Jeffrey J. L. Carson

Possible mechanisms by which extremely low frequency magnetic fields affect opioid function.

Although extremely low frequency (ELF, <300 Hz) magnetic fields exert a variety of biological effects, the magnetic field sensing/transduction mechanism (or mechanisms) remain to be identified. Using the well‐defined inhibitory effects that magnetic fields have on opioid peptide mediated antinocicep‐tion or “analgesia” in the land snail Cepaea nemoralis, we show that these actions only occur for certain frequency and amplitude combinations of time‐varying sinusoidal magnetic fields in a manner consistent with a direct influence of these fields. We exposed snails with augmented opioid activity to ELF magnetic fields, which were varied in both amplitude and frequency, along with a parallel static magnetic field. When the peak amplitude (0‐547 μT) of a magnetic field of 60 Hz was varied systematically, we observed a nonlinear response, i.e., a nonlinear reduction in analgesia as measured by the latency of a defined response by the snails to a thermal stimulus. When frequency (10‐240 Hz) was varied, keeping the amplitude constant (141 μT), we saw significant inhibitory effects between 30 and 35 Hz, 60 and 90 Hz and at 120 and 240 Hz. Finally, when the static field was varied but the amplitude and frequency of the time‐varying field were held constant, we observed significant inhibition at almost all amplitudes. This amplitude/frequency “resonance‐like” dependence of the magnetic field effects suggests that the mechanism (or mechanisms) of response to weak ELF fields likely involves a direct magnetic field detection mechanism rather than an induced current phenomenon. We examined the implications of our findings for several models proposed for the direct sensing of ELF magnetic fields.—Prato, F. S., Carson, J. J. L., Ossenkopp, K.‐P., Kavaliers, M. Possible mechanisms by which extremely low frequency magnetic fields affect opioid function. FASEB J. 9, 807‐814 (1995)

Continuous, Noninvasive, and Localized Microvascular Tissue Oximetry Using Visible Light Spectroscopy

Background: The authors evaluated the ability of visible light spectroscopy (VLS) oximetry to detect hypoxemia and ischemia in human and animal subjects. Unlike near-infrared spectroscopy or pulse oximetry (SpO2), VLS tissue oximetry uses shallow-penetrating visible light to measure microvascular hemoglobin oxygen saturation (StO2) in small, thin tissue volumes. Methods: In pigs, StO2 was measured in muscle and enteric mucosa during normoxia, hypoxemia (SpO2 = 40–96%), and ischemia (occlusion, arrest). In patients, StO2 was measured in skin, muscle, and oral/enteric mucosa during normoxia, hypoxemia (SpO2 = 60–99%), and ischemia (occlusion, compression, ventricular fibrillation). Results: In pigs, normoxic StO2 was 71 ± 4% (mean ± SD), without differences between sites, and decreased during hypoxemia (muscle, 11 ± 6%; P < 0.001) and ischemia (colon, 31 ± 11%; P < 0.001). In patients, mean normoxic StO2 ranged from 68 to 77% at different sites (733 measures, 111 subjects); for each noninvasive site except skin, variance between subjects was low (e.g., colon, 69% ± 4%, 40 subjects; buccal, 77% ± 3%, 21 subjects). During hypoxemia, StO2 correlated with SpO2 (animals, r2 = 0.98; humans, r2 = 0.87). During ischemia, StO2 initially decreased at −1.3 ± 0.2%/s and decreased to zero in 3–9 min (r2 = 0.94). Ischemia was distinguished from normoxia and hypoxemia by a widened pulse/VLS saturation difference (Δ < 30% during normoxia or hypoxemia vs. Δ > 35% during ischemia). Conclusions: VLS oximetry provides a continuous, noninvasive, and localized measurement of the StO2, sensitive to hypoxemia, regional, and global ischemia. The reproducible and narrow StO2 normal range for oral/enteric mucosa supports use of this site as an accessible and reliable reference point for the VLS monitoring of systemic flow.

Detection and Quantification of Myocardial Reperfusion Hemorrhage Using T2*-Weighted CMR

