A Feasibility Study of Nonlinear Spectroscopic Measurement of Magnetic Nanoparticles Targeted to Cancer Cells.

OBJECTIVE: Magnetic nanoparticles (MNPs) are an emerging platform for targeted diagnostics in cancer. An important component needed for translation of MNPs is the detection and quantification of targeted MNPs bound to tumor cells. METHOD: This study explores the feasibility of a multifrequency nonlinear magnetic spectroscopic method that uses excitation and pickup coils and is capable of discriminating between quantities of bound and unbound MNPs in 0.5 ml samples of KB and Igrov human cancer cell lines. The method is tested over a range of five concentrations of MNPs from 0 to 80 µg/ml and five concentrations of cells from 50 to 400 000 count per ml. RESULTS: A linear model applied to the magnetic spectroscopy data was able to simultaneously measure bound and unbound MNPs with agreement between the model-fit and lab assay measurements (p < 0.001). The detectable iron of the presented method to bound and unbound MNPs was < 2 µg in a 0.5 ml sample. The linear model parameters used to determine the quantities of bound and unbound nanoparticles in KB cells were also used to measure the bound and unbound MNP in the Igrov cell line and vice versa. CONCLUSION: Nonlinear spectroscopic measurement of MNPs may be a useful method for studying targeted MNPs in oncology. SIGNIFICANCE: Determining the quantity of bound and unbound MNP in an unknown sample using a linear model represents an exciting opportunity to translate multifrequency nonlinear spectroscopy methods to in vivo applications where MNPs could be targeted to cancer cells.

Extended arrays for nonlinear susceptibility magnitude imaging.

This study implements nonlinear susceptibility magnitude imaging (SMI) with multifrequency intermodulation and phase encoding. An imaging grid was constructed of cylindrical wells of 3.5-mm diameter and 4.2-mm height on a hexagonal two-dimensional 61-voxel pattern with 5-mm spacing. Patterns of sample wells were filled with 40-µl volumes of Fe3O4 starch-coated magnetic nanoparticles (mNPs) with a hydrodynamic diameter of 100 nm and a concentration of 25 mg/ml. The imaging hardware was configured with three excitation coils and three detection coils in anticipation that a larger imaging system will have arrays of excitation and detection coils. Hexagonal and bar patterns of mNP were successfully imaged (R2>0.9) at several orientations. This SMI demonstration extends our prior work to feature a larger coil array, enlarged field-of-view, effective phase encoding scheme, reduced mNP sample size, and more complex imaging patterns to test the feasibility of extending the method beyond the pilot scale. The results presented in this study show that nonlinear SMI holds promise for further development into a practical imaging system for medical applications.

Nonlinear Susceptibility Magnitude Imaging of Magnetic Nanoparticles.

This study demonstrates a method for improving the resolution of susceptibility magnitude imaging (SMI) using spatial information that arises from the nonlinear magnetization characteristics of magnetic nanoparticles (mNPs). In this proof-of-concept study of nonlinear SMI, a pair of drive coils and several permanent magnets generate applied magnetic fields and a coil is used as a magnetic field sensor. Sinusoidal alternating current (AC) in the drive coils results in linear mNP magnetization responses at primary frequencies, and nonlinear responses at harmonic frequencies and intermodulation frequencies. The spatial information content of the nonlinear responses is evaluated by reconstructing tomographic images with sequentially increasing voxel counts using the combined linear and nonlinear data. Using the linear data alone it is not possible to accurately reconstruct more than 2 voxels with a pair of drive coils and a single sensor. However, nonlinear SMI is found to accurately reconstruct 12 voxels (R2 = 0.99, CNR = 84.9) using the same physical configuration. Several time-multiplexing methods are then explored to determine if additional spatial information can be obtained by varying the amplitude, phase and frequency of the applied magnetic fields from the two drive coils. Asynchronous phase modulation, amplitude modulation, intermodulation phase modulation, and frequency modulation all resulted in accurate reconstruction of 6 voxels (R2 > 0.9) indicating that time multiplexing is a valid approach to further increase the resolution of nonlinear SMI. The spatial information content of nonlinear mNP responses and the potential for resolution enhancement with time multiplexing demonstrate the concept and advantages of nonlinear SMI.

