An approach for identifying brainstem dopaminergic pathways using resting state functional MRI.

Here, we present an approach for identifying brainstem dopaminergic pathways using resting state functional MRI. In a group of healthy individuals, we searched for significant functional connectivity between dopamine-rich midbrain areas (substantia nigra; ventral tegmental area) and a striatal region (caudate) that was modulated by both a pharmacological challenge (the administration of the dopaminergic agonist bromocriptine) and a dopamine-sensitive cognitive trait (an individual's working memory capacity). A significant inverted-U shaped connectivity pattern was found in a subset of midbrain-striatal connections, demonstrating that resting state fMRI data is sufficiently powerful to identify brainstem neuromodulatory brain networks

Dopamine, time perception, and future time perspective.

RationaleImpairment in time perception, a critical component of decision-making, represents a risk factor for psychiatric conditions including substance abuse. A therapeutic that ameliorates this impairment could be advantageous in the treatment of impulsivity and decision-making disorders.ObjectivesHere we hypothesize that the catechol-O-methyltransferase (COMT) inhibitor tolcapone, which increases dopamine tone in frontal cortex (Ceravolo et al Synapse 43:201-207, 2002), improves time perception, with predictive behavioral, genetic, and neurobiological components.MethodsSubjects (n = 66) completed a duration estimation task and other behavioral testing in each of two sessions after receiving a single oral dose of tolcapone (200 mg) or placebo in randomized, double-blind, counterbalanced, crossover fashion. Resting state fMRI data were obtained in a subset of subjects (n = 40). Subjects were also genotyped for the COMT (rs4680) polymorphism.ResultsTime perception was significantly improved across four proximal time points ranging from 5 to 60 s (T(524) = 2.04, p = 0.042). The degree of this improvement positively correlated with subjective measures of stress, depression, and alcohol consumption and was most robust in carriers of the COMT Val158 allele. Using seed regions defined by a previous meta-analysis (Wiener et al Neuroimage 49:1728-1740, 2010), we found not only that a connection from right inferior frontal gyrus (RIFG) to right putamen decreases in strength on tolcapone versus placebo (p < 0.05, corrected), but also that the strength of this decrease correlates inversely with the increase in duration estimation on tolcapone versus placebo (r = - 0.37, p = 0.02).ConclusionsCompressed time perception can be ameliorated by administration of tolcapone. Additional studies should be conducted to determine whether COMT inhibitors may be effective in treating decision-making disorders and addictive behaviors

Signatures of Accretion Disks in Quasar Microlensing

We propose that relative variability on short time-scales of the multiple images of a lensed quasar, after removal of the time delay, may be caused by hot spots or other moving structures in the accretion disk crossing microlens caustics caused by stellar mass objects in the lensing galaxy. Such variability has been reported in the two images of 0957+561. The short durations would be due to the high rotation speed of the disk (v/c ~ 0.1), rather than planetary mass objects in the slowly moving (v/c ~ 0.001) lens. This interpretation could be confirmed by finding periodicity, or correlations of the spectral and flux variations due to the Doppler effect in the disk. We also propose another signature of stationary accretion disks (with no intrinsic variability): the gradient of the magnification over the accretion disk should cause a relative color change between the images whose sign and amplitude are correlated with the time derivative of the flux difference between the images. Other color terms induced by the radial variation of disk colors are of second order in the magnification gradient. The methods proposed here can be used first to verify that accretion disks near supermassive black holes are the source of the continuum radiation from quasars, and then to study them.Comment: 11 pages plus 1 postscript figur

AltitudeOmics: Baroreflex Sensitivity During Acclimatization to 5,260 m.

