Magnetic Resonance Spectroscopy

Interpreting electron paramagnetic resonance (EPR) spectra commonly requires repeated forward simulation and optimization of spin Hamiltonian parameters. Established software provides mature simulation and fitting methods, but these calculations are not generally available as differentiable components within machine-learning workflows. We present TorchSpin, an open-source PyTorch framework that ports the organization and numerical conventions of EasySpin into a tensor-based computational environment. Representative calculations spanning continuous-wave EPR, ENDOR, pulse EPR, spin dynamics, trajectory simulation, and magnetometry closely reproduced corresponding EasySpin results. In matched benchmarks, TorchSpin CPU execution was faster than EasySpin for six of nine workloads although performance depended strongly on the calculation. We therefore focused on the capabilities enabled by automatic differentiation in PyTorch. In a Cu(II) powder-spectrum demonstration, feedback propagated through TorchSpin improved the quality of a supervised convolutional neural network (CNN) without using parameter labels during refinement. Models trained from randomly initialized CNNs using only noisy spectra and TorchSpin reconstruction loss achieved median similarities of $\geq$ 0.99. CNNs trained on TorchSpin-generated libraries also transferred without adaptation to independently generated EasySpin spectra with performance comparable to EasySpin-trained controls. Once trained, the CNN produced initial parameter estimates in approximately 1 ms per spectrum while a batch of 512 was processed in approximately 1.3 ms with GPU acceleration. TorchSpin therefore provides both a tested Python implementation of established EPR calculations and a differentiable physical layer for rapid learned inference, spectral refinement, and parameter-label-free training.

Following the molecular discovery and synthesis revolutions, scalable automated structure elucidation from routine spectroscopic data remains an outstanding challenge. Despite decades of computational efforts, no existing system achieved reliable reasoning over unseen spectra. Here, we propose MACROS, a multi-agent system automating structure elucidation by emulating expert iterative hypothesis-testing. Trained on 100M simulated and 1.6M experimental spectra-molecule pairs, it natively supports arbitrary combinations of routine spectroscopic techniques. It achieves unprecedented zero-shot generalization to diverse real-world samples, correctly identifying synthetic compounds, natural products and metabolites above 500 Da with 1D NMR. Remarkably, MACROS spontaneously recovers textbook spectroscopic correlations from unassigned data and exhibits emergent chemical intuition such as a ring-first parsing preference, learning fundamental chemical principles rather than memorizing database patterns. MACROS augments chemists via collaboration to deliver sixfold faster, 40% more accurate elucidation. MACROS establishes a scalable foundation for fully automated structure elucidation, and catalyzes accelerated molecular discovery toward autonomous laboratories.

Overlapping peaks and sample-dependent chemical shift variability prevent reliable metabolite recovery from complex biological spectra. This problem is critical in one-dimensional proton (1D 1H) NMR which has become the standard method providing fast acquisition and information-rich spectra in metabolomics and foodomics. This study demonstrates how chemical shifts can be utilised as a strength in 1D 1H NMR, when suitably modeled through the proposed Bayesian Shift-Invariant Non-negative Matrix Factorization (BSI-NMF) procedure. We find that BSI-NMF accurately recovers the underlying chemical signals in 1D 1H NMR spectra missed by existing analyses approaches across simulations, laboratory created datasets, and a large urine dataset obtained from 2439 people across Europe. Our study highlights how shifts in the chemical signatures - until now perceived as a nuisance - can in fact when suitably modelled be instrumental for unique recovery of metabolites. This creates an opportunity to experimentally induce chemical shifts changes to facilitate unique recovery of spectra.

