Biomedical subjects

Joseph J H Ackerman

Publications and source records attributed to Joseph J H Ackerman.

17 recordsLinked to original sources

PubMed2006

Modeling dendrite density from magnetic resonance diffusion measurements.

Diffusion-weighted imaging (DWI) provides a noninvasive tool to probe tissue microstructure. We propose a simplified model of neural cytoarchitecture intended to capture the essential features important for water diffusion as measured by NMR. Two components contribute to the NMR signal in this model: (i) the dendrites and axons, which are modeled as long cylinders with two diffusion coefficients, parallel (D(L)) and perpendicular (D(T)) to the cylindrical axis, and (ii) an isotropic monoexponential diffusion component describing water diffusion within and across all other structures, i.e., in extracellular space and glia cells. The model parameters are estimated from 153 diffusion-weighted images acquired from a formalin-fixed baboon brain. A close correspondence between the data and the signal model is found, with the model parameters consistent with literature values. The model provides an estimate of dendrite density from noninvasive MR diffusion measurements, a parameter likely to be of value for understanding normal as well as abnormal brain development and function.

Computer Simulation↗

PubMed2006

How the body controls brain temperature: the temperature shielding effect of cerebral blood flow.

Normal brain functioning largely depends on maintaining brain temperature. However, the mechanisms protecting brain against a cooler environment are poorly understood. Reported herein is the first detailed measurement of the brain-temperature profile. It is found to be exponential, defined by a characteristic temperature shielding length, with cooler peripheral areas and a warmer brain core approaching body temperature. Direct cerebral blood flow (CBF) measurements with microspheres show that the characteristic temperature shielding length is inversely proportional to the square root of CBF in excellent agreement with a theoretical model. This "temperature shielding effect" quantifies the means by which CBF prevents "extracranial cold" from penetrating deep brain structures. The effect is crucial for research and clinical applications; the relationship between brain, body, and extracranial temperatures can now be quantitatively predicted.

Adaptation, Physiological↗

PubMed2005

Sodium ion apparent diffusion coefficient in living rat brain.

The apparent diffusion coefficient (ADC) of Na(+) was determined in live rat brain. The brain extracellular-to-intracellular Na(+) content ratio is approximately 8:2, which is the inverse of that for water in these spaces. Consequently, the ADC of Na(+) is primarily affected by motion in the extracellular space, and Na(+) can be viewed as a reporter molecule for motion in that space. Likewise, water ADC is dominated by intracellular motion. The brain Na(+) ADC was 1.15 +/- 0.09 microm(2)/ms, which is 61% of the aqueous Na(+) free diffusion coefficient (D(free)) at 37 degrees C (1.9 microm(2)/ms), while the ADC for brain water is 28% of the water D(free) at 37 degrees C (3 microm(2)/ms). This suggests that the ADC of molecular species within the extracellular space is roughly twofold that within the intracellular space. In postmortem brain, both Na(+) and water decrease to 17% of the respective D(free) values. These results are consistent with Na(+) and water ADC values sharing the same biophysical determinants in postmortem brain. The observed difference between Na(+) and water ADC/D(free) ratios in living brain tissue may be attributable to the extracellular environment hindering molecular displacements twofold less than the intracellular environment.

Animals↗

PubMed2005

Biomedical applications of 133Cs NMR.

133Cs NMR is a valuable tool for non-invasively probing biological systems. As a congener of potassium, it accumulates in the intracellular space, primarily through the action of the Na+-K+ pump (ATPase). In addition, it is possible to resolve the MR signal of 133Cs in different tissue compartments on the basis of chemical shift or MR relaxation properties. This compartmental resolution applies not only to the intra- and extracellular spaces, but to subcellular compartments as well. In this review, we discuss the studies defining the ion transport, chemical shift and relaxation characteristics of 133Cs in living systems. We also review the application of 133Cs NMR to evaluation of ion transport across membranes and the kinetic/chemical environment of the intracellular space in systems ranging from red blood cells to rat brain.

