PATHOS Project (2019-2024).It is the purpose of PATHOS to pursue our potentially ground-breaking multidisciplinary effort in biomedical diagnostics. Starting from novel fundamental approaches to dynamical control, we seek to create new paradigms concerning control or guidance of spin evolutions in complex spin networks, so as to gear them to hitherto unforeseen MR applications in chemistry, biology and medicine. In a nutshell, PATHOS aims to further the very fruitful synergy pioneered by our partners towards developing new task-oriented comprehensive sensing strategies and exploring the new frontiers they entail for NMR, optical and MRI based analysis.
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More specifically, the PATHOS shared objectives are:
- Develop advanced control schemes:
- polarization transfer/cooling
- control of interacting spin systems
- Characterize and mitigate effects of (possibly unwanted) non-classical noise
- Study and characterize non-classical effects in spin networks:
- Classify network topology in the context of:
- polarization/cooling
- quantum state transfer
- Develop high-resolution, high-sensitivity, high-bandwidth sensing
The exploited complementary approaches are:
- Combine closely theory with experiment:
- NMR, NV, Optics
- machine learning classification approaches
- compressed sensing
- Sensing:
- radical sensing/imaging
- super-resolution microscopy
- feedback schemes
PATHOS FOR THE GENERAL AUDIENCE
During the last decades, the second quantum revolution has emerged: with the foundations firmly established, scientists are discovering a range of opportunities where quantum mechanics offers improvements on existing technologies and generating fundamentally new ones, such as quantum communication and quantum computing. In the context of magnetic resonance imaging, quantum mechanics has always been essential for understanding the phenomenon. Now, we are learning how quantum mechanics can be harnessed to improve the sensitivity, resolution and information content of the imaging process. In extreme cases, such as the one shown in the image above, it is possible to obtain images with atomic resolution, using atomic systems such as the nitrogen-vacancy center in diamond to emit single quanta of light (photons) and provide detailed information at the atomic scale on material properties or important biological samples.
The first field of application of this technique concerns NV based thermometry. We have demonstrated magnetic sensing and temperature measurements, starting to work with living cells. The current sensitivity for temperature measurements is in line with the state of the art, normalized to the sensing volume, [PHYSICAL REVIEW APPLIED 13, 054057 (2020)]. We expect to demonstrate enhanced sensitivity in such scenarios using the techniques developed here.
Furthermore, besides the well known NV centers, affected by broadband spectral emission at room temperature, a quest for more bright and more monochromatic centers is ongoing. In the course of the project, new promising colour centres in diamond besides NV, such as Pb and F, are being investigated [New J. Phys. 23 (2021) 063032, Sci. Rep. 10 21537 (2020)].
- Quantum sensing
We developed an optical microscope based on diamond defects, which allows the direct, non-invasive measurement of radical concentrations, with high-sensitivity and resolution.
On a more general note, we developed and demonstrated advanced techniques to enhance our sensitivity based on “compressed sensing”. In this approach only part of the data is sampled in an informed way, such that along with specialized algorithms we can extract the signal with high fidelity in a short amount of time.
- Polarizing (cooling) samples for MRI
Such alignment of the spins, called polarization (or cooling) is difficult to achieve in state-of-the-art techniques. We are working on novel techniques in which we can use a dense ensembles of diamond defects to polarize a contrast agent, e.g. for MRI. We proposed a scheme that improves over existing processes, and holds the promise of achieving enhanced polarization.
- Magnetic Resonance Imaging
Sensing via Zeno effects
Subsequently, a second experiment involving Zeno-dynamics for stochastic noise sensing in optical systems has begun. Suppose to have a system with D possible noise sources, stochastically distributed with different probabilities within our channel; the main purpose of this experiment is to reconstruct such noise probability distribution by performing a set of N Zeno-based samplings along the channel.
Zeno to the rescue: Tackling the Covid Pandemic with advanced quantum physics
For additional information on this project, see L. Frydman’s video in Bruker video interview: https://www.bruker.com/it/products-and-solutions/mr/make-mr-more-relevant/covid19-nmr-consortium.html, or written article in https://www.bruker.com/en/landingpages/bbio/resolution-in-a-new-dimension-for-solving-challenges-of-society/israeli-scientists-collaborate-to-speed-up-covid-19-rna-research-using-ultra-sensitive-nmr-techniques.html.
