Tracking the progress of inflammation with PET/MRI in a canine model of myocardial infarction.

BACKGROUND: Following myocardial infarction, tissue undergoes pathophysiological changes involving inflammation and scar tissue formation. However, little is known about the pathophysiology and prognostic significance of any corresponding changes in remote myocardium. The aim of this study was to investigate the potential application of a combined constant infusion of 18F-FDG and Gd-DTPA to quantitate inflammation and extracellular volume (ECV) from 3 to 40 days after myocardial infarction. METHODS: Eight canine subjects were imaged at multiple time points following induction of an MI with a 60-minute concurrent constant infusion of Gd-DTPA and 18F-FDG using a hybrid PET/MRI scanner. RESULTS: There was a significant increase in ECV in remote myocardium on day 14 post-MI (P = .034) and day 21 (P = .021) compared to the baseline. ECV was significantly elevated in the infarcted myocardium compared to remote myocardium at all time points post-MI (days 3, 7, 14, 21, and 40) (P < .001) while glucose uptake was also increased within the infarct on days 3, 7, 14, and 21 but not 40. CONCLUSIONS: The significant increase in ECV in remote tissue may be due to an ongoing inflammatory process in the early weeks post-infarct.

Simultaneous measurements of myocardial glucose metabolism and extracellular volumes with hybrid PET/MRI using concurrent injections of Gd-DTPA and [18F]FDG.

BACKGROUND: The aims of this study were to investigate the application of a constant infusion (CI) to mitigate the issue of constantly changing Gd-DTPA contrast levels in a bolus injection for extracellular volume (ECV) measurements by (a) comparing a CI alone to a bolus alone and a bolus followed by CI in healthy myocardium, (b) evaluating the impact of glucose suppression using heparin on ECV. METHODS: Five healthy canine subjects were imaged to compare three different protocols for injecting Gd-DTPA and FDG: bolus alone, CI alone, bolus followed by CI. Suppression of myocardial glucose uptake was induced using a continuous infusion of 20% lipid at a rate of 0.25 mL·min-1·kg-1 as well as 2000 units of intravenous heparin injected 20 minutes prior to FDG/Gd-DTPA injection. RESULTS: There was no significant effect on ECV measurement when heparin was used for glucose suppression at equilibrium irrespective of infusion protocol). Measurements of ECV in myocardium, regardless of infusion protocol showed no significant difference at all time points (P = 0.21) prior to washout. CONCLUSIONS: The suppression of myocardial uptake of [18F]FDG with heparin did not alter the determination of myocardial ECV though a larger sample size may show differences. Further, the infusion protocol (bolus or constant infusion) had no effect on the calculated ECV.

Hybrid PET/MR imaging in myocardial inflammation post-myocardial infarction.

Hybrid PET/MR imaging is an emerging imaging modality combining positron emission tomography (PET) and magnetic resonance imaging (MRI) in the same system. Since the introduction of clinical PET/MRI in 2011, it has had some impact (e.g., imaging the components of inflammation in myocardial infarction), but its role could be much greater. Many opportunities remain unexplored and will be highlighted in this review. The inflammatory process post-myocardial infarction has many facets at a cellular level which may affect the outcome of the patient, specifically the effects on adverse left ventricular remodeling, and ultimately prognosis. The goal of inflammation imaging is to track the process non-invasively and quantitatively to determine the best therapeutic options for intervention and to monitor those therapies. While PET and MRI, acquired separately, can image aspects of inflammation, hybrid PET/MRI has the potential to advance imaging of myocardial inflammation. This review contains a description of hybrid PET/MRI, its application to inflammation imaging in myocardial infarction and the challenges, constraints, and opportunities in designing data collection protocols. Finally, this review explores opportunities in PET/MRI: improved registration, partial volume correction, machine learning, new approaches in the development of PET and MRI pulse sequences, and the use of novel injection strategies.

Same day comparison of PET/CT and PET/MR in patients with cardiac sarcoidosis.