Animals↗

PubMed2005

Image artifacts in very low magnetic field MRI: the role of concomitant gradients.

While MRI at very low magnetic fields has certain potential advantages, it may also face problems that are not typical for MRI at conventional and high field (0.1-10T). Major differences arise due to the presence of concomitant components of inhomogeneous magnetic field (gradients) that are transverse to the major B(z) field, B(0). These concomitant transverse field components are inevitably generated by the same gradient coils that generate desired B(z) imaging gradients as routinely used in MRI for spatial encoding. In the hypothetical case (linear spatial variation of B(z) field amplitude due to the imaging gradients, no concomitant transverse field components, no B(0) and B(1) field inhomogeneities, etc.), Fourier transform MRI preserves the shape of the real object being examined. It is demonstrated herein that unavoidable concomitant transverse field gradients, G, result in an image deformation of the object's actual shape by bending straight lines and planes with a characteristic curvature radius R(c)=B(0)/G. For imaging gradients on the order of 10 mT/m and B(0) of 1T, the radius R(c) is about 100 m and image distortions are generally negligible. However, for B(0) of 1 mT, R(c) is 10 cm, which is less than a typical FOV in human studies. This manuscript derives expressions describing geometrical relationships between the imaged object and the obtained MR data. In addition to geometrical distortions, image intensity will be modulated in a complex, spatially dependent manner. Hence, if unaccounted for, corresponding image distortions-geometry and intensity-will create substantial difficulties in very low field image interpretation.

Artifacts↗

PubMed2005

Defining the pHi-hyperthermia sensitivity relationship for the RIF-1 tumor in vivo: a 31P MR spectroscopy study.

This study quantifies the enhancement of the therapeutic efficacy of hyperthermia resulting from an acutely acidified and accurately monitored intracellular pH (pHi) in a mouse tumor model in vivo. Metabolic manipulation of the physiology of RIF-1 tumor (subcutaneous, on the hind flanks of female C3H/HeJ mice) achieved by i.p. bolus injection of glucose (glycolytic tumor acidification) or 3-O-methylglucose (non-glycolytic tumor acidification) was monitored by 31P magnetic resonance (31P MR) prior to, during and up to 1 h after localized hyperthermia. The pre-hyperthermia 31P MR-observable metabolic parameter that correlates most strongly with thermal sensitivity is pHi. Thermal sensitivity increases linearly with decreasing pHi regardless of the mechanism (glycolytic or non-glycolytic) of metabolic manipulation. The quantitative relationship is described by log10(SF)/EQ43=0.0079 pHi,preHT -0.0606 (R=0.63, P<0.0001), where EQ43 is the thermal heat dose delivered to the tumor (in units of equivalent minutes at 42.5 degrees C), pHi,preHT is the intracellular pH immediately prior to hyperthermia, and SF is the surviving fraction. The therapeutic enhancement is not as dramatic as expected based upon previously reported in vitro studies but is generally consistent with other in vivo studies. The method still represents a viable strategy for enhancing the therapeutic efficacy of hyperthermia, especially when used in combination with other therapeutic modalities.

3-O-Methylglucose↗

PubMed2004

Effects of physiologic challenge on the ADC of intracellular water in the Xenopus oocyte.

The biophysical determinants of the intracellular water apparent diffusion coefficient (ADC) in mammalian tissues are poorly understood. Model systems that are more amenable to physical measurements may provide insights into the behavior of more complex systems. Toward that end, we used MRI to evaluate the effects of altered microtubule concentration, nuclear breakdown, and ATP depletion on intracellular water ADC in the Xenopus oocyte. Water ADC did not change in response to polymerization of microtubules with taxol or depolymerization with nocodazole. Water ADC did not change following the breakdown of the nucleus in healthy cells. Short-term depletion of ATP (approximately 20% of normal levels following 4 hr of exposure to sodium azide and 2-deoxy-D-glucose) was not associated with a change in intracellular ADC. Long-term depletion of ATP (approximately 20% of normal levels following 2 days of exposure to antimycin A) was associated with a significant decrease in intracellular water ADC. These findings suggest that intracellular water diffusion in oocytes is not dependent on the state of microtubule polymerization or short-term ATP depletion, although long-term ATP depletion is associated with changes that lead to a decrease in intracellular water ADC.

