David B. Hackney

Magnetic resonance microimaging of intraaxonal water diffusion in live excised lamprey spinal cord

Anisotropy of water diffusion in axon tracts, as determined by diffusion-weighted MRI, has been assumed to reflect the restriction of water diffusion across axon membranes. Reduction in this anisotropy has been interpreted as degeneration of axons. These interpretations are based primarily on a priori reasoning that has had little empirical validation. We used the experimental advantages of the sea lamprey spinal cord, which contains several very large axons, to determine whether intraaxonal diffusion is isotropic and whether anisotropy is attributable to restriction of water mobility by axon surface membranes. Through the application of magnetic resonance microimaging, we were able to measure the purely intraaxonal diffusion characteristics of the giant reticulospinal axons (20–40 μm in diameter). The intraaxonal apparent diffusion coefficients of water parallel (longitudinal ADC, l-ADC) and perpendicular (transverse ADC, t-ADC) to the long axis were 0.98 ± 0.06 (10−3 mm2/sec) and 0.97 ± 0.11 (10−3 mm2/sec), respectively. In white matter regions that included multiple axons, l-ADCs were almost identical regardless of axon density in the sampled axon tract. By comparison, t-ADCs were reduced and varied inversely with the number of axons (and thus axolemmas) in a fixed cross-sectional area. Thus, diffusion was found to be isotropic when measured entirely within a single axon and anisotropic when measured in regions that included multiple axons. These findings support the hypothesis that the cell membrane is the primary source of diffusion anisotropy in fiber tracts of the central nervous system.

MR diagnosis of acute disseminated encephalomyelitis

High-field magnetic resonance (MR) imaging was performed in three patients with clinically diagnosed acute disseminated encephalomyelitis (ADEM). Contrast enhanced CT was normal in all cases. Magnetic resonance demonstrated multiple foci of demyelination in the brain stem, cerebrum, and cerebellum. Lesions were characteristic, in that they were relatively few in number, frequently present in the brain stem and posterior fossa, nonhemorrhagic, asymmetric, and easily correlated with clinical symptoms and signs. Follow-up MR in one patient who had clinically improved after steroid therapy showed marked resolution of previously documented lesions. Typical MR findings in combination with the appropriate clinical presentation can confirm the diagnosis of ADEM, obviate other more invasive diagnostic tests, identify the extent and sites of involvement, and follow response to therapy.

MRI diffusion coefficients in spinal cord correlate with axon morphometry.

Following spinal cord injury, diffusion MRI (DWI) has been shown to detect injury and functionally significant neuroprotection following treatment that otherwise would go undetected with conventional MRI. The underlying histologic correlates to directional apparent diffusion coefficients (ADC) obtained with DWI have not been determined, however, and we address this issue by directly correlating ADC values with corresponding axon morphometry in the normal rat cervical spinal cord. ADC values transverse (perpendicular) and longitudinal (parallel) to axons both correlate with axon counts, however each directional ADC reflects distinct histologic parameters. DWI may therefore be capable of providing specific histologic data regarding the integrity of white matter.

Reading impairment in the neuronal migration disorder of periventricular nodular heterotopia.

Objective: To define the behavioral profile of periventricular nodular heterotopia (PNH), a malformation of cortical development that is associated with seizures but reportedly normal intelligence, and to correlate the results with anatomic and clinical features of this disorder. Methods: Ten consecutive subjects with PNH, all with epilepsy and at least two periventricular nodules, were studied with structural MRI and neuropsychological testing. Behavioral results were statistically analyzed for correlation with other features of PNH. Results: Eight of 10 subjects had deficits in reading skills despite normal intelligence. Processing speed and executive function were also impaired in some subjects. More marked reading difficulties were seen in subjects with more widely distributed heterotopia. There was no correlation between reading skills and epilepsy severity or antiepileptic medication use. Conclusion: The neuronal migration disorder of periventricular nodular heterotopia is associated with an impairment in reading skills despite the presence of normal intelligence.

MR Imaging of Intracranial Metastatic Melanoma

Ten patients with intracerebral metastases from malignant melanoma were evaluated with magnetic resonance (MR) imaging performed at 1.5 T using spin-echo techniques. On the basis of histopathologic findings in three of 10 cases and CT appearances in all 10 cases, three patterns were identified on analysis of MR signal intensities in both short repetition time/echo time (TR/TE) and long TR/TE spin-echo scans. In comparison to normal cortex, non-hemorrhagic melanotic melanoma appeared markedly hyperintense on short TR/TE images and isointense, mildly hypointense on long TR/TE images. Nonhemorrhagic, amelanotic melanoma appeared isointense or mildly hypointense on short TR/TE and isointense or mildly hyperintense on long TR/TE images. Hemorrhagic melanoma varied in appearance, depending on the stage of hemorrhage. Melanotic, nonhemorrhagic melanoma can be distinguished from early and late subacute hemorrhage by its signal intensity on long TR/TE images. Spin-echo MR appears to be the method of choice for diagnosing melanotic metastases.

