Perfect state transfers by selective quantum interferences within complex spin networks

We present a method that implement directional, perfect state transfers within a branched spin network by exploiting quantum interferences in the time-domain. That provides a tool to isolate subsystems from a large and complex one. Directionality is achieved by interrupting the spin-spin coupled evolution with periods of free Zeeman evolutions, whose timing is tuned to be commensurate with the relative phases accrued by specific spin pairs. This leads to a resonant transfer between the chosen qubits, and to a detuning of all remaining pathways in the network, using only global manipulations. As the transfer is perfect when the selected pathway is mediated by 2 or 3 spins, distant state transfers over complex networks can be achieved by successive recouplings among specific pairs/triads of spins. These effects are illustrated with a quantum simulator involving 13C NMR on Leucine's backbone; a six-spin network.Comment: 5 pages, 3 figure

Evaluating the potential of hyperpolarised [1-13C] L-lactate as a neuroprotectant metabolic biosensor for stroke.

Cerebral metabolism, which can be monitored by magnetic resonance spectroscopy (MRS), changes rapidly after brain ischaemic injury. Hyperpolarisation techniques boost <sup>13</sup> C MRS sensitivity by several orders of magnitude, thereby enabling in vivo monitoring of biochemical transformations of hyperpolarised (HP) <sup>13</sup> C-labelled precursors with a time resolution of seconds. The exogenous administration of the metabolite L-lactate was shown to decrease lesion size and ameliorate neurological outcome in preclinical studies in rodent stroke models, as well as influencing brain metabolism in clinical pilot studies of acute brain injury patients. The aim of this study was to demonstrate the feasibility of measuring HP [1- <sup>13</sup> C] L-lactate metabolism in real-time in the mouse brain after ischaemic stroke when administered after reperfusion at a therapeutic dose. We showed a rapid, time-after-reperfusion-dependent conversion of [1- <sup>13</sup> C] L-lactate to [1- <sup>13</sup> C] pyruvate and [ <sup>13</sup> C] bicarbonate that brings new insights into the neuroprotection mechanism of L-lactate. Moreover, this study paves the way for the use of HP [1- <sup>13</sup> C] L-lactate as a sensitive molecular-imaging biosensor in ischaemic stroke patients after endovascular clot removal

Measuring glucose cerebral metabolism in the healthy mouse using hyperpolarized ¹³C magnetic resonance.

The mammalian brain relies primarily on glucose as a fuel to meet its high metabolic demand. Among the various techniques used to study cerebral metabolism, <sup>13</sup> C magnetic resonance spectroscopy (MRS) allows following the fate of <sup>13</sup> C-enriched substrates through metabolic pathways. We herein demonstrate that it is possible to measure cerebral glucose metabolism in vivo with sub-second time resolution using hyperpolarized <sup>13</sup> C MRS. In particular, the dynamic <sup>13</sup> C-labeling of pyruvate and lactate formed from <sup>13</sup> C-glucose was observed in real time. An ad-hoc synthesis to produce [2,3,4,6,6- <sup>2</sup> H <sub>5</sub> , 3,4- <sup>13</sup> C <sub>2</sub> ]-D-glucose was developed to improve the <sup>13</sup> C signal-to-noise ratio as compared to experiments performed following [U- <sup>2</sup> H <sub>7</sub> , U- <sup>13</sup> C]-D-glucose injections. The main advantage of only labeling C3 and C4 positions is the absence of <sup>13</sup> C- <sup>13</sup> C coupling in all downstream metabolic products after glucose is split into 3-carbon intermediates by aldolase. This unique method allows direct detection of glycolysis in vivo in the healthy brain in a noninvasive manner

Noninvasive rapid detection of metabolic adaptation in activated human T lymphocytes by hyperpolarized ¹³C magnetic resonance.

The metabolic shift induced in human CD4 <sup>+</sup> T lymphocytes by stimulation is characterized by an upregulation of glycolysis, leading to an augmentation in lactate production. This adaptation has already been highlighted with various techniques and reported in several previous studies. We herein propose a method to rapidly and noninvasively detect the associated increase in flux from pyruvate to lactate catalyzed by lactate dehydrogenase using hyperpolarized <sup>13</sup> C magnetic resonance, a technique which can be used for in vivo imaging. It was shown that the conversion of hyperpolarized <sup>13</sup> C-pyruvate to <sup>13</sup> C-lactate during the one-minute measurement increased by a mean factor of 3.6 in T cells stimulated for 5 days as compared to resting T cells. This method can be extended to other metabolic substrates and is therefore a powerful tool to noninvasively analyze T cell metabolism, possibly in vivo

Hyperpolarized ¹³C Magnetic Resonance Spectroscopy Reveals the Rate-Limiting Role of the Blood-Brain Barrier in the Cerebral Uptake and Metabolism of l-Lactate in Vivo.