BACKGROUND: Inflammatory cardiac disorders, in particular, sarcoidosis, play an important role in left ventricular dysfunction, conduction abnormalities, and arrhythmias. In this study, we compared the imaging characteristics and diagnostic information obtained when patients were imaged sequentially with PET/CT and then with hybrid PET/MRI on the same day following a single 18F-FDG injection. METHODS: Ten patients with known or suspected sarcoidosis underwent imaging in sequence of (a) 99mTc-MIBI, (b) 18F-FDG with PET/CT, and (c) 18F-FDG with 3T PET/MRI. Images were compared quantitatively by determination of SUVmax and SUV on a voxel by voxel basis, and qualitatively by two experienced observers. RESULTS: When both platforms were compared quantitatively, similar data for the evaluation of enhanced 18F-FDG uptake were obtained. Qualitatively, there were (1) several instances of normal perfusion with delayed enhancement and/or focal 18F-FDG uptake, (2) comparable enhanced 18F-FDG uptake on PET/CT vs. PET/MRI, and (3) diversity in disease patterns with delayed enhancement only, increased 18F-FDG uptake only, or both. CONCLUSION: In this limited patient study, PET/CT and PET/MR provided similar diagnostic data for 18F-FDG uptake, and the concurrent acquisition of MR images provided further insight into the disease process.

Neurophysiological and behavioral effects of a 60 Hz, 1,800 µT magnetic field in humans.

The effects of time-varying magnetic fields (MF) on humans have been actively investigated for the past three decades. One important unanswered question is the potential for MF exposure to have acute effects on human biology. Different strategies have been used to tackle this question using various physiological, neurophysiological and behavioral indicators. For example, researchers investigating electroencephalography (EEG) have reported that extremely low frequency (ELF, <300 Hz) MF can increase resting occipital alpha rhythm (8-12 Hz). Interestingly, other studies have demonstrated that human motricity can be modulated by ELF MF: a reduction of anteroposterior standing balance or a decrease of physiological tremor intensity have been reported as consequences of exposure. However, the main limitation in this domain lies in the lack of results replication, possibly originating from the large variety of experimental approaches employed. Therefore, the present study aimed to investigate the effects of a 60 Hz, 1,800 µT MF exposure on neurophysiological (EEG) and neuromotor (standing balance, voluntary motor function, and physiological tremor) aspects in humans using a single experimental procedure. Though results from this study suggest a reduction of human standing balance with MF exposure, as well as an increase of physiological tremor amplitude within the frequency range associated with central nervous system contribution, no exposure effect appeared on other investigated parameters (e.g., EEG or voluntary motor control). These results suggest that 1 h of 60 Hz, 1,800 µT MF exposure may modulate human involuntary motor control without being detected in the cortical electrical activity.

A comparison of MR-based attenuation correction in PET versus SPECT.

Attenuation correction (AC) is a critical step in the reconstruction of quantitatively accurate positron emission tomography (PET) and single photon emission computed tomography (SPECT) images. Several groups have proposed magnetic resonance (MR)-based AC algorithms for application in hybrid PET/MR systems. However, none of these approaches have been tested on SPECT data. Since SPECT/MR systems are under active development, it is important to ascertain whether MR-based AC algorithms validated for PET can be applied to SPECT. To investigate this issue, two imaging experiments were performed: one with an anthropomorphic chest phantom and one with two groups of canines. Both groups of canines were imaged from neck to abdomen, one with PET/CT and MR (n = 4) and the other with SPECT/CT and MR (n = 4), while the phantom was imaged with all modalities. The quality of the nuclear medicine reconstructions using MR-based attenuation maps was compared between PET and SPECT on global and local scales. In addition, the sensitivity of these reconstructions to variations in the attenuation map was ascertained. On both scales, it was found that the SPECT reconstructions were of higher fidelity than the PET reconstructions. Further, they were less sensitive to changes to the MR-based attenuation map. Thus, MR-based AC algorithms that have been designed for PET/MR can be expected to demonstrate improved performance when used for SPECT/MR.

Effects of acute hypoxia on postural and kinetic tremor.