OBJECTIVES The purpose of this study was to validate T2*-weighted cardiac magnetic resonance (T2*-CMR) for the detection and quantification of reperfusion hemorrhage in vivo against an ex vivo gold standard, and to investigate the relationship of hemorrhage to microvascular obstruction, infarct size, and left ventricular (LV) functional parameters. BACKGROUND Hemorrhage can contribute to reperfusion injury in myocardial infarction and may have significant implications for patient management. There is currently no validated imaging method to assess reperfusion hemorrhage in vivo. T2*-CMR appears suitable because it can create image contrast on the basis of magnetic field effects of hemoglobin degradation products. METHODS In 14 mongrel dogs, myocardial infarction was experimentally induced. On day 3 post-reperfusion, an in vivo CMR study was performed including a T2*-weighted gradient-echo imaging sequence for hemorrhage, standard sequences for LV function, and post-contrast sequences for microvascular obstruction and myocardial necrosis. Ex vivo, thioflavin S imaging and triphenyl-tetrazoliumchloride (TTC) staining were performed to assess microvascular obstruction, hemorrhage, and myocardial necrosis. Images were analyzed by blinded observers, and comparative statistics were performed. RESULTS Hemorrhage occurred only in the dogs with the largest infarctions and the greatest extent of microvascular obstruction, and it was associated with more compromised LV functional parameters. Of 40 hemorrhagic segments on TTC staining, 37 (92.5%) were positive for hemorrhage on T2*-CMR (kappa = 0.96, p < 0.01 for in vivo/ex vivo segmental agreement). The amount of hemorrhage in 13 affected tissue slices as determined by T2*-CMR in vivo correlated strongly with ex vivo results (20.3 ± 2.3% vs. 17.9 ± 1.6% per slice; Pearson r = 0.91; r(2) = 0.83, p < 0.01 for both). Hemorrhage size was not different between in vivo T2*-CMR and ex vivo TTC (mean difference 2.39 ± 1.43%; p = 0.19). CONCLUSIONS T2*-CMR accurately quantified myocardial reperfusion hemorrhage in vivo. Hemorrhage was associated with more severe infarct-related injury.

Three-dimensional photoacoustic imaging by sparse-array detection and iterative image reconstruction

Photoacoustic imaging (PAI) has the potential to acquire 3-D optical images at high speed. Attempts at 3-D photoacoustic imaging have used a dense 2-D array of ultrasound detectors or have densely scanned a single detector on a 2-D surface. The former approach is costly and complicated to realize, while the latter is inherently slow. We present a different approach based on a sparse 2-D array of detector elements and an iterative reconstruction algorithm. This approach has the potential for fast image acquisition, since no mechanical scanning is required, and for simple and compact construction due to the smaller number of detector elements. We obtained spatial sensitivity maps of the sparse array and used them to optimize the image reconstruction algorithm. We then validated the method on phantoms containing 3-D distributions of optically absorbing point sources. Reconstruction of the point sources from the time-domain signals resulted in images with good contrast and accurate localization (< or =1 mm error). Image acquisition time was 1 s. The results suggest that 3-D PAI with a sparse array of detector elements is a viable approach. Furthermore, the rapid acquisition speed indicates the possibility of high frame rate 3-D PAI.

Depth of photothermal conversion of gold nanorods embedded in a tissue-like phantom

Gold nanorod (AuNR)-assisted photothermal therapy has emerged as a viable method for selective killing of cancer cells and shows promise for tumor destruction in vivo. This study examined the distribution of AuNR conversion expected to occur during photothermal therapy in vivo. Tissue-like phantoms were prepared with polyethylene glycol AuNRs distributed homogeneously at a concentration representative of a systemic injection. Phantoms were illuminated with a nanosecond pulsed laser (800 nm) at a variety of combinations of pulse energy (12-120 mJ) and pulse count (1-1000). Operating at the American National Standards Institute safety limit for human skin exposure (30 mJ cm(-2)), a diameter of 13 mm and a depth of 7.6 mm of AuNR conversion were observed in the gel phantoms after 1000 laser pulses (100 s exposure). Significant AuNR conversion was measured to a depth of 6 mm after only 100 pulses. Comparison of the measured AuNR conversion distribution with Monte Carlo simulation suggested that the fluence threshold for AuNR conversion estimated from phantom measurements was in the range of 20-43 mJ cm(-2). The results suggest that AuNR-assisted photothermal therapy will be effective for tumors within 10 mm of the illuminated tissue surface.

3D photoacoustic imaging

Our group has concentrated on development of a 3D photoacoustic imaging system for biomedical imaging research. The technology employs a sparse parallel detection scheme and specialized reconstruction software to obtain 3D optical images using a single laser pulse. With the technology we have been able to capture 3D movies of translating point targets and rotating line targets. The current limitation of our 3D photoacoustic imaging approach is its inability ability to reconstruct complex objects in the field of view. This is primarily due to the relatively small number of projections used to reconstruct objects. However, in many photoacoustic imaging situations, only a few objects may be present in the field of view and these objects may have very high contrast compared to background. That is, the objects have sparse properties. Therefore, our work had two objectives: (i) to utilize mathematical tools to evaluate 3D photoacoustic imaging performance, and (ii) to test image reconstruction algorithms that prefer sparseness in the reconstructed images. Our approach was to utilize singular value decomposition techniques to study the imaging operator of the system and evaluate the complexity of objects that could potentially be reconstructed. We also compared the performance of two image reconstruction algorithms (algebraic reconstruction and l1-norm techniques) at reconstructing objects of increasing sparseness. We observed that for a 15-element detection scheme, the number of measureable singular vectors representative of the imaging operator was consistent with the demonstrated ability to reconstruct point and line targets in the field of view. We also observed that the l1-norm reconstruction technique, which is known to prefer sparseness in reconstructed images, was superior to the algebraic reconstruction technique. Based on these findings, we concluded (i) that singular value decomposition of the imaging operator provides valuable insight into the capabilities of a 3D photoacoustic imaging system, and (ii) that reconstruction algorithms which favor sparseness can significantly improve imaging performance. These methodologies should provide a means to optimize detector count and geometry for a multitude of 3D photoacoustic imaging applications.