Adenosine Triphosphate↗

PubMed2004

On the nature of the NAA diffusion attenuated MR signal in the central nervous system.

In the brain, on a macroscopic scale, diffusion of the intraneuronal constituent N-acetyl-L-aspartate (NAA) appears to be isotropic. In contrast, on a microscopic scale, NAA diffusion is likely highly anisotropic, with displacements perpendicular to neuronal fibers being markedly hindered, and parallel displacements less so. In this report we first substantiate that local anisotropy influences NAA diffusion in vivo by observing differing diffusivities parallel and perpendicular to human corpus callosum axonal fibers. We then extend our measurements to large voxels within rat brains. As expected, the macroscopic apparent diffusion coefficient (ADC) of NAA is practically isotropic due to averaging of the numerous and diverse fiber orientations. We demonstrate that the substantially non-monoexponential diffusion-mediated MR signal decay vs. b value can be quantitatively explained by a theoretical model of NAA confined to an ensemble of differently oriented neuronal fibers. On the microscopic scale, NAA diffusion is found to be strongly anisotropic, with displacements occurring almost exclusively parallel to the local fiber axis. This parallel diffusivity, ADCparallel, is 0.36 +/- 0.01 microm2/ms, and ADCperpendicular is essentially zero. From ADCparallel the apparent viscosity of the neuron cytoplasm is estimated to be twice as large as that of a temperature-matched dilute aqueous solution.

Animals↗

PubMed2003

Albumin-binding MR blood pool agents as MRI contrast agents in an intracranial mouse glioma model.

Intravenous MRI contrast agents are commonly used to improve the detection of intracranial tumors and other central nervous system (CNS) lesions for diagnosis and treatment planning. Two small-molecule, albumin-binding blood pool contrast agents (MP-2269 and MS-325) of potential clinical significance were evaluated at 1.5 Tesla in a mouse glioma model and compared with an extracellular contrast agent (OptiMARK). Tumor image contrast was significantly enhanced and long-lived following administration of 30 micromole/kg of the blood pool agents: specifically, contrast enhancement peaked slowly at 25-30 min following administration, remained constant for >3 hr, and returned to baseline within 20 hr. Comparable but "transient" enhancement was achieved using 100 micromole/kg OptiMARK: specifically, contrast enhancement peaked rapidly at 2-5 min following administration and then declined over 40 min. The blood pool contrast agents demonstrated an approximately threefold increased dose-effectiveness and a lengthened window of tumor contrast enhancement in comparison to commonly available extracellular contrast agents. This demonstrates the potential of alternative contrast-enhanced (CE) MRI examination protocols for tumor detection.

Albumins↗

PubMed2003

Equilibrium water exchange between the intra- and extracellular spaces of mammalian brain.

This report describes the measurement of water preexchange lifetimes and intra/extracellular content in intact, functioning mammalian brain. Intra- and extracellular water magnetic resonance (MR) signals from rat brain in vivo were quantitatively resolved in the longitudinal relaxation domain following administration of an MR relaxation agent into the extracellular space. The estimated intracellular water content fraction was 81% +/- 8%, and the intra- to extracellular exchange rate constant was 1.81 +/- 0.89 s(-1) (mean +/- SD, N = 9), corresponding to an intracellular water preexchange lifetime of approximately 550 ms. These results provide a temporal framework for anticipating the water exchange regime (fast, intermediate, or slow) underlying a variety of compartment-sensitive measurements. The method also supplies a means by which to evaluate membrane water permeability and intra/extracellular water content serially in intact tissue. The data are obtained in an imaging mode that permits detection of regional variations in these parameters.

Animals↗

PubMed2003

Statistical model for diffusion attenuated MR signal.