More details for Experts
- Quantum sensing
We developed an optical microscope based on shallow NVs in a diamond substrate, in which the radical sample placed near the diamond modifies the NV charge state, leading to changes in the measured fluorescence spectrum. We have demonstrated this effect using hydroxyl radicals, exhibiting direct, non-invasive measurement of radical concentrations, with a sensitivity of and a spatial resolution of [Y. Ninio et. al., ACS Photonics, 8,1917-1921 (2021)].
We have further addressed the limited bandwidth of NV-based magnetic sensing in the large-field regime, by utilizing compressed sensing techniques to improve the accuracy of sub-sampling. We demonstrated significant improvements of the resulting measurement error, specifically for short-time measurements [G. Haim et. al., in preparation].
- Spin bath cooling (hyperpolarization)
We analyzed these dynamics theoretically and developed a general framework for the control of interacting spin systems in the average Hamiltonian picture [K. Ben’Attar et. al., PRR 2, 013061 (2020)]. We then utilized this framework to develop and optimize a polarization transfer scheme which combines resonant transfer approaches (such as Hartmann-Hahn) with decoupling protocols. We showed that our approach can improve over existing methods in terms of achievable polarization level and speed of polarization transfer [K. Ben’Attar et. al., in preparation].
Sensing via Zeno effects
To do so, we exploit an optical setup in which a laser, collimated in a Gaussian mode and prepared in the polarisation state |+⟩=1/√2 (|H⟩+|V⟩), is sent to a series of N=6 steps, each composed of a pair of birefringent crystals and a polariser projecting the photons onto the |+⟩ state. In each step, a birefringent crystal pair (playing the role of our stochastic noise) can be chosen among a set of D=5 possible thickness entries (0, g, 2g, 3g, and 4g, being g the minimum thickness available). At the end of the optical path, photons are detected by an EM-CCD: from the final photon count distribution registered by the EM-CCD, we are able to extract the exact number and type of birefringent crystals encountered by the photons, i.e. the probability distribution of the D noise sources along our optical channel.
AZE for Biomolecular NMR Improvements
PATHOS Deliverables so far
Deliverable Number |
Deliverable
Title |
WP |
Lead
beneficiary |
Type |
Dissemination
Level |
Due
Date (in
months) |
D4.1 |
WEB |
4 |
UNIFI |
Web,
etc. |
Public |
2 |
D4.2 |
Data Management Plan |
4 |
Weizmann |
ORDP |
Public |
6 |
D4.9 |
Dissemination &
Exploitation Plan 1 |
4 |
Weizmann |
Report |
Confidential |
6 |
D2.5 |
Non-Markovian probes |
2 |
UNIFI |
Report |
Public |
11 |
D1.5 |
AZE heteronuclear |
1 |
Weizmann |
Report |
Confidential |
12 |
D1.6 |
AZD homonuclear |
1 |
Weizmann |
Report |
Public |
12 |
D3.5 |
NV imager |
3 |
HUJI |
Report |
Public |
12 |
D3.6 |
Optical CS imaging |
3 |
HUJI |
Report |
Public |
12 |
D2.6 |
DD Spectral density |
2 |
TUDO |
Report |
Public |
18 |
D1.1 |
AZE cooling |
1 |
Weizmann |
Report |
Public |
24 |
D2.1 |
DD probing |
2 |
UNIFI |
Report |
Public |
24 |
D3.1 |
NV-imaging + CS |
3 |
HUJI |
Report |
Public |
24 |
D3.7 |
ODMR neurons |
3 |
INRIM |
Report |
Public |
24 |
D1.2 |
ADRT cooling |
1 |
HUJI |
Report |
Public |
36 |
D2.2 |
Optical ZD |
2 |
INRIM |
Report |
Public |
36 |
D2.3 |
Correlated spectra |
2 |
HUJI |
Report |
Public |
40 |
D3.2 |
Magnetic sensing |
3 |
TUDO |
Report |
Public |
36 |
D4.1 WEB
D4.2 Data Management Plan
D2.5 Non-Markovian Probes
D1.6 AZD homonuclear
D3.5 NV imager
D3.6 Optical CS imaging
D2.6 Spectral density
D1.1 AZE cooling: Refs. 23-25, 33-34 in Dissemination
D2.1 DD probing
D3.1 NV-imaging+CS
D3.7 ODMR neurons
D.1.2 ADRT cooling
D2.2 Optical ZD
D2.3 Correlated spectra
D3.2 Magnetic sensing
Work performed from the beginning of the project
During the first reporting period of PATHOS, we have advanced as planned towards the expected long-term objectives. From the theory side, we have introduced conceptually novel approaches to the enhancement of heteronuclear spin-polarization transfer by means of repeated measurements, phase flips or spin-orientation flips for one of the spin species (alias the probe). Secondly, we have proposed new optics experiments for Zeno-based noise spectroscopy and studied several aspects of non-Markovian probes where the noise is correlated in time.
