129Xe Dynamic Nuclear Polarization Demystified: The Influence of the Glassing Matrix on the Radical Properties.

129Xe dissolution dynamic nuclear polarization (DNP) is a controversial topic. The gold standard technique for hyperpolarized xenon magnetic resonance imaging (MRI) is spin exchange optical pumping, which received FDA approval in 2022. Nevertheless, the versatility of DNP for enhancing the signal of any NMR active nucleus might provide new perspectives for hyperpolarized 129Xe NMR/MRI. Initial publications about 129Xe DNP underlined the increased complexity in the sample preparation and lower polarization levels when compared to more conventional 13C-labeled molecules, at same experimental conditions, despite very close gyromagnetic ratios. Herein, we introduce, using a Custom Fluid Path system, a user-friendly and very robust sample preparation method. Moreover, investigating the radical properties at real DNP conditions by means of LOngitudinal Detected Electron Spin Resonance, we discovered a dramatic shortening of the electron spin longitudinal relaxation time (T1e) of nitroxyl radicals in xenon DNP samples' matrices, with respect to more commonly used water:glycerol ones. Mitigating those challenges through microwave frequency modulation, we achieved over 20% 129Xe polarization without employing any deuterated solvent.

Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior.

Mood disorders (MD) are a major burden on society as their biology remains poorly understood, challenging both diagnosis and therapy. Among many observed biological dysfunctions, homeostatic dysregulation, such as metabolic syndrome (MeS), shows considerable comorbidity with MD. Recently, CREB-regulated transcription coactivator 1 (CRTC1), a regulator of brain metabolism, was proposed as a promising factor to understand this relationship. Searching for imaging biomarkers and associating them with pathophysiological mechanisms using preclinical models can provide significant insight into these complex psychiatric diseases and help the development of personalized healthcare. Here, we used neuroimaging technologies to show that deletion of Crtc1 in mice leads to an imaging fingerprint of hippocampal metabolic impairment related to depressive-like behavior. By identifying a deficiency in hippocampal glucose metabolism as the underlying molecular/physiological origin of the markers, we could assign an energy-boosting mood-stabilizing treatment, ebselen, which rescued behavior and neuroimaging markers. Finally, our results point toward the GABAergic system as a potential therapeutic target for behavioral dysfunctions related to metabolic disorders. This study provides new insights on Crtc1's and MeS's relationship to MD and establishes depression-related markers with clinical potential.

Hyperpolarized (1-13C)Alaninamide Is a Multifunctional In Vivo Sensor of Aminopeptidase N Activity, pH, and CO2.

Spin hyperpolarization enables real-time metabolic imaging of carbon-13-labeled substrates. While hyperpolarized l-(1-13C)alaninamide is a probe of the cell-surface tumor marker aminopeptidase-N (APN, CD13), its activity in vivo has not been described. Scanning the kidneys of rats infused with hyperpolarized alaninamide shows both conversion to [1-13C]alanine and several additional spectral peaks with distinct temporal dynamics. The (1-13C)alaninamide chemical shift is pH-sensitive, with a pKa of 7.9 at 37 °C, and the peaks correspond to at least three different compartments of pH 7.46 ± 0.02 (1), 7.21 ± 0.02 (2), and 6.58 ± 0.05 (3). An additional peak was assigned to the carboxyamino adduct formed by reaction with dissolved CO2. Spectroscopic imaging showed nonuniform distribution, with the low-pH signal more concentrated in the inner medulla. Treatment with the diuretic acetazolamide resulted in significant pH shifts in compartment 1 to 7.38 ± 0.03 (p = 0.0057) and compartment 3 to 6.80 ± 0.05 (p = 0.0019). While the pH of compartment 1 correlates with blood pH, the pH of compartment 3 did not correspond to the pH of urine. In vitro experiments show that alaninamide readily enters blood cells and can detect intracellular pH. While carbamate formation depends on pH and pCO2, the carbamate-to-alaninamide ratio did not correlate with either arterial blood pH or pCO2, suggesting that it may reflect variations in tissue pH and pCO2. This study demonstrates the feasibility of using hyperpolarized sensors to simultaneously image enzyme activity, pCO2, and pH in vivo.