<b>Introduction:</b> Baroreflex sensitivity (BRS) is essential to ensure rapid adjustment to variations in blood pressure (BP). Little is known concerning the adaptive responses of BRS during acclimatization to high altitude at rest and during exercise. <b>Methods:</b> Twenty-one healthy sea-level residents were tested near sea level (SL, 130 m), the 1st (ALT1) and 16th day (ALT16) at 5,260 m using radial artery catheterization. BRS was calculated using the sequence method (direct interpretation of causal link between BP and heartrate). At rest, subjects breathed a hyperoxic mixture (250 mmHg O <sub>2</sub> , end tidal) to isolate the preponderance of CO <sub>2</sub> chemoreceptors. End-tidal CO <sub>2</sub> varied from 20 to 50 mmHg to assess peripheral chemoreflex. Rebreathing provoked incremental increase in CO <sub>2</sub> , increasing BP to assess baroreflex. During incremental cycling exercise to exhaustion, subjects breathed room air. <b>Results:</b> Resting BRS decreased in ALT1 which was exacerbated in ALT16. This decrease in ALT1 was reversible upon additional inspired CO <sub>2</sub> , but not in ALT16. BRS decrease during exercise was greater and occurred at lower workloads in ALT1 compared to SL. At ALT16, this decrease returned toward SL values. <b>Discussion/Conclusion:</b> This study is the first to report attenuated BRS in acute hypoxia, exacerbated in chronic hypoxia. In ALT1, hypocapnia triggered BRS reduction whilst in ALT16 resetting of chemoreceptor triggered BRS reduction. The exercise BRS resetting was impaired in ALT1 but normalized in ALT16. These BRS decreases indicate decreased control of BP and may explain deteriorations of cardiovascular status during exposure to high altitude

Enhancing dopamine tone modulates global and local cortical perfusion as a function of COMT Val158Met genotype

The cognitive effects of pharmacologically enhancing cortical dopamine (DA) tone are variable across healthy human adults. It has been postulated that individual differences in drug responses are linked to baseline cortical DA activity according to an inverted-U-shaped function. To better understand the effect of divergent starting points along this curve on DA drug responses, researchers have leveraged a common polymorphism (rs4680) in the gene encoding the enzyme catechol-O-methyltransferase (COMT) that gives rise to greater (Met allele) or lesser (Val allele) extracellular levels of cortical DA. Here we examined the extent to which changes in resting cortical perfusion following the administration of two mechanistically-distinct dopaminergic drugs vary by COMT genotype, and thereby track predictions of the inverted-U model. Using arterial spin labeling (ASL) and a double-blind, within-subject design, perfusion was measured in 75 healthy, genotyped participants once each after administration of tolcapone (a COMT inhibitor), bromocriptine (a DA D2/3 agonist), and placebo. COMT genotype and drug interacted such that COMT Val homozygotes exhibited increased prefusion in response to both drugs, whereas Met homozygotes did not. Additionally, tolcapone-related perfusion changes in the right inferior frontal gyrus correlated with altered performance on a task of executive function. No comparable effects were found for a genetic polymorphism (rs1800497) affecting striatal DA system function. Together, these results indicate that both the directionality and magnitude of drug-induced perfusion change provide meaningful information about individual differences in response to enhanced cortical DA tone

Differential Brain and Muscle Tissue Oxygenation Responses to Exercise in Tibetans Compared to Han Chinese