Human physiological tremor is a complex phenomenon that is modulated by numerous mechanical, neurophysiological, and environmental conditions. Researchers investigating tremor have suggested that acute hypoxia increases tremor amplitude. Based on the results of prior studies, we hypothesized that human participants exposed to a simulated altitude of 4,500 m would display an increased tremor amplitude within the 6-12 Hz frequency range. Postural and kinetic tremors were recorded with a laser system in 23 healthy male participants before, during, and after 1 h of altitude-induced hypoxia. A large panel of tremor characteristics was used to investigate the effect of hypoxia. Acute hypoxia increased tremor frequency content between 6 and 12 Hz during both postural and kinetic tremor tasks (P < 0.05, F = 6.142, Eta(2) = 0.24 and P < 0.05, F = 3.767 Eta(2) = 0.14, respectively). Although the physiological mechanisms underlying the observed changes in tremor are not completely elucidated yet, this study confirms that acute hypoxia increases tremor frequency in the 6-12 Hz range. Furthermore, this study indicates that changes in physiological tremor can be detected at lower hypoxemic levels than previously reported (blood saturation in oxygen = 80.9%). The effects of hypoxia mainly result from a cascade of events starting with the activation of the hypothalamic-pituitary-adrenal axis causing in turn an increase in catecholamine release, leading to an augmentation of tremor amplitude in the 6- to 12-Hz interval and heart rate increase.

Deep brain stimulation, vagal nerve stimulation and transcranial stimulation: An overview of stimulation parameters and neurotransmitter release.

Neurological disorders are among the most challenging medical problems faced by science today. To treat these disorders more effectively, new technologies are being developed by reviving old ideas such as brain stimulation. This review aims to compile stimulation techniques that are currently in use to explore or treat neurological disorders. Transcranial magnetic stimulation is a non-invasive method of modulating neuronal activity with induced electric currents. Other more invasive methods, such as deep brain stimulation and vagal nerve stimulation, use implanted probes to introduce brain activity alterations. Scientific and clinical applications have largely preceded the development of extensive animal models, presenting a challenge for researchers. This has left researchers with information on alleviating symptoms in humans but without solid research as to the mechanisms and neurobiological effects of the devices. This review combines stimulation parameters developed in animal models and stimulation techniques used in human treatment; thus, resulting in a greater understanding of the mechanisms and neurobiological effects of neuromodulation devices.

Changes in human EEG alpha activity following exposure to two different pulsed magnetic field sequences.

The present study investigates the effects of a weak (+/-200 microT(pk)), pulsed, extremely low frequency magnetic field (ELF MF) upon the human electroencephalogram (EEG). We have previously determined that exposure to pulsed ELF MFs can affect the EEG, notably the alpha frequency (8-13 Hz) over the occipital-parietal region of the scalp. In the present study, subjects (n = 32) were exposed to two different pulsed MF sequences (1 and 2, used previously) that differed in presentation rate, in order to examine the effects upon the alpha frequency of the human EEG. Results suggest that compared to sham exposure, alpha activity was lowered over the occipital-parietal regions of the brain during exposure to Sequence 1, while alpha activity over the same regions was higher after Sequence 2 exposure. These effects occurred after approximately 5 min of pulsed MF exposure. The results also suggest that a previous exposure to the pulsed MF sequence determined subjects' responses in the present experiment. This study supports our previous observation of EEG changes after 5 min pulsed ELF MF exposure. The results of this study are also consistent with existing EEG experiments of ELF MF and mobile phone effects upon the brain.

Quantification of pain-induced changes in cerebral blood flow by perfusion MRI.

The purpose of this study was to assess if the functional activation caused by painful stimuli could be detected with arterial spin labeling (ASL), which is a non-invasive magnetic resonance imaging (MRI) technique for measuring cerebral blood flow (CBF). Because ASL directly measures blood flow, it is well suited to pain conditions that are difficult to assess with current functional MRI, such as chronic pain. However, the use of ASL in neuroimaging has been hampered by its low sensitivity. Recent improvements in MRI technology, namely increased magnetic field strengths and phased array receiver coils, should enable ASL to measure the small changes in CBF associated with pain. In this study, healthy volunteers underwent two ASL imaging sessions, during which a painful thermal stimulus was applied to the left hand. The results demonstrated that the ASL technique measured changes in regional CBF in brain regions that have been previously identified with pain perception. These included bilateral CBF changes in the insula, secondary somatosensory, and cingulate cortices, as well as the supplementary motor area (SMA). Also observed were contralateral primary somatosensory and ipsilateral thalamic CBF changes. The average change in CBF for all regions of interest was 3.68ml/100g/min, ranging from 2.97ml/100g/min in ipsilateral thalamus to 4.91ml/100g/min in contralateral insula. The average resting global CBF was 54+/-9.7ml/100g/min, and there was no change in global CBF due to the noxious thermal stimulus.