Determining molecular structures from spectroscopic data remains fundamentally challenging because the inverse problem is intrinsically underdetermined: individual spectra are sparse, low-dimensional, and encode only partial structural evidence relative to the vast space of possible molecules. We address this challenge by formulating automated structure elucidation as a scalable hypothesis-refinement paradigm that tightly integrates spectral evidence with large-scale molecular priors. To supply structure-resolving NMR signals for multimodal learning, we construct QM9SPIN, a DFT-derived dataset comprising diverse 1D and 2D spectra, including J-coupling, DEPT experiments, and explicit spin--spin interactions. On this foundation, we introduce SpectroMol, a spectrum-to-structure model that proposes chemically valid molecular hypotheses conditioned on multimodal spectral inputs. Complementarily, we develop MS-Mol2Mol, a high-resolution mass-constrained molecular generator that integrates molecular formula, exact mass, and degree of unsaturation within a conditional generative prior trained on 400 million molecules, ensuring global compositional consistency and chemically realistic refinement. The integrated system achieves 93.8% top-1 accuracy on the simulated benchmark, adapts effectively from simulated to experimental spectra with limited experimental fine-tuning, and further improves experimental predictions through mass-guided refinement, establishing a scalable route toward automated, data-driven organic structure elucidation.

Here, we present a platform built on our inverted Graph Transformer Network, IMPRESSION-G2, which can accurately and rapidly reconstruct molecular bonding directly from experimental nuclear magnetic resonance (NMR) spectroscopic information. It comprises three interconnected stages: a one-shot model that predicts bond connectivity between atoms; a structure-correction stage that corrects the predicted structures by removing uncertain bonds and iteratively reassigning them; noise-augmented multi-shot prediction, generating an ensemble of candidate structures, which are ranked to identify the best-fit structure. By integrating a range of $^{1}$H and $^{13}$C NMR data, including two-dimensional (2D) experiments such as COSY, HSQC, and HMBC, the inverse-IMPRESSION platform correctly identifies the structures of 77.8% of molecules with up to 30 heavy atoms (H, C, N, O and F) using simulated NMR data, and 10 of 19 (53%) molecules using experimental NMR data. The experimental structures solved have molecular weights of up to 480 Da and are representative of the complex structures in synthetic and natural products that routinely challenge chemists. The inverse-IMPRESSION framework thus provides the first effective approach for automated molecular structure elucidation using graph-based machine learning on experimental data.

Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful tool for molecular structure analysis, and spectral artificial intelligence offers great potential for its rapid and automated interpretation. However, the scarcity of experimental NMR datasets has constrained deep learning in this domain to narrow, task-specific applications that lack broad generalization. Here, we introduce UltraNMR, a large-scale foundation model for NMR that leverages the intrinsic properties of NMR spectra to learn generalizable spectral representations. We collected 158 million paired simulated $^{1}$H and $^{13}$C NMR spectra to train UltraNMR, employing multiple domain-specific pre-training objectives. UltraNMR captures both intra-spectral and inter-spectral dependencies, enabling seamless simulation-to-real adaptation. We demonstrate that adapting UltraNMR to a range of molecular structure analysis tasks on experimental NMR spectra consistently yields state-of-the-art performance and clearly outperforms UltraNMR variants trained directly on downstream data without simulation pre-training. We also construct a large-scale NMR spectral vector library by encoding simulated NMR spectra using UltraNMR, covering 94 million unique molecules and enabling effective structure-aware retrieval. In real-world applications, UltraNMR facilitates the structural elucidation of two previously unknown natural products from Chinese herbal medicines recorded in the Chinese Pharmacopoeia. These results suggest that large-scale simulation pre-training can effectively bridge the simulation-to-real gap, enabling robust and generalizable molecular structure analysis of real-world NMR spectra.

Nuclear magnetic resonance (NMR) spectroscopy provides an experimental readout of local chemical environments, but its use in molecular representation learning has been constrained by heterogeneous data and incomplete atom-level assignments. Here we construct complementary high-fidelity experimental and computational 13C NMR resources, which reveal a recurrent form of representational collapse: atoms that are equivalent in molecular topology can remain experimentally distinct in their real chemical environments, whereas explicit 3D descriptions are further limited by static conformations in dynamic regimes. To alleviate this bottleneck, we develop CLAIM (Contrastive Learning for Atom-to-molecule Inference of Molecular NMR), a framework that aligns efficient topological molecular inputs with atom-resolved NMR observables. Through hierarchical chemical priors and cross-level contrastive learning, CLAIM restores lost chemical resolution and markedly improves atom-level molecule-spectrum retrieval. CLAIM remains robust in flexible and tautomeric systems for 13C NMR prediction, improves stereoisomer discrimination without explicit 3D modelling, and transfers to broader molecular property tasks including ADMET prediction and fluorescence estimation. These results establish physically grounded spectral alignment as an effective strategy for alleviating chemical-environment collapse and for guiding experimentally grounded molecular representation learning.