From the experimental side, we have constructed a widefield NV-based magnetic microscope, to form the basis for the experimental demonstrations in this project. We have initiated studies of enhanced magnetic sensing capabilities through compressed sensing techniques. We have developed novel schemes for controlling dense, interacting spin ensembles, through robust pulses relying on rapid adiabatic passage, as well as generalized sequences based on the icosahedral symmetry group. Besides, we have studied spin bath coupling through advanced noise spectroscopy schemes, achieving both efficient bath characterization using uneven echo sequences, as well as detailed spectroscopy with modulated, continuous control (the gDYSCO scheme).
During its second reporting period, at Weizmann we have found that the Anti-Zeno Effect (AZE) can lead to ≥500-fold reductions in the effective acquisition times in NMR experiments that are crucial for assigning protons in RNAs like those forming the genome of the SARS-CoV-2 viruses. In parallel, at HUJI we have developed and demonstrated enhanced magnetic and noise sensing using our diamond-based magnetic microscope, along with a novel optical scheme for radical concentration characterization. At INRIM we have completed the realization of an optical set up for quantum Zeno measurements (started during RP1). In addition, we have exploited our ODMR setup for magnetic sensing, showing 40 nT/Hz^1/2 magnetic sensitivity in continuous excitation and 70 nT/Hz^½ in biocompatible conditions. Furthermore, while at TUDO new dynamical decoupling (DD) pulse sequences have been proposed and experimentally tested in MRI systems, at UNIFI we have also started to develop other optimization methods based on Machine Learning (ML) methods, to predict the unknown noise spectrum avoiding the very large sets of DD measurements.
During its third reporting period, we have performed (at Weizmann) further experimental progress on the use of AZE to optimize heteronuclear polarization transfer in the presence of fast solvent chemical exchanges, demonstrating sensitivity-enhancing performance on RNA fragments derived from the SARS-CoV-2 genome. Novel 2D NMR techniques has been experimentally implemented it on murine brains in vivo at 15.2 T and ex vivo at 14.1 T. At HUJI we have further contributed to the use of NVs for enhanced sensing, aimed at using shallow NVs for thermal sensing and relaxometry in biological contexts. We have also studied advanced control techniques based on compressed sensing (CS) for improved sensitivity in ODMR. At INRIM, we have developed a dedicated setup for the simultaneous detection of neural cell activity and temperature NV sensing. Furthermore, we have published in Phys. Rev. Lett. a joint, involving INRIM, UNIFI and Weizmann, on Zeno-based photonic noise sensing. Another theoretical and experimental collaboration involving the same three PATHOS partners has led to another noise-sensing technique being able to unravel microscopic noise events affecting a continuous variable of a quantum system. At INRIM we have also demonstrated for the first time the detection of neural temperature variations (1 °C) associated with potentiation and inhibition of neuronal firing, by exploiting a nanoscale NV thermometer based on nanodiamond ODMR. Finally, at UNIFI, we have designed a new protocol of quantum pattern recognition, tested also on binary images of human blood vessel obtained from MRI (at TUDO).
PATHOS Objectives
Objective WP1: Achieving orders-of-magnitude improvement of imaging, spectroscopy and/or thermometry resolution/quality, by experimentally demonstrating the efficacy of conceptually innovative dynamically controlled cooling schemes, pioneered by our partners, based on alternating coherent and stochastic spin control pulses, towards realistic NMR/MRI medical diagnostic applications.