The Tibetans’ better aerobic exercise capacity at altitude remains ill-understood. We tested the hypothesis that Tibetans display better muscle and brain tissue oxygenation during exercise in hypoxia. Using near-infrared spectrometry (NIRS) to provide indices of tissue oxygenation, we measured oxy- and deoxy-hemoglobin ([O2Hb] and [HHb], respectively) responses of the vastus lateralis muscle and the right prefrontal cortex in ten Han Chinese and ten Tibetans during incremental cycling to exhaustion in a pressure-regulated chamber at simulated sea-level (air at 1 atm: normobaric normoxia) and 5,000 m (air at 0.5 atm: hypobaric hypoxia). Hypoxia reduced aerobic capacity by ∼22% in both groups (d = 0.8, p < 0.001 vs. normoxia), while Tibetans consistently outperformed their Han Chinese counterpart by ∼32% in normoxia and hypoxia (d = 1.0, p = 0.008). We found cerebral [O2Hb] was higher in Tibetans at normoxic maximal effort compared Han (p = 0.001), while muscle [O2Hb] was not different (p = 0.240). Hypoxic exercise lowered muscle [O2Hb] in Tibetans by a greater extent than in Han (interaction effect: p < 0.001 vs. normoxic exercise). Muscle [O2Hb] was lower in Tibetans when compared to Han during hypoxic exercise (d = 0.9, p = 0.003), but not during normoxic exercise (d = 0.4, p = 0.240). Muscle [HHb] was not different between the two groups during normoxic and hypoxic exercise (p = 0.778). Compared to Han, our findings revealed a higher brain tissue oxygenation in Tibetans during maximal exercise in normoxia, but lower muscle tissue oxygenation during exercise in hypoxia. This would suggest that the Tibetans privileged oxygenation of the brain at the expense of that of the muscle

Large-kernel Attention for Efficient and Robust Brain Lesion Segmentation

Vision transformers are effective deep learning models for vision tasks, including medical image segmentation. However, they lack efficiency and translational invariance, unlike convolutional neural networks (CNNs). To model long-range interactions in 3D brain lesion segmentation, we propose an all-convolutional transformer block variant of the U-Net architecture. We demonstrate that our model provides the greatest compromise in three factors: performance competitive with the state-of-the-art; parameter efficiency of a CNN; and the favourable inductive biases of a transformer. Our public implementation is available at https://github.com/liamchalcroft/MDUNet

A spectroscopy-based Age-Metallicity Relation of the SMC

The Small Magellanic Cloud (SMC) is the only dwarf galaxy in the Local Group that is known to have formed and preserved populous star clusters continuously over the past 12 Gyr. Due to its proximity (≈ 60 kpc), stars can be resolved well below the oldest main sequence turnoff points. This facilitates accurate age and metallicity determinations without suffering from the age-metallicity degeneracy. Therefore, the SMC star clusters provide a unique closely spaced set of single-age, single-metallicity tracers to derive a well-sampled age-metallicity relation required for the understanding of the star formation history of this satellite galaxy. Up to date spectroscopically based metallicity estimates exist only for the small number of 7 clusters (Da Costa & Hatzidimitriou 1998). Our project now more than doubles the available data set by the observation of 10 additional cluster

AltitudeOmics: Spontaneous Baroreflex Sensitivity During Acclimatization to 5,260 m: A Comparison of Methods

Baroreflex sensitivity (BRS) is essential to ensure rapid adjustment to variations in blood pressure (BP). Spontaneous baroreflex function can be assessed using continuous recordings of blood pressure. The goal of this study was to compare four methods for BRS quantification [the sequence, Bernardi's (BER), frequency and transfer function methods] to identify the most consistent method across an extreme range of conditions: rest and exercise, in normoxia, hypoxia, hypocapnia, and hypercapnia. Using intra-radial artery BP in young healthy participants, BRS was calculated and compared using the four methods in normoxia, acute and chronic hypoxia (terrestrial altitude of 5,260 m) in hypocapnia (hyperventilation), hypercapnia (rebreathing) and during ramp exercise to exhaustion. The sequence and BER methods for BRS estimation showed good agreement during the resting and exercise protocols, whilst the ultra- and very-low frequency bands of the frequency and transfer function methods were more discrepant. Removing respiratory frequency from the blood pressure traces affected primarily the sequence and BER methods and occasionally the frequency and transfer function methods. The sequence and BER methods contained more respiratory related information than the frequency and transfer function methods, indicating that the former two methods predominantly rely on respiratory effects of BRS. BER method is recommended because it is the easiest to compute and even though it tends to overestimate BRS compared to the sequence method, it is consistent with the other methods, whilst its interquartile range is the smallest