Purpose: Proton magnetic resonance spectroscopic imaging ($^1$H MRSI) enables the mapping of whole-brain metabolites concentrations in-vivo. However, a long-standing problem for its clinical applicability is the metabolic quantification, which can require extensive time for spectral fitting. Recently, deep learning methods have been able to provide whole-brain metabolic quantification in only a few seconds. However, neural network implementations often lack configurability and require retraining to change predefined parameter settings. Methods: We introduce HyperFitS, a hypernetwork for spectral fitting for metabolite quantification in whole-brain $^1$H MRSI that flexibly adapts to a broad range of baseline corrections and water suppression factors. Metabolite maps of human subjects acquired at 3T and 7T with isotropic resolutions of 10 mm, 3.4 mm and 2 mm by water-suppressed and water-unsuppressed MRSI were quantified with HyperFitS and compared to conventional LCModel fitting. Results: Metabolic maps show a substantial agreement between the new and gold-standard methods, with significantly faster fitting times by HyperFitS. Quantitative results further highlight the impact of baseline parametrization on metabolic quantification, which can alter results by up to 30%. Conclusion: HyperFitS shows strong agreement with state-of-the-art conventional methods, while reducing processing times from hours to a few seconds. Compared to prior deep learning based spectral fitting methods, HyperFitS enables a wide range of configurability and can adapt to data quality acquired with multiple protocols and field strengths without retraining.

Protein structural ensembles from NMR spectroscopy capture biologically important conformational heterogeneity, but it remains difficult to determine whether observed variation reflects coordinated motion or noise-like artifacts. We evaluate the Spectral Coherence Index (SCI), a model-free, rotation-invariant summary derived from the participation-ratio effective rank of the inter-model pairwise distance-variance matrix. Under grouped primary analysis of a Main110 cohort of 110 NMR ensembles (30--403 residues; 10--30 models per entry), SCI separated experimental ensembles from matched synthetic incoherent controls with AUC-ROC $= 0.973$ and Cliff's $δ= -0.945$. Relative to an internal 27-protein pilot, discrimination softened modestly, showing that pilot-era thresholds do not transfer perfectly to a larger, more heterogeneous cohort: the primary operating point $τ= 0.811$ yielded 95.5% sensitivity and 89.1% specificity. PDB-level sensitivity remained nearly unchanged (AUC $= 0.972$), and an independent 11-protein holdout reached AUC $= 0.983$. Across 5-fold grouped stratified cross-validation and leave-one-function-class-out testing, SCI remained strong (AUC $= 0.968$ and $0.971$), although $σ_{R_g}$ was the stronger single-feature discriminator and a QC-augmented multifeature model generalized best (AUC $= 0.989$ and $0.990$). Residue-level validation linked SCI-derived contributions to experimental RMSF across 110 proteins and showed broad concordance with GNM-based flexibility patterns. Rescue analyses showed that Main110 softening arose mainly from size and ensemble normalization rather than from loss of spectral signal. Together, these results establish SCI as an interpretable, bounded coherence summary that is most useful when embedded in a multimetric QC workflow for heterogeneous protein ensembles.

Magnetic resonance spectroscopy (MRS) provides clinically valuable metabolic characterization of brain tumors, but its utility depends on accurate placement of the spectroscopy volume-of-interest (VOI). However, VOI placement typically has a broad operating window: for a given tumor there are multiple possible VOIs that would lead to high-quality MRS measurements. Thus, a VOI place-ment can be tuned for clinician preference, case-specific anatomy, and clinical pri-orities, which leads to high inter-operator variability, especially for heterogeneous tumors. We propose an agentic large language model (LLM) workflow that de-composes VOI placement into generation of diverse candidate VOIs, from which the LLM selects an optimal one based on quantitative metrics. Candidate VOIs are generated by vision transformer-based placement models trained with differ-ent objective function preferences, which allows selection from acceptable alterna-tives rather than a single deterministic placement. On 110 clinical brain tumor cas-es, the agentic workflow achieves improved solid tumor coverage and necrosis avoidance depending on the user preferences compared to the general-purpose expert placements. Overall, the proposed workflow provides a strategy to adapt VOI placement to different clinical objectives without retraining task-specific models.

