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# A CMOS NMR needle for probing brain physiology with high spatial and temporal resolution

## Abstract

Magnetic resonance imaging and spectroscopy are versatile methods for probing brain physiology, but their intrinsically low sensitivity limits the achievable spatial and temporal resolution. Here, we introduce a monolithically integrated NMR-on-a-chip needle that combines an ultra-sensitive 300 µm NMR coil with a complete NMR transceiver, enabling in vivo measurements of blood oxygenation and flow in nanoliter volumes at a sampling rate of 200 Hz.

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## Data availability

The data that support the findings of this study are available from the corresponding authors upon request.

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## Acknowledgements

We thank H. Merkle (LFMI-NINDS, National Institutes of Health, Bethesda, MD, USA) for building the surface coils and for suggestions on the in vitro setup. We thank J. Leupold and M. Wapler (University of Freiburg, Germany) for providing us with the laser-cut polyimide foil. We thank M. Ortmanns (University of Ulm, Germany) for hosting J.A. and J.H. in his lab and providing access to software tools and mixed-signal electrical characterization equipment. We thank C. Kranz (University of Ulm, Germany) for applying a biocompatible Parylene-C coating to an intermediate cable prototype. This work was supported by the German research foundation, Deutsche Forschungsgemeinschaft Grant AN 984/4-1 (J.A.) and KS 658/7-1 (K.S.).

## Author information

Authors

### Contributions

J.A., N.F. and K.S. conceived and supervised the project. J.A. and J.H. designed the CMOS ASIC. J.H. and M.P.-R. designed the experimental setups. A.B. and F.V. developed and performed the needle postprocessing. M.B. and M.P.-R. conducted the animal surgeries. J.A., J.H., M.P.-R., R.P., K.S. and X.Y. designed the experiments. J.H. and M.P.-R. performed the experiments. J.H., M.P.-R. and K.S. performed the data analysis. J.A., J.H. and K.S. wrote the manuscript. All authors discussed the results and reviewed the manuscript.

### Corresponding authors

Correspondence to Jonas Handwerker or Jens Anders or Klaus Scheffler.

## Ethics declarations

### Competing interests

A.B., N.F. and F.V. are employees of Bruker BioSpin AG. The other authors declare no competing interests.

Peer review information Nina Vogt was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

## Integrated supplementary information

### Supplementary Fig. 1 In vitro NMR characterization of the NMR needle immersed in DI water.

a, Averaged quadrature output signal at an offset frequency of 70 kHz (N = 1,000) showing the exponential decay of the free induction decay (FID), the 90° phase shift between the in-phase (I) and quadrature (Q) signal can be seen in the inset. b, Corresponding spectrum of the complex FID, the water peak at 4.7 ppm has a linewidth of 12 Hz (corresponding to 0.02 ppm) after manual shimming.

### Supplementary Fig. 2 Magnitude of the complex FID signals recorded with the NMR needle during the in vivo neuronal experiments shown in Fig. 2e with different TR.

Each plot shows the first 30 s stimulation block (N = 1, data representative of 20 blocks per experiment and of 7 animals) containing a stimulation period of tstim = 6 s, which is indicated by the gray background. The magnified inset shows a duration of 100 ms containing 1, 2 and 20 FIDs, respectively. The signals shown here are the magnitude values of the complex raw output signals, which have been bandpass filtered around the low-IF frequency of 70 kHz with a Gaussian filter with a bandwidth of 1 kHz. For short TR values, the amplitude of each FID is lower than for long TR values due to saturation effects. For TR = 5 ms, the FID amplitude does not decay to zero between the acquisitions, allowing for an almost (except for the 10 µs excitation pulse) continuous recording of the MR signal. The measured $$T_2^ \ast$$ of the signals is around 6 ms, corresponding to a linewidth of 53 Hz (or 0.09 ppm).

### Supplementary Fig. 3 Simulated and measured sensitive volume of the NMR needle in transmit/receive operation.

a-d, Simulated magnitude images obtained from a finite element electromagnetic field simulation with an isotropic voxel size of 2 µm and a pulse duration of 13 µs. e-h, Single-shot (that is no averaging, N = 1) 3DGRE TX/RX magnitude images (zoom of the entire FOV) with an isotropic voxel size of 13 µm. The simulated and measured signals are shown in the x-slices in a and e, y-slices in b and f and z-slices in c and g. The sensitive volumes in d and h are defined with a threshold of 10% of $$\hat S$$ (Methods). Despite the symmetrical outer dimensions of the on-chip coil, its simulated and measured sensitivity profiles have different y and z dimensions, because only the Bxy-field contributes to the signal, leading to an elliptical shape of the sensitive region. The dark areas within the sensitive volume are regions with local flip angles with integer multiples of 180°.