Segmenting electroencephalography wires reduces radiofrequency shielding artifacts in simultaneous electroencephalography and functional magnetic resonance imaging at 7 T.

PURPOSE: Simultaneous scalp electroencephalography and functional magnetic resonance imaging (EEG-fMRI) enable noninvasive assessment of brain function with high spatial and temporal resolution. However, at ultra-high field, the data quality of both modalities is degraded by mutual interactions. Here, we thoroughly investigated the radiofrequency (RF) shielding artifact of a state-of-the-art EEG-fMRI setup, at 7 T, and design a practical solution to limit this issue. METHODS: Electromagnetic field simulations and MR measurements assessed the shielding effect of the EEG setup, more specifically the EEG wiring. The effectiveness of segmenting the wiring with resistors to reduce the transmit field disruption was evaluated on a wire-only EEG model and a simulation model of the EEG cap. RESULTS: The EEG wiring was found to exert a dominant effect on the disruption of the transmit field, whose intensity varied periodically as a function of the wire length. Breaking the electrical continuity of the EEG wires into segments shorter than one quarter RF wavelength in air (25 cm at 7 T) reduced significantly the RF shielding artifacts. Simulations of the EEG cap with segmented wires indicated similar improvements for a moderate increase of the power deposition. CONCLUSION: We demonstrated that segmenting the EEG wiring into shorter lengths using commercially available nonmagnetic resistors is effective at reducing RF shielding artifacts in simultaneous EEG-fMRI. This prevents the formation of RF-induced standing waves, without substantial specific absorption rate (SAR) penalties, and thereby enables benefiting from the functional sensitivity boosts achievable at ultra-high field.

[13C]bicarbonate labelled from hyperpolarized [1-13C]pyruvate is an in vivo marker of hepatic gluconeogenesis in fasted state.

Hyperpolarized [1-13C]pyruvate enables direct in vivo assessment of real-time liver enzymatic activities by 13C magnetic resonance. However, the technique usually requires the injection of a highly supraphysiological dose of pyruvate. We herein demonstrate that liver metabolism can be measured in vivo with hyperpolarized [1-13C]pyruvate administered at two- to three-fold the basal plasma concentration. The flux through pyruvate dehydrogenase, assessed by 13C-labeling of bicarbonate in the fed condition, was found to be saturated or partially inhibited by supraphysiological doses of hyperpolarized [1-13C]pyruvate. The [13C]bicarbonate signal detected in the liver of fasted rats nearly vanished after treatment with a phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, indicating that the signal originates from the flux through PEPCK. In addition, the normalized [13C]bicarbonate signal in fasted untreated animals is dose independent across a 10-fold range, highlighting that PEPCK and pyruvate carboxylase are not saturated and that hepatic gluconeogenesis can be directly probed in vivo with hyperpolarized [1-13C]pyruvate.

Evaluation of the whole auditory pathway using high-resolution and functional MRI at 7T parallel-transmit.

PURPOSE: The aim of the present study is to show a MR procedure for the evaluation of simultaneous left and right auditory functions with functional MRI, and high-resolution acquisition of anatomical auditory pathway using parallel-transmit (pTx) methods at 7T. METHODS: The time-efficient MR acquisition included two steps: RF weights were optimized for the regions-of-interest and high-resolution MR images of the inner-ear were acquired for the first 30 min (400 µm-iso resolution) followed by functional MRI acquisitions along the whole auditory pathway during the next 20 minutes. Data was processed with a linear cross-correlation analysis to define frequency preferences for each voxel in the auditory relays. RESULTS: Tonotopic maps revealed ordered bilateral frequency gradients in the auditory relays whereas at the level of the cochlear nuclei and superior olivary complexes the frequency gradients were less evident. A 21% increase in transmit-field efficiency was achieved over the left/right inner-ear regions and thus its main structures were clearly discernible using the pTx methods, compared to a single transmit RF coil. CONCLUSION: Using 7T pTx allows a fast (less than 60 min in total) and qualitative evaluation of the simultaneous left and right auditory response along the entire auditory pathway, together with high-resolution anatomical images of the inner-ear. This could be further used for patient examination at 7T.

Probiotics combined with rifaximin influence the neurometabolic changes in a rat model of type C HE.

Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by chronic liver disease. Management of type C HE remains an important challenge because treatment options are limited. Both the antibiotic rifaximin and probiotics have been reported to reduce the symptoms of HE, but longitudinal studies assessing their effects on brain metabolism are lacking and the molecular mechanisms underpinning their effects are not fully understood. Therefore, we evaluated in detail the effects of these different treatments on the neurometabolic changes associated with type C HE using a multimodal approach including ultra-high field in vivo 1H MRS. We analyzed longitudinally the effect of rifaximin alone or in combination with the probiotic Vivomixx on the brain metabolic profile in the hippocampus and cerebellum of bile duct ligated (BDL) rats, an established model of type C HE. Overall, while rifaximin alone appeared to induce no significant effect on the neurometabolic profile of BDL rats, its association with the probiotic resulted in more attenuated neurometabolic alterations in BDL rats followed longitudinally (i.e. a smaller increase in Gln and milder decrease in Glu and Cr levels). Given that both rifaximin and some probiotics are used in the treatment of HE, the implications of these findings may be clinically relevant.

Measuring Glycolytic Activity with Hyperpolarized [2H7, U-13C6] D-Glucose in the Naive Mouse Brain under Different Anesthetic Conditions.

Glucose is the primary fuel for the brain; its metabolism is linked with cerebral function. Different magnetic resonance spectroscopy (MRS) techniques are available to assess glucose metabolism, providing complementary information. Our first aim was to investigate the difference between hyperpolarized 13C-glucose MRS and non-hyperpolarized 2H-glucose MRS to interrogate cerebral glycolysis. Isoflurane anesthesia is commonly employed in preclinical MRS, but it affects cerebral hemodynamics and functional connectivity. A combination of low doses of isoflurane and medetomidine is routinely used in rodent fMRI and shows similar functional connectivity, as in awake animals. As glucose metabolism is tightly linked to neuronal activity, our second aim was to assess the impact of these two anesthetic conditions on the cerebral metabolism of glucose. Brain metabolism of hyperpolarized 13C-glucose and 2H-glucose was monitored in two groups of mice in a 9.4 T MRI system. We found that the very different duration and temporal resolution of the two techniques enable highlighting the different aspects in glucose metabolism. We demonstrate (by numerical simulations) that hyperpolarized 13C-glucose reports on de novo lactate synthesis and is sensitive to CMRGlc. We show that variations in cerebral glucose metabolism, under different anesthesia, are reflected differently in hyperpolarized and non-hyperpolarized X-nuclei glucose MRS.

Radical-free hyperpolarized MRI using endogenously occurring pyruvate analogues and UV-induced nonpersistent radicals.

It was recently demonstrated that nonpersistent radicals can be generated in frozen solutions of metabolites such as pyruvate by irradiation with UV light, enabling radical-free dissolution dynamic nuclear polarization. Although pyruvate is endogenous, the presence of pyruvate may interfere with metabolic processes or the detection of pyruvate as a metabolic product, making it potentially unsuitable as a polarizing agent. Therefore, the aim of the current study was to characterize solutions containing endogenously occurring alternatives to pyruvate as UV-induced nonpersistent radical precursors for in vivo hyperpolarized MRI. The metabolites alpha-ketovalerate (αkV) and alpha-ketobutyrate (αkB) are analogues of pyruvate and were chosen as potential radical precursors. Sample formulations containing αkV and αkB were studied with UV-visible spectroscopy, irradiated with UV light, and their nonpersistent radical yields were quantified with electron spin resonance and compared with pyruvate. The addition of 13 C-labeled substrates to the sample matrix altered the radical yield of the precursors. Using αkB increased the 13 C-labeled glucose liquid-state polarization to 16.3% ± 1.3% compared with 13.3% ± 1.5% obtained with pyruvate, and 8.9% ± 2.1% with αkV. For [1-13 C]butyric acid, polarization levels of 12.1% ± 1.1% for αkV, 12.9% ± 1.7% for αkB, 1.5% ± 0.2% for OX063 and 18.7% ± 0.7% for Finland trityl, were achieved. Hyperpolarized [1-13 C]butyrate metabolism in the heart revealed label incorporation into [1-13 C]acetylcarnitine, [1-13 C]acetoacetate, [1-13 C]butyrylcarnitine, [5-13 C]glutamate and [5-13 C]citrate. This study demonstrates the potential of αkV and αkB as endogenous polarizing agents for in vivo radical-free hyperpolarized MRI. UV-induced, nonpersistent radicals generated in endogenous metabolites enable high polarization without requiring radical filtration, thus simplifying the quality-control tests in clinical applications.