Exposure to ELF magnetic and ELF-modulated radiofrequency fields: the time course of physiological and cognitive effects observed in recent studies (2001-2005).

In 2002, we published a review of the cognitive and physiological effects of extremely low frequency magnetic fields (ELF MFs) and ELF-modulated radiofrequency fields associated with mobile phones. Since the original preparation of that review, a significant number of studies have been published using techniques such as electroencephalography, event-related potentials and positron emission tomography to investigate electromagnetic field effects upon human physiology and various measures of performance (cognitive, perceptual, behavioral). We review these recent studies, and when effects were observed, we reference the time course of observed effects (immediate or delayed). In our concluding remarks, we discuss a number of variables that are not often considered in human bioelectromagnetics studies, such as personality, individual differences and the specific laterality of ELF MF and mobile phone exposure over the brain. We also consider the sensitivity of various physiological assays and performance measures in the study of biological effects of electromagnetic fields.

Modeling (1H) exchange: an estimate of the error introduced in MRI by assuming the fast exchange limit in bolus tracking.

A simulation is presented which calculates the MRI signal expected from a model tissue for a given pulse sequence after a bolus injection of a contrast agent. The calculation assumes two physiologic compartments only, the intravascular and extravascular spaces. The determination of the concentration of contrast in each compartment as a function of time and position has been outlined in a previous publication (Moran and Prato, Magn Reson Med 2001;45:42-45). These contrast agent concentrations are used here to determine the NMR relaxation times as a function of time and position within the tissue. Knowledge of this simulated tissue 'map' of relaxation times as a function of time provides the information required to determine whether the proton exchange rate is fast or slow on the NMR timescale. Since with a bolus injection the concentration of contrast and hence the relaxation time may vary with position along the capillary, some segments of the capillary are allowed to be in fast exchange with the extravascular space, while others may be in slow exchange. Using this information, and parameters specific to a given tissue, the MRI signal for a given pulse sequence is constructed which correctly accounts for differences in proton exchange across the length of the capillary. It is shown that extravascular contrast agents show less signal dependence on water exchange, and thus may be more appropriate for quantitative imaging when using fast exchange assumptions. It is also shown that nondistributed compartment models can incorrectly estimate the water exchange that is occurring at the capillary level if exchange-minimizing pulse sequences are not used.

An investigation of the toxicity of gadolinium based MRI contrast agents using neutron activation analysis.

The toxicity of gadolinium (Gd) based MRI contrast agents, is based upon the amount of Gd that dissociates from its chelate and deposits in tissues. In this study, the toxicities of two contrast agents were tested using different injection strategies in two animal models. Following a bolus injection of 0.2 mmol/kg of Gd-DTPA in a pilot study with a single canine, Gd levels were as high as 2.05 +/- 0.17 ppm and 0.47 +/- 0.11 ppm 2 weeks post injection in the kidney and liver tissues, respectively. To evaluate the role that the injection strategy plays in toxicity, 0.8 mmol/kg of Gd-(HP-DO3A) was injected into rats, in a second study, via bolus and constant infusion techniques. Gd was only detected in the kidney in the bolus injected rats but in the lung as well in the constant infusion injected rats. Concentrations detected in the kidney for both strategies, were comparable within error: 1.37 +/- 0.46 ppm for the bolus and 1.24 +/- 0.39 ppm for the bolus/constant infusion strategy and 0.16 +/- 0.14 ppm in the lung for the constant infusion technique. The contrast infusion technique does not appear to present an increased risk of toxicity over the bolus technique except perhaps to a small degree in the lung.

Myocardial viability imaging using Gd-DTPA: physiological modeling of infarcted myocardium, and impact on injection strategy and imaging time.

