic.

Prepolarized MRI of hard tissues and solid-state matter.

Prepolarized MRI (PMRI) is a long-established technique conceived to counteract the loss in signal-to-noise ratio (SNR) inherent to low-field MRI systems. When it comes to hard biological tissues and solid-state matter, PMRI is severely restricted by their ultra-short characteristic relaxation times. Here we demonstrate that efficient hard-tissue prepolarization is within reach with a special-purpose 0.26 T scanner designed for ex vivo dental MRI and equipped with suitable high-power electronics. We have characterized the performance of a 0.5 T prepolarizer module, which can be switched on and off in 200 µs. To this end, we have used resin, dental and bone samples, all with T1 times of the order of 20 ms at our field strength. The measured SNR enhancement is in good agreement with a simple theoretical model, and deviations in extreme regimes can be attributed to mechanical vibrations due to the magnetic interaction between the prepolarization and main magnets.

Magneto-stimulation limits in medical imaging applications with rapid field dynamics.

Objective.The goal of this work is to extend previous peripheral nerve stimulation (PNS) studies to scenarios relevant to magnetic particle imaging (MPI) and low-field magnetic resonance imaging (MRI), where field dynamics can evolve at kilo-hertz frequencies.Approach.We have constructed an apparatus for PNS threshold determination on a subject's limb, capable of narrow and broad-band magnetic stimulation with pulse characteristic times down to 40µs.Main result.From a first set of measurements on 51 volunteers, we conclude that the PNS dependence on pulse frequency/rise-time is compatible with traditional stimulation models where nervous responses are characterized by a rheobase and a chronaxie. Additionally, we have extended pulse length studies to these fast timescales and confirm thresholds increase significantly as trains transition from tens to a few pulses. We also look at the influence of field spatial distribution on PNS effects, and find that thresholds are higher in an approximately linearly inhomogeneous field (relevant to MRI) than in a rather homogeneous distribution (as in MPI).Significance.PNS constrains the clinical performance of MRI and MPI systems. Extensive magneto-stimulation studies have been carried out recently in the field of MPI, where typical operation frequencies range from single to tens of kilo-hertz. However, PNS literature is scarce for MRI in this fast regime, relevant to small (low inductance) dedicated MRI setups, and where the resonant character of MPI coils prevents studies of broad-band stimulation pulses. This work advances in this direction.

Effects of average reward rate on vigor as a function of individual variation in striatal dopamine.

RATIONALE: We constantly need to decide not only which actions to perform, but also how vigorously to perform them. In agreement with an earlier theoretical model, it has been shown that a significant portion of the variance in our action vigor can be explained by the average rate of rewards received for that action. Moreover, this invigorating effect of average reward rate was shown to vary with within-subject changes in dopamine, both in human individuals and experimental rodents. OBJECTIVES: Here, we assessed whether individual differences in the effect of average reward rate on vigor are related to individual variation in a stable measure of striatal dopamine function in healthy, unmedicated participants. METHODS: Forty-four participants performed a discrimination task to test the effect of average reward rate on response times to index vigor and completed an [18F]-DOPA PET scan to index striatal dopamine synthesis capacity. RESULTS: We did not find an interaction between dopamine synthesis capacity and average reward rate across the entire group. However, a post hoc analysis revealed that participants with higher striatal dopamine synthesis capacity, particularly in the nucleus accumbens, exhibited a stronger invigorating effect of average reward rate among the 30 slowest participants. CONCLUSIONS: Our findings provide converging evidence for a role of striatal dopamine in average reward rate signaling, thereby extending the current literature on the mechanistic link between average reward rate, vigor, and dopamine.

Striatal dopamine synthesis capacity reflects smartphone social activity.

Striatal dopamine and smartphone behavior have both been linked with behavioral variability. Here, we leverage day-to-day logs of natural, unconstrained smartphone behavior and establish a correlation between a measure of smartphone social activity previously linked with behavioral variability and a measure of striatal dopamine synthesis capacity using [18F]-DOPA PET in (N = 22) healthy adult humans. Specifically, we find that a higher proportion of social app interactions correlates with lower dopamine synthesis capacity in the bilateral putamen. Permutation tests and penalized regressions provide evidence that this link between dopamine synthesis capacity and social versus non-social smartphone interactions is specific. These observations provide a key empirical grounding for current speculations about dopamine's role in digital social behavior.