A general statistical model that can describe a rather large number of experimental results related to the structure of the diffusion-attenuated MR signal in biological systems is introduced. The theoretical framework relies on a phenomenological model that introduces a distribution function for tissue apparent diffusion coefficients (ADC). It is shown that at least two parameters--the position of distribution maxima (ADC) and the distribution width (sigma)--are needed to describe the MR signal in most regions of a human brain. A substantial distribution width, on the order of 36% of the ADC, was found for practically all brain regions examined. This method of modeling the MR diffusion measurement allows determination of an intrinsic tissue-specific ADC for a given diffusion time independent of the strength of diffusion sensitizing gradients. The model accounts for the previously found biexponential behavior of the diffusion-attenuated MR signal in CNS.

Brain↗

PubMed2003

Magnetic resonance measurement of tetramethylammonium diffusion in rat brain: Comparison of magnetic resonance and ionophoresis in vivo diffusion measurements.

Magnetic resonance (MR) and ionophoresis are two experimental methods that provide measurements of molecular diffusion in living tissue. Typical experimental settings yield MR studies that are sensitive to mean molecular displacements of approximately 5 microm, and ionophoresis experiments to displacements of > or =100 microm. An assessment of the correspondence between the methods is hampered by the fact that no common probe molecule has been used. One of the most frequently utilized probe molecules in ionophoresis measurements is the tetramethylammonium (TMA) ion. In the current work the diffusion properties of TMA were studied in rat brain in vivo with localized (1)H MR spectroscopy (MRS). Standard treatment of the MR data yielded a 3.6-fold lower apparent diffusion coefficient (ADC) compared to ionophoresis. To explore the source of this discrepancy, a separate data processing scheme was applied to the MR data to monitor individual elapsed displacement-distance subpopulations of TMA molecules. This analysis revealed a dependence of the ADC estimation on a given subpopulation's elapsed displacement distance. The MR-derived ADC approached the ionophoresis-derived value as the elapsed displacement distance increased to 15 microm. These observations demonstrate that MR and ionophoresis studies provide complementary information, and that ADC estimates obtained from the two techniques are sensitive to different biophysical determinants.

Animals↗

PubMed2002

Improved magnetic resonance imaging detection of prostate cancer in a transgenic mouse model.

Transgenic mouse models of prostate cancer provide an opportunity to conduct genetic tests of the molecular mechanisms underlying initiation and progression of tumorigenesis. They also allow assessment of the effects of various pharmacological interventions. However, one limitation that has impeded full exploitation of these models is the lack of in vivo imaging procedures of sufficient sensitivity and resolution to detect and follow tumors at early stages of growth. We have addressed this problem through the use of diffusion-weighted magnetic resonance imaging (DWI). A transgenic mouse model (CR2-TAg) of prostate cancer was used to show that DWI can detect tumors <1 mm in diameter. Markedly enhanced DWI contrast results from a 2-fold difference in apparent diffusion coefficient between benign and malignant prostatic tissue (P < 0.00001). Clinical application of DWI may offer advantages over current T2-weighted magnetic resonance imaging methods.

Animals↗

PubMed2002

Investigation of mechanisms underlying transient T2 normalization in longitudinal studies of ischemic stroke.

PURPOSE: To determine if the phenomenon of transient normalization of T2 relaxation in the subacute stage of ischemic stroke is associated with either magnetic susceptibility effects secondary to hemorrhage or changes in tissue water content. MATERIALS AND METHODS: We utilized a rat model of transient, focal, cerebral ischemia. The possibility of hemorrhage was evaluated with T2*-weighted (T2*W) imaging and histology. Changes in water content were assessed by brain wet-to-dry weight. RESULTS: Susceptibility effects were not evident in T2*W images, and neither red blood cells nor unchelated Fe(III) was found in hematoxylin and eosin (H-E)- or Prussian Blue-stained sections, respectively. However, between the peak of T2 contrast and the point of transient T2 normalization, water content consistently decreased by an average of 3%. CONCLUSION: Transient T2 normalization is associated with normalization of water content and can occur without evidence of hemorrhage.