Results of simulations are shown which illustrate how the concentration-time curves of an extravascular extracellular (EVEC) contrast agent, such as Gd-DTPA, vary in myocardial tissue. The simulations show that the variable permeability of dead myocytes within a recent myocardial infarction will significantly alter delayed enhancement patterns following a bolus injection, invariably reducing the sensitivity of this technique for the detection of permanently damaged tissue. It is further predicted that if the bolus injection is followed by a suitably selected constant infusion, the infarct size and infarct volume of distribution may be more accurately determined, even though the degree of enhancement of an infarcted region (with normal flow) above normal tissue is slightly higher for the bolus technique within the first 30 min following the injection. The degree of enhancement of an infarcted region (with normal flow) above normal tissue was comparable between the two techniques at the point in the constant infusion at which the volume of contrast injected was the same as in the bolus case, i.e., at approximately 30 min after the bolus injection. The constant infusion approach became superior thereafter as overall tissue concentrations became greater in both normal and infarcted tissue, and these concentrations remained more stable with the constant infusion approach. Preliminary experimental results in a canine model of infarction/reperfusion illustrated a delayed wash-in of contrast agent in infarcted tissue, which may be explained by a physiological model in which dead myocytes in infarcted myocardium have non-infinite permeability.

Human electrophysiological and cognitive effects of exposure to ELF magnetic and ELF modulated RF and microwave fields: a review of recent studies.

The investigation of weak (<500 microT), extremely low frequency (ELF, 0-300 Hz) magnetic field (MF) exposure upon human cognition and electrophysiology has yielded incomplete and contradictory evidence that MFs interact with human biology. This may be due to the small number of studies undertaken examining ELF MF effects upon the human electroencephalogram (EEG), and the associated analysis of evoked related potentials (ERPs). Relatively few studies have examined how MF exposure may affect cognitive and perceptual processing in human subjects. The introduction of this review considers some of the recent studies of ELF MF exposure upon the EEG, ERPs and cognitive and perceptual tasks. We also consider some of the confounding factors within current human MF studies and suggest some new strategies for further experimentation.

Shielding, but not zeroing of the ambient magnetic field reduces stress-induced analgesia in mice.

Magnetic field exposure was consistently found to affect pain inhibition (i.e. analgesia). Recently, we showed that an extreme reduction of the ambient magnetic and electric environment, by mu-metal shielding, also affected stress-induced analgesia (SIA) in C57 mice. Using CD1 mice, we report here the same findings from replication studies performed independently in Pisa, Italy and London, ON, Canada. Also, neither selective vector nulling of the static component of the ambient magnetic field with Helmholtz coils, nor copper shielding of only the ambient electric field, affected SIA in mice. We further show that a pre-stress exposure to the mu-metal box is necessary for the anti-analgesic effects to occur. The differential effects of the two near-zero magnetic conditions may depend on the elimination (obtained only by mu-metal shielding) of the extremely weak time-varying component of the magnetic environment. This would provide the first direct and repeatable evidence for a behavioural and physiological effect of very weak time-varying magnetic fields, suggesting the existence of a very sensitive magnetic discrimination in the endogenous mechanisms that underlie SIA. This has important implications for other reported effects of exposures to very weak magnetic fields and for the theoretical work that considers the mechanisms underlying the biological detection of weak magnetic fields.

Magnetic field exposure and behavioral monitoring system.

To maximize the availability and usefulness of a small magnetic field exposure laboratory, we designed a magnetic field exposure system that has been used to test human subjects, caged or confined animals, and cell cultures. The magnetic field exposure system consists of three orthogonal pairs of coils 2 m square x 1 m separation, 1.751 m x 0.875 m separation, and 1.5 m x 0.75 m separation. Each coil consisted of ten turns of insulated 8 gauge stranded copper conductor. Each of the pairs were driven by a constant-current amplifier via digital to analog (D/A) converter. A 9 pole zero-gain active Bessel low-pass filter (1 kHz corner frequency) before the amplifier input attenuated the expected high frequencies generated by the D/A conversion. The magnetic field was monitored with a 3D fluxgate magnetometer (0-3 kHz, +/- 1 mT) through an analog to digital converter. Behavioral monitoring utilized two monochrome video cameras (viewing the coil center vertically and horizontally), both of which could be video recorded and real-time digitally Moving Picture Experts Group (MPEG) encoded to CD-ROM. Human postural sway (standing balance) was monitored with a 3D forceplate mounted on the floor, connected to an analog to digital converter. Lighting was provided by 12 offset overhead dimmable fluorescent track lights and monitored using a digitally connected spectroradiometer. The dc resistance, inductance of each coil pair connected in series were 1.5 m coil (0.27 Omega, 1.2 mH), 1.75 m coil (0.32 Omega, 1.4 mH), and 2 m coil (0.38 Omega, 1.6 mH). The frequency response of the 1.5 m coil set was 500 Hz at +/- 463 microT, 1 kHz at +/- 232 microT, 150 micros rise time from -200 microT(pk) to + 200 microT(pk) (square wave) and is limited by the maximum voltage ( +/- 146 V) of the amplifier (Bessel filter bypassed).