Simultaneous imaging of hard and soft biological tissues in a low-field dental MRI scanner.

Magnetic Resonance Imaging (MRI) of hard biological tissues is challenging due to the fleeting lifetime and low strength of their response to resonant stimuli, especially at low magnetic fields. Consequently, the impact of MRI on some medical applications, such as dentistry, continues to be limited. Here, we present three-dimensional reconstructions of ex-vivo human teeth, as well as a rabbit head and part of a cow femur, all obtained at a field strength of 260 mT. These images are the first featuring soft and hard tissues simultaneously at sub-Tesla fields, and they have been acquired in a home-made, special-purpose, pre-medical MRI scanner designed with the goal of demonstrating dental imaging at low field settings. We encode spatial information with two pulse sequences: Pointwise-Encoding Time reduction with Radial Acquisition and a new sequence we have called Double Radial Non-Stop Spin Echo, which we find to perform better than the former. For image reconstruction we employ Algebraic Reconstruction Techniques (ART) as well as standard Fourier methods. An analysis of the resulting images shows that ART reconstructions exhibit a higher signal-to-noise ratio with a more homogeneous noise distribution.

The cognitive effects of a promised bonus do not depend on dopamine synthesis capacity.

Reward motivation is known to enhance cognitive control. However, detrimental effects have also been observed, which have been attributed to overdosing of already high baseline dopamine levels by further dopamine increases elicited by reward cues. Aarts et al. (2014) indeed demonstrated, in 14 individuals, that reward effects depended on striatal dopamine synthesis capacity, measured with [18F]FMT-PET: promised reward improved Stroop control in low-dopamine individuals, while impairing it in high-dopamine individuals. Here, we aimed to assess this same effect in 44 new participants, who had previously undergone an [18F]DOPA-PET scan to quantify dopamine synthesis capacity. This sample performed the exact same rewarded Stroop paradigm as in the prior study. However, we did not find any correlation between reward effects on cognitive control and striatal dopamine synthesis capacity. Critical differences between the radiotracers [18F]DOPA and [18F]FMT are discussed, as the discrepancy between the current and our previous findings might reflect the use of the potentially less sensitive [18F]DOPA radiotracer in the current study.

Methylphenidate boosts choices of mental labor over leisure depending on striatal dopamine synthesis capacity.

The cognitive enhancing effects of methylphenidate are well established, but the mechanisms remain unclear. We recently demonstrated that methylphenidate boosts cognitive motivation by enhancing the weight on the benefits of a cognitive task in a manner that depended on striatal dopamine. Here, we considered the complementary hypothesis that methylphenidate might also act by changing the weight on the opportunity cost of a cognitive task, that is, the cost of foregoing alternative opportunity. To this end, 50 healthy participants (25 women) completed a novel cognitive effort-discounting task that required choices between task and leisure. They were tested on methylphenidate, placebo, as well as the selective D2-receptor agent sulpiride, the latter to strengthen inference about dopamine receptor selectivity of methylphenidate's effects. Furthermore, they also underwent an [18F]DOPA PET scan to quantify striatal dopamine synthesis capacity. Methylphenidate boosted choices of cognitive effort over leisure across the group, and this effect was greatest in participants with more striatal dopamine synthesis capacity. The effects of sulpiride did not reach significance. This study strengthens the motivational account of methylphenidate's effects on cognition, and suggests that methylphenidate reduces the cost of mental labor by increasing striatal dopamine.

Ultra-soft X-ray system for imaging the early cellular responses to X-ray induced DNA damage.