Objective WP2: Exploit optimal control theory to extract more information from the noise that the bio-system exerts on the probes, to be compared with the existing diagnostic schemes and tested with NV centre and NMR platforms.
Objective WP3: Develop and demonstrate novel data processing tools, and utilize information from environment correlations, combining the WP2 tools with CS schemes and testing them on NV, MRI and optical platforms.
In order to further proceed towards these objectives, we have implemented the expected tasks for each WP with an overall progress being well inline with PATHOS planned research activities.
Objectives achieved in RP2
- Novel control schemes for enhanced sensitivity and polarization transfer. The polarization transfer rate has been improved by over a factor of 2.
- Demonstration of NV magnetic sensing with compressed sensing, achieving improved bandwidth and sensitivity. Achieved bandwidth improvement (for similar sensitivity) of over a factor of 4.
- Study of multiple spin baths - characterization of radicals through noise on shallow NVs, demonstrating a sensitivity of ~10 nMol/Hz^½ with sub-micron resolution.
- AZE-related sensitivity enhancements up to ≥500-fold reductions in the effective acquisition times for NMR experiments involving RNA imino protons, like those forming the genome of the SARS-CoV-2 viruses.
- Temperature sensing (with possible application in biological samples) based on ODMR measurement (sensitivity 5 mK/Hz^½) in bulk diamond.
- ODMR sensing protocols with NV centres showing 40 nT/Hz^1/2 magnetic sensitivity in continuous excitation (70 nT/Hz^½ in biocompatible conditions).
- Discrimination between Markovian and non-Markovian noise sources via machine learning algorithms with a theoretically predicted classification mean absolute error of around 5% (that will be experimentally tested).
- Automatic assignment of MRI voxels to tissue / liquid with high fidelity.
- Efficient quantum state tomography for 2 spin qubits of NV center with the minimum number of measurements (16) and high fidelity (99%).
Objectives achieved in RP3
- A complex molecular environment (as murine brain) was explored using both in and ex vivo at high (14.1, 15.2T) fields, using both conventional 2D NMR and our new AZE technique. In conjunction, these high field experiments have revealed ca. 10 and 29 metabolites in in and ex vivo, respectively, and lead to the assignment of 137 cross-peaks in total.
- Neuronal temperature variation (1K) at single-cell level correlated to modified network firing pattern detected via nanodiamond sensor based on optically detected magnetic resonance.
- Theoretical schemes for enhanced sensitivity and polarization transfer in spin networks have been developed to fight disorder localization. Network symmetry bottlenecks have been identified and their overriding is being sought (in progress).
- Theoretical and experimental demonstration of NV-spin coherence time enhancement by 10^3 due to nuclear spin bath noise filtering via AZE measurements.
- Single-spin sensor for RF fields with unknown frequency, phase and orientation.
- Extended measurement times for hybrid electron-nuclear spin system beyond T1(electron).
- Enhanced stability and coherence of shallow NVs through novel nitrogen termination processes, enabling higher sensitivity noise sensing and coupling to external spin baths (in collaboration with Alon Hoffman).
- Enhanced coupling and polarization transfer between NV and the surrounding nuclear spin bath, through tuning the magnetic field through the level anticrossing, leading to longer coherence times (T2*, by up to almost a factor of 2).
- Demonstrate robust noise characterization, specifically correlations in spin-bath environments, through novel control and fidelity measurement schemes, suppressing effects of coherent errors (in collaboration with Raam Uzdin).
- Enhanced magnetic sensing (in the context of ODMR) through both compressed sensing and machine learning schemes (HUJI-UNIFI) - achieve nearly order-of-magnitude improvement in the sensitivity-bandwidth product.
- Advanced implementations of noise sensing (developed previously in the context of radicals) to singlet-triplet transitions in retinal excitation dynamics and to noise in magnetic excitations.
- Advanced theoretical analysis of the control and polarization transfer in interacting spin ensembles, working toward characterization of the interplay between interactions and disorder, further improved polarization transfer schemes, and rigorous description of the coherence decay in relevant scenarios.