Gd-DTPA bolus tracking in the myocardium using T1 fast acquisition relaxation mapping (T1 FARM).

MRI methods currently used for bolus tracking in the myocardium, such as saturation recovery turbo-fast low-angle shot (FLASH) (srTFL), are limited by signal intensity (SI) saturation at high contrast agent (CA) concentrations. By using T1 fast acquisition relaxation mapping (T1 FARM), a Gd-DTPA bolus (0.075 vs. 0.025 mmol/kg) may be injected without causing saturation. This study tested the feasibility of in vivo T1 FARM bolus tracking under rest/stress conditions in seven beagles with multiple permanently occluded branches of the left anterior descending (LAD) coronary artery. Although it underestimated the myocardial perfusion reserve (MPR) measured ex vivo using radioactive microspheres (mean +/- SEM; 3.60 +/- 0.26), the MPR determined upon application of the modified Kety model (1.86 +/- 0.10) enabled distinction between normal and infarcted tissue. The partition coefficient (lambda) estimated at rest and stress using the modified Kety model underestimated ex vivo radioactive measurements in infarcted tissue (0.25 +/- 0.01 vs. 0.26 +/- 0.01 vs. 0.79 +/- 0.08 ml/g, P < 0.0001) yet was accurate in normal tissue (0.28 +/- 0.01 vs. 0.30 +/- 0.01 vs. 0.33 +/- 0.01 ml/g, P = NS). Thus, although unsuitable for myocardial viability assessment, T1 FARM bolus tracking shows potential for assessment of myocardial perfusion.

A comparison of rheumatoid arthritis and fibromyalgia patients and healthy controls exposed to a pulsed (200 microT) magnetic field: effects on normal standing balance.

Specific weak time varying pulsed magnetic fields (MF) have been shown to alter animal and human behaviors, including pain perception and postural sway. Here we demonstrate an objective assessment of exposure to pulsed MF's on Rheumatoid Arthritis (RA) and Fibromyalgia (FM) patients and healthy controls using standing balance. 15 RA and 15 FM patients were recruited from a university hospital outpatient Rheumatology Clinic and 15 healthy controls from university students and personnel. Each subject stood on the center of a 3-D forceplate to record postural sway within three square orthogonal coil pairs (2 m, 1.75 m, 1.5 m) which generated a spatially uniform MF centered at head level. Four 2-min exposure conditions (eyes open/eyes closed, sham/MF) were applied in a random order. With eyes open and during sham exposure, FM patients and controls appeared to have similar standing balance, with RA patients worse. With eyes closed, postural sway worsened for all three groups, but more for RA and FM patients than controls. The Romberg Quotient (eyes closed/eyes open) was highest among FM patients. Mixed design analysis of variance on the center of pressure (COP) movements showed a significant interaction of eyes open/closed and sham/MF conditions [F=8.78(1,42), P<0.006]. Romberg Quotients of COP movements improved significantly with MF exposure [F=9.5(1,42), P<0.005] and COP path length showed an interaction approaching significance with clinical diagnosis [F=3.2(1,28), P<0.09]. Therefore RA and FM patients, and healthy controls, have significantly different postural sway in response to a specific pulsed MF.

Human standing balance is affected by exposure to pulsed ELF magnetic fields: light intensity-dependent effects.

There is evidence in animals that behavioral and physiological responses to static and extremely low frequency magnetic fields (ELFMF) is affected by the presence of light during magnetic field exposures. Here we report that the effect of a specific pulsed ELFMF (PEMF) on human standing balance is modulated by light intensity during exposure. Under a low light condition (0.12 W/m2), nine healthy human volunteers stood on a 3D forceplate, throughout four 2 min exposures (eyes open/eyes close, sham/PEMF of 200 +/- 1 microTpk, order randomized). There was a significant increase in standing movement during PEMF exposure during eyes closed. In a second experiment on 26 normal subjects exposed to the identical protocol, but at greater light intensities (0.51 W/m2), a significant but opposite effect was observed.