The majority of the proteins involved in processing of DNA double-strand breaks (DSBs) accumulate at the damage sites. Real-time imaging and analysis of these processes, triggered by the so-called microirradiation using UV lasers or heavy particle beams, yielded valuable insights into the underlying DSB repair mechanisms. To study the temporal organization of DSB repair responses triggered by a more clinically-relevant DNA damaging agent, we developed a system coined X-ray multi-microbeam microscope (XM3), capable of simultaneous high dose-rate (micro)irradiation of large numbers of cells with ultra-soft X-rays and imaging of the ensuing cellular responses. Using this setup, we analyzed the changes in real-time kinetics of MRE11, MDC1, RNF8, RNF168 and 53BP1-proteins involved in the signaling axis of mammalian DSB repair-in response to X-ray and UV laser-induced DNA damage, in non-cancerous and cancer cells and in the presence or absence of a photosensitizer. Our results reveal, for the first time, the kinetics of DSB signaling triggered by X-ray microirradiation and establish XM3 as a powerful platform for real-time analysis of cellular DSB repair responses.

Meta-analysis of DNA double-strand break response kinetics.

Most proteins involved in the DNA double-strand break response (DSBR) accumulate at the damage sites, where they perform functions related to damage signaling, chromatin remodeling and repair. Over the last two decades, studying the accumulation of many DSBR proteins provided information about their functionality and underlying mechanisms of action. However, comparison and systemic interpretation of these data is challenging due to their scattered nature and differing experimental approaches. Here, we extracted, analyzed and compared the available results describing accumulation of 79 DSBR proteins at sites of DNA damage, which can be further explored using Cumulus (http://www.dna-repair.live/cumulus/)-the accompanying interactive online application. Despite large inter-study variability, our analysis revealed that the accumulation of most proteins starts immediately after damage induction, occurs in parallel and peaks within 15-20 min. Various DSBR pathways are characterized by distinct accumulation kinetics with major non-homologous end joining proteins being generally faster than those involved in homologous recombination, and signaling and chromatin remodeling factors accumulating with varying speeds. Our meta-analysis provides, for the first time, comprehensive overview of the temporal organization of the DSBR in mammalian cells and could serve as a reference for future mechanistic studies of this complex process.

Anomalously phosphorylated tau and Abeta fragments in the CSF correlates with cognitive impairment in MCI subjects.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of extracellular amyloid deposits, consisting largely of Abeta peptide and the presence of intraneuronal aggregates of neurofibillary tangles formed by tau. Development of cerebrospinal fluid (CSF) biomarkers has become a rapidly growing research field, considering the need for diagnostic tools for AD, thus allowing therapeutic compounds to have the greatest potential for being effective. We have focused on the relationships between critical biomarkers such as tau and Abeta in the CSF and the cognitive impairment of patients, as assessed by a battery of neuropsychological tests derived from CDR and CERAD, of value in the evaluation of AD patients. As part of a longitudinal study, we analyzed by ELISA and Western blots the levels and molecular patterns of hyperphosphorylated tau in the CSF of three different groups of patients: AD patients between 69- and 73-years-old, a group characterized with mild cognitive impairment (MCI) between 65- and 70-years-old, and a non-demented neurological control group of comparable ages. The levels of AT8-reactive phosphorylated tau were significantly higher (P<0.05) in AD patients (0.604+/-0.078, n=23) as compared with the control group (0.457+/-0.086, n=25). No differences between the levels of AT8-reactive tau of MCI patients (0.510+/-0.090, n=45) and controls were observed. However, when the MCI group was divided on the basis of the total box score (TBS) from CDR, those subjects with a TBS<1.5 presented tau levels (0.456+/-0.032, n=31) similar to controls, whereas those patients with TBS>or=1.5 displayed tau levels (0.590+/-0.086, n=14) comparable with those of AD. Western blot analyses revealed a higher AT8 reactivity in CSF samples of AD patients as compared with MCI and control samples, indicating higher levels of AD tau phosphoepitopes in the CSF. Tau heterogeneity was observed in samples of AD and MCI with higher impairment as compared with controls. As expected from previous reports, levels of Abeta (1-42) were lower (0.052+/-0.005) than controls (0.070+/-0.010), whereas the levels of MCI group were 0.060+/-0.007. The MCI group with a TBS>or=1.5 presented Abeta levels of 0.053+/-0.005 similar to those of AD patients, whereas the MCI group with TBS<1.5 exhibited Abeta levels (0.066+/-0.007) similar to controls. Studies highlight the relationships between anomalously phosphorylated tau markers in CSF with the information from TBS analysis of the different groups of patients.