PIRACY: An Optimized Pipeline for Functional Connectivity Analysis in the Rat Brain.

Resting state functional MRI (rs-fMRI) is a widespread and powerful tool for investigating functional connectivity (FC) and brain disorders. However, FC analysis can be seriously affected by random and structured noise from non-neural sources, such as physiology. Thus, it is essential to first reduce thermal noise and then correctly identify and remove non-neural artifacts from rs-fMRI signals through optimized data processing methods. However, existing tools that correct for these effects have been developed for human brain and are not readily transposable to rat data. Therefore, the aim of the present study was to establish a data processing pipeline that can robustly remove random and structured noise from rat rs-fMRI data. It includes a novel denoising approach based on the Marchenko-Pastur Principal Component Analysis (MP-PCA) method, FMRIB's ICA-based Xnoiseifier (FIX) for automatic artifact classification and cleaning, and global signal regression (GSR). Our results show that: (I) MP-PCA denoising substantially improves the temporal signal-to-noise ratio, (II) the pre-trained FIX classifier achieves a high accuracy in artifact classification, and (III) both independent component analysis (ICA) cleaning and GSR are essential steps in correcting for possible artifacts and minimizing the within-group variability in control animals while maintaining typical connectivity patterns. Reduced within-group variability also facilitates the exploration of potential between-group FC changes, as illustrated here in a rat model of sporadic Alzheimer's disease.

Hyperpolarized 13C-glucose magnetic resonance highlights reduced aerobic glycolysis in vivo in infiltrative glioblastoma.

Glioblastoma (GBM) is the most aggressive brain tumor type in adults. GBM is heterogeneous, with a compact core lesion surrounded by an invasive tumor front. This front is highly relevant for tumor recurrence but is generally non-detectable using standard imaging techniques. Recent studies demonstrated distinct metabolic profiles of the invasive phenotype in GBM. Magnetic resonance (MR) of hyperpolarized 13C-labeled probes is a rapidly advancing field that provides real-time metabolic information. Here, we applied hyperpolarized 13C-glucose MR to mouse GBM models. Compared to controls, the amount of lactate produced from hyperpolarized glucose was higher in the compact GBM model, consistent with the accepted "Warburg effect". However, the opposite response was observed in models reflecting the invasive zone, with less lactate produced than in controls, implying a reduction in aerobic glycolysis. These striking differences could be used to map the metabolic heterogeneity in GBM and to visualize the infiltrative front of GBM.

The relationship between EEG and fMRI connectomes is reproducible across simultaneous EEG-fMRI studies from 1.5T to 7T.

Both electroencephalography (EEG) and functional Magnetic Resonance Imaging (fMRI) are non-invasive methods that show complementary aspects of human brain activity. Despite measuring different proxies of brain activity, both the measured blood-oxygenation (fMRI) and neurophysiological recordings (EEG) are indirectly coupled. The electrophysiological and BOLD signal can map the underlying functional connectivity structure at the whole brain scale at different timescales. Previous work demonstrated a moderate but significant correlation between resting-state functional connectivity of both modalities, however there is a wide range of technical setups to measure simultaneous EEG-fMRI and the reliability of those measures between different setups remains unknown. This is true notably with respect to different magnetic field strengths (low and high field) and different spatial sampling of EEG (medium to high-density electrode coverage). Here, we investigated the reproducibility of the bimodal EEG-fMRI functional connectome in the most comprehensive resting-state simultaneous EEG-fMRI dataset compiled to date including a total of 72 subjects from four different imaging centers. Data was acquired from 1.5T, 3T and 7T scanners with simultaneously recorded EEG using 64 or 256 electrodes. We demonstrate that the whole-brain monomodal connectivity reproducibly correlates across different datasets and that a moderate crossmodal correlation between EEG and fMRI connectivity of r ≈ 0.3 can be reproducibly extracted in low- and high-field scanners. The crossmodal correlation was strongest in the EEG-ß frequency band but exists across all frequency bands. Both homotopic and within intrinsic connectivity network (ICN) connections contributed the most to the crossmodal relationship. This study confirms, using a considerably diverse range of recording setups, that simultaneous EEG-fMRI offers a consistent estimate of multimodal functional connectomes in healthy subjects that are dominantly linked through a functional core of ICNs across spanning across the different timescales measured by EEG and fMRI. This opens new avenues for estimating the dynamics of brain function and provides a better understanding of interactions between EEG and fMRI measures. This observed level of reproducibility also defines a baseline for the study of alterations of this coupling in pathological conditions and their role as potential clinical markers.