Nano-hole array structure with improved surface plasmon energy matching characteristics

We present a nano-hole array structure in an opaque gold film that contains a cavity beneath each nano-hole. The cavity contributes to surface plasmon energy matching between the top and bottom surfaces of the gold and within the nano-hole structures. Based on bulk surface plasmon resonance (SPR) sensing experiments, the SP-matched structure had 2.8-fold higher differential transmission, 2-fold higher sensitivity, and a 7-fold higher ratio of extraordinary optical transmission at resonance to the nearby minimum compared to a conventional NHA. The results suggest that the structure with cavities has potential to improve performance of bulk SPR sensing applications.

Effect of surface plasmon energy matching on the sensing capability of metallic nano-hole arrays

We report on a nano-hole array structure with a single cavity beneath the perforated gold film. Structures were fabricated with a variety of cavity depths. The optical resonance of each structure as well as the surface plasmon (SP) energy matching between the top and bottom of the gold film were investigated. We also experimentally evaluated the sensitivity of the structures as surface plasmon resonance (SPR) sensors. We observed a 1.6-fold enhancement in bulk SPR sensitivity and a 3-fold improvement in figure of merit for a structure with a 350-nm cavity depth compared to a structure with a 5-nm cavity depth.We report on a nano-hole array structure with a single cavity beneath the perforated gold film. Structures were fabricated with a variety of cavity depths. The optical resonance of each structure as well as the surface plasmon (SP) energy matching between the top and bottom of the gold film were investigated. We also experimentally evaluated the sensitivity of the structures as surface plasmon resonance (SPR) sensors. We observed a 1.6-fold enhancement in bulk SPR sensitivity and a 3-fold improvement in figure of merit for a structure with a 350-nm cavity depth compared to a structure with a 5-nm cavity depth.

Four-dimensional photoacoustic imaging of moving targets

Photoacoustic imaging provides optical contrast with improved tissue penetration and spatial resolution compared to pure optical techniques. Three-dimensional photoacoustic imaging is particularly advantageous for visualizing non-planar light absorbing structures, such as blood vessels, internal organs or tumours. We have developed a fast 3-D photoacoustic imaging system for small animal research based on a sparse array of ultrasonic detectors and iterative image reconstruction. The system can acquire 3-D images with a single laser-shot at a frame rate of 10 Hz. To demonstrate the imaging capabilities we have constructed phantoms made of a scanning point source and a rotating line object and imaged them at a rate of 10 frames per second. The resulting 4-D photoacoustic images depicted well the motion of each target. Comparison of the perceived motion in the images with the known velocity of the target showed good agreement. To our knowledge, this is the first report of single-shot high frame-rate 3-D photoacoustic imaging system. With further developments, this system could bring to bear its inherent speed for applications in small animal research, such as motion tracking of tumour outline during respiration, and rapid monitoring of contrast agent kinetics.

Behavioural responses to magnetic fields by land snails are dependent on both magnetic field direction and light

A variety of sensing—transduction mechanisms have been proposed to explain the biological effects of magnetic fields. Previous studies have established the well-defined inhibitory effects which magnetic fields have on opioid-peptide-mediated antinociception or ‘analgaesia’ as an appropriate system for examining these mechanisms. Here, we show that the inhibitory effects of magnetic fields on opioid-mediated ‘analgaesia’ in the land snail, Cepaea nemoralis, are dependent on: (i) the relative direction of a weak static and 60 Hz magnetic field; and (ii) the presence of light. In the absence of light, the attenuation of opioid-induced analgaesia was markedly reduced in extent and no longer dependent on the relative direction of the magnetic fields. The directional sensitivity in the presence of light is consistent with the direct detection of magnetic fields through amplitude-frequency dependent resonance mechanisms such as described in the ‘parametric resonance model’. This mechanism has properties similar to magnetoreception models involving resonant reactions of excited triplet state macromolecules originally proposed for avian orientation and recently evoked in light-dependent magnetic compass orientation. We suggest that the biophysical sensing-transduction mechanisms for the present light-dependent, non-orientational responses to magnetic fields and light-dependent magnetic compass orientation may be closely related. This raises the possibility of a common underlying mechanism(s) for various behavioural effects of magnetic fields.