The development of deep learning methods for magnetic resonance spectroscopy (MRS) is often hindered by limited availability of large, high-quality training datasets. While physics-based simulations are commonly used to mitigate this limitation, accurately modeling all in-vivo signal components remains challenging. In this work, we propose a data-driven framework for synthesizing in-vivo MRS data using a variational autoencoder (VAE) trained exclusively on measured single-voxel spectroscopy data. The model learns a low-dimensional latent representation of complex-valued spectra and enables generation of new samples through latent-space sampling and interpolation. The generative performance of the proposed approach is evaluated using a comprehensive set of complementary analyses, including reconstruction quality, feature-level similarity using low-dimensional embeddings, application-based signal quality metrics, and metabolite quantification agreement. The results demonstrate that the VAE accurately reconstructs dominant spectral patterns and generates synthetic spectra that occupy the same feature space as in-vivo data. In an example application targeting GABA-edited spectroscopy, augmenting limited subsets of transients with synthetic spectra improves signal quality metrics such as signal-to-noise ratio, linewidth, and shape scores. However, the results also reveal limitations of the generative approach, including under-representation of stochastic noise and reduced accuracy in absolute metabolite quantification, particularly for applications sensitive to concentration estimates. These findings highlight both potential and limitations of data-driven MRS synthesis. Beyond the proposed model, this study introduces a structured evaluation framework for generative MRS methods, emphasizing the importance of application-aware validation when synthetic data are used for downstream analysis.

Magnetic resonance spectroscopy (MRS) is used to quantify metabolites in vivo and estimate biomarkers for conditions ranging from neurological disorders to cancers. Quantifying low-concentration metabolites such as GABA ($γ$-aminobutyric acid) is challenging due to low signal-to-noise ratio (SNR) and spectral overlap. We investigate and validate deep learning for quantifying complex, low-SNR, overlapping signals from MEGA-PRESS spectra, devise a convolutional neural network (CNN) and a Y-shaped autoencoder (YAE), and select the best models via Bayesian optimisation on 10,000 simulated spectra from slice-profile-aware MEGA-PRESS simulations. The selected models are trained on 100,000 simulated spectra. We validate their performance on 144 spectra from 112 experimental phantoms containing five metabolites of interest (GABA, Glu, Gln, NAA, Cr) with known ground truth concentrations across solution and gel series acquired at 3 T under varied bandwidths and implementations. These models are further assessed against the widely used LCModel quantification tool. On simulations, both models achieve near-perfect agreement (small MAEs; regression slopes $\approx 1.00$, $R^2 \approx 1.00$). On experimental phantom data, errors initially increased substantially. However, modelling variable linewidths in the training data significantly reduced this gap. The best augmented deep learning models achieved a mean MAE for GABA over all phantom spectra of 0.151 (YAE) and 0.160 (FCNN) in max-normalised relative concentrations, outperforming the conventional baseline LCModel (0.220). A sim-to-real gap remains, but physics-informed data augmentation substantially reduced it. Phantom ground truth is needed to judge whether a method will perform reliably on real data.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique to measure the metabolic composition of tissues, offering valuable insights into neurological disorders, tumor detection, and other metabolic dysfunctions. However, accurate metabolite quantification is hindered by challenges such as spectral overlap, low signal-to-noise ratio, and various artifacts. Traditional methods like linear-combination modeling are susceptible to ambiguities and commonly only provide a theoretical lower bound on estimation accuracy in the form of the Cramér-Rao bound. This work introduces a Bayesian inference framework using Sylvester normalizing flows (SNFs) to approximate posterior distributions over metabolite concentrations, enhancing quantification reliability. A physics-based decoder incorporates prior knowledge of MRS signal formation, ensuring realistic distribution representations. We validate the method on simulated 7T proton MRS data, demonstrating accurate metabolite quantification, well-calibrated uncertainties, and insights into parameter correlations and multi-modal distributions.