Analysis of Variance↗

PubMed2002

Apparent diffusion of water, ions, and small molecules in the Xenopus oocyte is consistent with Brownian displacement.

The incoherent displacement of water in living tissues is of considerable interest because of the widespread use of diffusion-weighted MRI, for which image contrast is based on the water apparent diffusion coefficient (ADC). It has been hypothesized that the decrease in water ADC associated with brain injury is primarily due to a reduction in the ADC of water in the intracellular space. Xenopus oocytes permit direct measurement of ADC values for intracellular molecules, thereby providing insight into the nature of intracellular motion. In this study, the measured ADC values of small molecules and ions are shown to be primarily size-dependent, indicating that intracellular water motion in the oocyte is mainly Brownian displacement with little or no role for cytoplasmic streaming. Further, intracellular water ADC values show no dependence on diffusion time over a broad range (3.4-100 ms), suggesting that barriers to displacement are finely spaced (< or = 2-3 microm). The water diffusion shows some small anisotropy, suggesting that the cell has structure, giving water displacement a directional preference. The calculated intracellular apparent viscosity, which reflects the combined effects of barriers to motion, intermolecular binding, and fluid phase viscosity was 2.07 +/- 0.09 cP.

Animals↗

PubMed2002

Evidence that both fast and slow water ADC components arise from intracellular space.

Evaluation of water diffusion in the brain has revealed both fast- and slow-diffusing water populations. It has been suggested that these populations represent extra- and intracellular water, respectively. We have identified and characterized both populations in the intracellular space of the Xenopus oocyte. We have also determined their T(1) and T(2) relaxation properties. The fast and slow intracellular populations have diffusion coefficients of 1.06 +/- 0.05 microm(2)/ms and 0.16 +/- 0.02 microm(2)/ms, respectively, with the fast fraction representing 89% +/- 1% of the total water signal. These values are quite similar to those for total water in brain and are observed in the absence of signal from the perfusate (extracellular) water population. Volumetric swelling (16% +/- 4%) of the oocyte in hypoosmotic media increased the diffusion coefficients of both intracellular populations (fast = 1.27 +/- 0.03 microm(2)/ms, slow = 0.22 +/- 0.02 microm(2)/ms), but did not change their relative signal fractions. This phenomenon runs counter to the effects observed in brain injury, following which the apparent diffusion coefficient (ADC) decreases 30-50%. The results presented herein suggest that this ADC decrease in brain occurs despite cell swelling, which by itself would be expected to induce an increase in intracellular diffusion coefficients.

Animals↗

PubMed2002

Importance of intracellular water apparent diffusion to the measurement of membrane permeability.

The exchange of water across biological membranes is of fundamental significance to both animal and plant physiology. Diffusional membrane permeability (P(d)) for the Xenopus oocyte, an important model system for water channel investigation, is typically calculated from intracellular water pre-exchange lifetime, cell volume, and cell surface area. There is debate, however, whether intracellular water motion affects water lifetime, and thereby P(d). Mathematical modeling of water transport is problematic because the intracellular water diffusion rate constant (D) for cells is usually unknown. The measured permeability may be referred to as the apparent diffusional permeability, P, to acknowledge this potential error. Herein, we show that magnetic resonance (MR) spectroscopy can be used to measure oocyte water exchange with greater temporal resolution and higher signal-to-noise ratio than other methods. MR imaging can be used to assess both oocyte geometry and intracellular water diffusion for the same single cells. MR imaging is used to confirm the dependence of intracellular water lifetime on intracellular diffusion. A model is presented to relate intracellular lifetime to true membrane diffusional permeability. True water diffusional permeability (2.7 +/- 0.4 microm/s) is shown to be 39 +/- 6% greater than apparent diffusional permeability for 8 oocytes. This discrepancy increases with cell size and permeability (such as after water channel expression) and decreases with increasing intracellular water D.

Animals↗