Late post-natal neurometabolic development in healthy male rats using 1 H and 31 P magnetic resonance spectroscopy.

Brain metabolism evolves rapidly during early post-natal development in the rat. While changes in amino acids, energy metabolites, antioxidants or metabolites involved in phospholipid metabolism have been reported in the early stages, neurometabolic changes during the later post-natal period are less well characterized. Therefore, we aimed to assess the neurometabolic changes in male Wistar rats between post-natal days 29 and 77 (p29-p77) using longitudinal magnetic resonance spectroscopy (MRS) in vivo at 9.4 Tesla. 1 H MRS was performed in the hippocampus between p29 and p77 at 1-week intervals (n = 7) and in the cerebellum between p35 and p77 at 2-week intervals (n = 7) using the SPECIAL sequence at ultra-short echo-time. NOE enhanced and 1 H decoupled 31 P MR spectra were acquired at p35, p48 and p63 (n = 7) in a larger voxel covering cortex, hippocampus and part of the striatum. The hippocampus showed a decrease in taurine concentration and an increase in glutamate (with more pronounced changes until p49), seemingly a continuation of their well-described changes in the early post-natal period. A constant increase in myo-inositol and choline-containing compounds in the hippocampus (in particular glycero-phosphocholine as shown by 31 P MRS) was measured throughout the observation period, probably related to membrane metabolism and myelination. The cerebellum showed only a significant increase in myo-inositol between p35 and p77. In conclusion, this study showed important changes in brain metabolites in both the hippocampus and cerebellum in the later post-natal period (p29/p35-p77) of male rats, something previously unreported. Based on these novel data, changes in some neurometabolites beyond p28-35, conventionally accepted as the cut off for adulthood, should be taken into account in both experimental design and data interpretation in this animal model.

Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-13C6]glucose.

Hippocampus plays a critical role in linking brain energetics and behavior typically associated to stress exposure. In this study, we aimed to simultaneously assess excitatory and inhibitory neuronal metabolism in mouse hippocampus in vivo by applying 18FDG-PET and indirect 13C magnetic resonance spectroscopy (1H-[13C]-MRS) at 14.1 T upon infusion of uniformly 13C-labeled glucose ([U-13C6]Glc). Improving the spectral fitting by taking into account variable decoupling efficiencies of [U-13C6]Glc and refining the compartmentalized model by including two γ-aminobutyric acid (GABA) pools permit us to evaluate the relative contributions of glutamatergic and GABAergic metabolism to total hippocampal neuroenergetics. We report that GABAergic activity accounts for ∼13% of total neurotransmission (VNT) and ∼27% of total neuronal TCA cycle (VTCA) in mouse hippocampus suggesting a higher VTCA/VNT ratio for inhibitory neurons compared to excitatory neurons. Finally, our results provide new strategies and tools for bringing forward the developments and applications of 13C-MRS in specific brain regions of small animals.

B0 shimming for in vivo magnetic resonance spectroscopy: Experts' consensus recommendations.

Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) allow the chemical analysis of physiological processes in vivo and provide powerful tools in the life sciences and for clinical diagnostics. Excellent homogeneity of the static B0 magnetic field over the object of interest is essential for achieving high-quality spectral results and quantitative metabolic measurements. The experimental minimization of B0 variation is performed in a process called B0 shimming. In this article, we summarize the concepts of B0 field shimming using spherical harmonic shimming techniques, specific strategies for B0 homogenization and crucial factors to consider for implementation and use in both brain and body. In addition, experts' recommendations are provided for minimum requirements for B0 shim hardware and evaluation criteria for the primary outcome of adequate B0 shimming for MRS and MRSI, such as the water spectroscopic linewidth.