Algorithm to find high density EEG scalp coordinates and analysis of their correspondence to structural and functional regions of the brain.

BACKGROUND: Interpretation and analysis of electroencephalography (EEG) measurements relies on the correspondence of electrode scalp coordinates to structural and functional regions of the brain. NEW METHOD: An algorithm is introduced for automatic calculation of the International 10-20, 10-10, and 10-5 scalp coordinates of EEG electrodes on a boundary element mesh of a human head. The EEG electrode positions are then used to generate parcellation regions of the cerebral cortex based on proximity to the EEG electrodes. RESULTS: The scalp electrode calculation method presented in this study effectively and efficiently identifies EEG locations without prior digitization of coordinates. The average of electrode proximity parcellations of the cortex were tabulated with respect to structural and functional regions of the brain in a population of 20 adult subjects. COMPARISON WITH EXISTING METHODS: Parcellations based on electrode proximity and EEG sensitivity were compared. The parcellation regions based on sensitivity and proximity were found to have 44.0 ± 11.3% agreement when demarcated by the International 10-20, 32.4 ± 12.6% by the 10-10, and 24.7 ± 16.3% by the 10-5 electrode positioning system. CONCLUSIONS: The EEG positioning algorithm is a fast and easy method of locating EEG scalp coordinates without the need for digitized electrode positions. The parcellation method presented summarizes the EEG scalp locations with respect to brain regions without computation of a full EEG forward model solution. The reference table of electrode proximity versus cortical regions may be used by experimenters to select electrodes that correspond to anatomical and functional regions of interest.

Correspondence of electroencephalography and near-infrared spectroscopy sensitivities to the cerebral cortex using a high-density layout.

This study investigates the correspondence of the cortical sensitivity of electroencephalography (EEG) and near-infrared spectroscopy (NIRS). EEG forward model sensitivity to the cerebral cortex was calculated for 329 EEG electrodes following the 10-5 EEG positioning system using a segmented structural magnetic resonance imaging scan of a human subject. NIRS forward model sensitivity was calculated for the same subject using 156 NIRS source-detector pairs selected from 32 source and 32 detector optodes positioned on the scalp using a subset of the 10-5 EEG positioning system. Sensitivity correlations between colocalized NIRS source-detector pair groups and EEG channels yielded R = 0.46 ± 0.08. Groups of NIRS source-detector pairs with maximum correlations to EEG electrode sensitivities are tabulated. The mean correlation between the point spread functions for EEG and NIRS regions of interest (ROI) was R = 0.43 ± 0.07. Spherical ROIs with radii of 26 mm yielded the maximum correlation between EEG and NIRS averaged across all cortical mesh nodes. These sensitivity correlations between EEG and NIRS should be taken into account when designing multimodal studies of neurovascular coupling and when using NIRS as a statistical prior for EEG source localization.

Compliant head probe for positioning electroencephalography electrodes and near-infrared spectroscopy optodes.

A noninvasive head probe that combines near-infrared spectroscopy (NIRS) and electroencephalography (EEG) for simultaneous measurement of neural dynamics and hemodynamics in the brain is presented. It is composed of a compliant expandable mechanism that accommodates a wide range of head size variation and an elastomeric web that maintains uniform sensor contact pressure on the scalp as the mechanism expands and contracts. The design is intended to help maximize optical and electrical coupling and to maintain stability during head movement. Positioning electrodes at the inion, nasion, central, and preauricular fiducial locations mechanically shapes the probe to place 64 NIRS optodes and 65 EEG electrodes following the 10-5 scalp coordinates. The placement accuracy, precision, and scalp pressure uniformity of the sensors are evaluated. A root-mean-squared (RMS) positional precision of 0.89 ± 0.23 mm, percent arc subdivision RMS accuracy of 0.19 ± 0.15%, and mean normal force on the scalp of 2.28 ± 0.88 N at 5 mm displacement were found. Geometric measurements indicate that the probe will accommodate the full range of adult head sizes. The placement accuracy, precision, and uniformity of sensor contact pressure of the proposed head probe are important determinants of data quality in noninvasive brain monitoring with simultaneous NIRS-EEG.