### Supplementary Fig. 4 In vitro single-average 3DGRE imaging of a grated polyimide foil with 13 µm isotropic resolution.

a, Micrograph of the polyimide foil phantom showing the 50 µm × 50 µm wide laser-cut openings. b, Setup photo of the polyimide foil imaging experiment showing the foil immersed in 10 mM Gd-doped water with the microcoil placed directly above the foil. c, Zoomed version of the x-slice of the 3DGRE image of the polyimide foil (N = 1). The openings appear as bright objects in the image due to the water proton signal while the foil appears in black.

### Supplementary Fig. 5 Spectral analysis and time-domain output signals with different filters from the in vivo rat forepaw stimulation experiments with TR = 5 ms.

a, Spectrum of a contralateral signal of a full 600 s experiment comprising 20 subsequent stimulation blocks recorded with the NMR needle, spectrum of the raw signal of the breathing pad and histogram of the heart rate, all recorded during the same in vivo stimulation experiment (N = 1). The additional peaks in the needle signal are the harmonics of the heart rate, which are not represented in the heart rate histogram. b, Mean μ and standard deviation σ of the time-domain output signal of the NMR needle (average of N = 20 blocks) sampled at TR = 5 ms without filter, filtered for physiological noise only and with a Gaussian lowpass filter with a bandwidth of 3 Hz. The stimulation period tstim=6 s is indicated by the gray background. The presented data for a and b are representative of 7 animals.

### Supplementary Fig. 6 Simulation results of the inflow-related signal increase ΔM0 and blood oxygenation dependent relaxation rate changes $${\mathrm{\Delta }}R_2^ \ast$$.

a, Simulation of the inflow-related signal increase ΔM0 of unsaturated blood for different excitation flip angles and blood flow changes ΔCBF. b, Monte Carlo simulation of changes in the relaxation rate $${\mathrm{\Delta }}R_2^ \ast$$ versus the vessel radius for different FBV of 1% and 2% and ΔLOX of 10% and 20%.

### Supplementary Fig. 7 Simulated unitary B1-field of the planar microcoil and comparison of the simulated and measured output amplitude versus excitation pulse duration.

a-c, Simulated cross sectional views of the magnitude of the unitary Bxy-field of the integrated planar microcoil obtained in a finite element simulation. Voxels with x-coordinates between −100 µm and 0 µm show zero magnitude since the CMOS chip does not contribute to the proton NMR signal. d, Simulated and measured normalized output signal amplitude for different pulse times to find the optimum pulse duration. The measured curve was recorded with the needle immersed in 10 mM Gd-doped water with TR = 1 s, Tacq = 50 ms, Nsteps = 51, N = 5 averages per step. The plotted amplitudes are the peak values of the frequency spectra. The signal intensity does not return to zero after the first maximum due to the inhomogeneous flip angle distribution over the sample.

### Supplementary Fig. 8 In vitro measurement of the B0-map and magnitude images of the NMR needle immersed in DI water.

a-c, Single-shot (that is no averaging, N = 1) B0-map showing the field variation due to susceptibility artifacts caused by the NMR needle in x- (a) y- (b) and z- (c) direction. The maximum deviation at the tip of the needle is about ±500 Hz. d-f, Magnitude images from the B0-map experiment. The images of the NMR needle were recorded with a 10 mm surface coil operated in TX/RX mode and connected to the Bruker spectrometer.

### Supplementary Fig. 9 In vitro 3DGRE images of homogeneous water phantoms for image SNR comparison of an 8 mm surface coil and the NMR needle.

a, Single-shot (that is no averaging, N = 1) magnitude image with an isotropic resolution of $$\Delta _{{\mathrm{coil}}}^3 = \left( {100\,{{\upmu {\mathrm{m}}}}} \right)^3$$ recorded with a conventional 8 mm surface coil. The image SNR is determined in the slice parallel to the coil surface with a distance of 800 µm. The asymmetric shape is due to the feed lines. b, Single-average magnitude image (N = 1) recorded with the NMR needle with an isotropic resolution of $$\Delta _{{\mathrm{needle}}}^3 = \left( {13\,{{\upmu {\mathrm{m}}}}} \right)^3$$. The image SNR of the NMR needle is determined in the slice parallel to the coil surface with a distance of 26 µm. The image is a zoomed-out version of Supplementary Fig. 3e. In both figures, the noise ROIs are indicated with red squares in the four corners of each figure, the signal ROI in the middle of the coils is indicated with green squares.

## Supplementary Information

### Supplementary Information

Supplementary Figs.1–9 and Table 1.

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Handwerker, J., Pérez-Rodas, M., Beyerlein, M. et al. A CMOS NMR needle for probing brain physiology with high spatial and temporal resolution. Nat Methods 17, 64–67 (2020). https://doi.org/10.1038/s41592-019-0640-3

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