Contribution of macromolecules to brain 1 H MR spectra: Experts' consensus recommendations.

Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low molecular weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field, which are all summarized at the end of the paper.

Mitochondrial gene signature in the prefrontal cortex for differential susceptibility to chronic stress.

Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress.

13C Dynamic Nuclear Polarization using SA-BDPA at 6.7 T and 1.1 K: Coexistence of Pure Thermal Mixing and Well-Resolved Solid Effect.

SA-BDPA is a water-soluble, narrow-line width radical previously used for dynamic nuclear polarization (DNP) signal enhancement in solid-state magic angle spinning NMR spectroscopy. Here, we report the first study using SA-BDPA under dissolution DNP conditions (6.7 T and 1.15 K). Longitudinal-detected (LOD)-electron spin resonance (ESR) and 13C DNP measurements were performed on samples containing 8.4 M [13C]urea dissolved in 50:50 water:glycerol (v/v) doped with either 60 or 120 mM SA-BDPA. Two distinct DNP mechanisms, both "pure" thermal mixing and a well-resolved solid effect could clearly be identified. The radical's ESR line width (30-40 MHz), broadened predominantly by dipolar coupling, excluded any contribution from the cross effect. Microwave frequency modulation increased the enhancement by DNP at the lower radical concentration but not at the higher radical concentration. These results are compared to data acquired with trityl radical AH111501, highlighting the unusual 13C DNP properties of SA-BDPA.

Impact of aerobic exercise type on blood flow, muscle energy metabolism, and mitochondrial biogenesis in experimental lower extremity artery disease.

Exercise training (ET) is recommended for lower extremity artery disease (LEAD) management. However, there is still little information on the hemodynamic and metabolic adaptations by skeletal muscle with ET. We examined whether hindlimb perfusion/vascularization and muscle energy metabolism are altered differently by three types of aerobic ET. ApoE-/- mice with LEAD were assigned to one of four groups for 4 weeks: sedentary (SED), forced treadmill running (FTR), voluntary wheel running (VWR), or forced swimming (FS). Voluntary exercise capacity was improved and equally as efficient with FTR and VWR, but remained unchanged with FS. Neither ischemic hindlimb perfusion and oxygenation, nor arteriolar density and mRNA expression of arteriogenic-related genes differed between groups. 18FDG PET imaging revealed no difference in the steady-state levels of phosphorylated 18FDG in ischemic and non-ischemic hindlimb muscle between groups, nor was glycogen content or mRNA and protein expression of glucose metabolism-related genes in ischemic muscle modified. mRNA (but not protein) expression of lipid metabolism-related genes was upregulated across all exercise groups, particularly by non-ischemic muscle. Markers of mitochondrial content (mitochondrial DNA content and citrate synthase activity) as well as mRNA expression of mitochondrial biogenesis-related genes in muscle were not increased with ET. Contrary to FTR and VWR, swimming was ineffective in improving voluntary exercise capacity. The underlying hindlimb hemodynamics or muscle energy metabolism are unable to explain the benefits of running exercise.

Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans.

Substantial evidence implicates the nucleus accumbens in motivated performance, but very little is known about the neurochemical underpinnings of individual differences in motivation. Here, we applied 1H magnetic resonance spectroscopy (1H-MRS) at ultra-high-field in the nucleus accumbens and inquired whether levels of glutamate (Glu), glutamine (Gln), GABA or their ratios predict interindividual differences in effort-based motivated task performance. Given the incentive value of social competition, we also examined differences in performance under self-motivated or competition settings. Our results indicate that higher accumbal Gln-to-Glu ratio predicts better overall performance and reduced effort perception. As performance is the outcome of multiple cognitive, motor and physiological processes, we applied computational modeling to estimate best-fitting individual parameters related to specific processes modeled with utility, effort and performance functions. This model-based analysis revealed that accumbal Gln-to-Glu ratio specifically relates to stamina; i.e., the capacity to maintain performance over long periods. It also indicated that competition boosts performance from task onset, particularly for low Gln-to-Glu individuals. In conclusion, our findings provide novel insights implicating accumbal Gln and Glu balance on the prediction of specific computational components of motivated performance. This approach and findings can help developing therapeutic strategies based on targeting metabolism to ameliorate deficits in effort engagement.