The dynamics of l-lactate transport across the blood-brain barrier (BBB) and its cerebral metabolism are still subject to debate. We studied lactate uptake and intracellular metabolism in the mouse brain using hyperpolarized <sup>13</sup> C magnetic resonance spectroscopy (MRS). Following the intravenous injection of hyperpolarized [1- <sup>13</sup> C]lactate, we observed that the distribution of the <sup>13</sup> C label between lactate and pyruvate, which has been shown to be representative of their pool size ratio, is different in NMRI and C57BL/6 mice, the latter exhibiting a higher level of cerebral lactate dehydrogenase A ( Ldha) expression. On the basis of this observation, and an additional set of experiments showing that the cerebral conversion of [1- <sup>13</sup> C]lactate to [1- <sup>13</sup> C]pyruvate increases after exposing the brain to ultrasound irradiation that reversibly opens the BBB, we concluded that lactate transport is rate-limited by the BBB, with a 30% increase in lactate uptake after its disruption. It was also deduced from these results that hyperpolarized <sup>13</sup> C MRS can be used to detect a variation in cerebral lactate uptake of <40 nmol in a healthy brain during an in vivo experiment lasting only 75 s, opening new opportunities to study the role of lactate in brain metabolism

Localized in vivo hyperpolarization transfer sequences.

In vivo localized and fully adiabatic homonuclear and heteronuclear polarization transfer experiments were designed and performed in the rat brain at 9.4 T after infusion of hyperpolarized sodium [1,2-(13)C(2)] and sodium [1-(13)C] acetate. The method presented herein leads to highly enhanced in vivo detection of short-T(1) (13)C as well as attached protons. This indirect detection scheme allows for probing additional molecular sites in hyperpolarized substrates and their metabolites and can thus lead to improved spectral resolution such as in the case of (13)C-acetate metabolism

Influence of DNP Polarizing Agents on Biochemical Processes: TEMPOL in Transient Ischemic Stroke.

Hyperpolarization of <sup>13</sup> C by dissolution dynamic nuclear polarization (dDNP) boosts the sensitivity of magnetic resonance spectroscopy (MRS), making possible the monitoring in vivo and in real time of the biochemical reactions of exogenously infused <sup>13</sup> C-labeled metabolic tracers. The preparation of a hyperpolarized substrate requires the use of free radicals as polarizing agents. Although added at very low doses, these radicals are not biologically inert. Here, we demonstrate that the presence of the nitroxyl radical TEMPOL influences significantly the cerebral metabolic readouts of a hyperpolarized [1- <sup>13</sup> C] lactate bolus injection in a mouse model of ischemic stroke with reperfusion. Thus, the choice of the polarizing agent in the design of dDNP hyperpolarized MRS experiments is of great importance and should be taken into account to prevent or to consider significant effects that could act as confounding factors

Correcting surface coil excitation inhomogeneities in single-shot SPEN MRI.

Given their high sensitivity and ability to limit the field of view (FOV), surface coils are often used in magnetic resonance spectroscopy (MRS) and imaging (MRI). A major downside of surface coils is their inherent radiofrequency (RF) B1 heterogeneity across the FOV, decreasing with increasing distance from the coil and giving rise to image distortions due to non-uniform spatial responses. A robust way to compensate for B1 inhomogeneities is to employ adiabatic inversion pulses, yet these are not well adapted to all imaging sequences - including to single-shot approaches like echo planar imaging (EPI). Hybrid spatiotemporal encoding (SPEN) sequences relying on frequency-swept pulses provide another ultrafast MRI alternative, that could help solve this problem thanks to their built-in heterogeneous spatial manipulations. This study explores how this intrinsic SPEN-based spatial discrimination, could be used to compensate for the B1 inhomogeneities inherent to surface coils. Experiments carried out in both phantoms and in vivo rat brains demonstrate that, by suitably modulating the amplitude of a SPEN chirp pulse that progressively excites the spins in a direction normal to the coil, it is possible to compensate for the RF transmit inhomogeneities and thus improve sensitivity and image fidelity