Biexponential diffusion attenuation in the rat spinal cord: Computer simulations based on anatomic images of axonal architecture

Water diffusion in neurological tissues is known to possess multicomponent diffusion behavior. The fractions of fast and slow apparent diffusion components have often been attributed to the volume fractions of extracellular space (ECS) and intracellular space (ICS) although diffusion fractions are at variance with the tissue compartment volume ratios. In this article this puzzle was examined with a finite difference diffusion simulation model on the basis of optical images from sectioned rat spinal cord. Here the results show that assignment of fractions obtained from biexponential fits of fast and slow diffusion attenuation to ECS and ICS volume ratios is not correct. Rather, the observed multicomponent diffusion behavior is caused by motional restriction and limited intercompartmental water exchange in that at long diffusion times diffusion attenuation is shown to become monoexponential. Although the measured apparent diffusion fractions also depend on T2 relaxation time of water protons in the various compartments, the sensitivity to T2 is small and thus T2 differences are unlikely to explain the mismatch between apparent diffusion fractions and cellular volume fractions. Magn Reson Med 47:455–460, 2002.

Diffusion-weighted MRI and the evaluation of spinal cord axonal integrity following injury and treatment

Diffusion-based magnetic resonance imaging (MRI) (DWI) has been shown experimentally to detect both injury and functionally significant neuroprotection of injured spinal cord white matter that would otherwise go undetected with conventional MRI techniques. The diffusion of water in the central nervous system (CNS) is thought to be affected by both its location (intracellular or extracellular), and by diffusion barriers formed by cell membranes and myelin sheaths. There is, however, controversy concerning how to obtain, interpret, and present DWI data. Computer simulations and MR microscopy have been helpful in resolving some of these issues, as well as determining exact histologic correlates to DWI findings.

Advances in neuroimaging of traumatic brain injury and posttraumatic stress disorder

Improved diagnosis and treatment of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are needed for our military and veterans, their families, and society at large. Advances in brain imaging offer important biomarkers of structural, functional, and metabolic information concerning the brain. This article reviews the application of various imaging techniques to the clinical problems of TBI and PTSD. For TBI, we focus on findings and advances in neuroimaging that hold promise for better detection, characterization, and monitoring of objective brain changes in symptomatic patients with combat-related, closed-head brain injuries not readily apparent by standard computed tomography or conventional magnetic resonance imaging techniques.

Association Between Serum Ferritin Level and Perihematoma Edema Volume in Patients With Spontaneous Intracerebral Hemorrhage

Background and Purpose— Preclinical evidence indicates that iron plays a key role in mediating neuronal injury and edema formation after intracerebral hemorrhage (ICH). However, the clinical role of iron in patients with ICH has not been well studied. We undertook this exploratory study to investigate the association of serum ferritin, as an indicator of body iron load, with perihematoma edema after ICH. Methods— We retrospectively reviewed prospectively-collected clinical and laboratory data from 23 consecutive patients with acute spontaneous ICH who had a CT scan and serum ferritin checked on admission, and a follow-up CT scan 3 to 4 days afterward. We measured hematoma and edema volumes on admission and follow-up scans, and calculated the relative edema volume to correct for hematoma volume. We used Spearman correlation coefficient to determine the association of various variables with relative perihematoma edema volume. Results— Whereas the median hematoma volume increased by approximately 28% from baseline to day 3 to 4, the relative edema volume almost doubled during this time period. We observed a significant positive correlation between serum ferritin and relative perihematoma edema volume on day 3 to 4 (r=0.78; P=0.002), but not at baseline; and little correlation between the changes in hematoma volumes and corresponding relative edema volumes (r=0.14). There was a trend for a positive correlation between body temperature and relative edema volumes. Conclusions— Our findings support the notion that delayed iron toxicity plays a role in causing brain injury and edema formation after ICH. These findings are preliminary and need to be further investigated in future studies.

Direct magnetic resonance detection of myelin and prospects for quantitative imaging of myelin density

Magnetic resonance imaging has previously demonstrated its potential for indirectly mapping myelin density, either by relaxometric detection of myelin water or magnetization transfer. Here, we investigated whether myelin can be detected and possibly quantified directly. We identified the spectrum of myelin in the spinal cord in situ as well as in myelin lipids extracted via a sucrose gradient method, and investigated its spectral properties. High-resolution solution NMR spectroscopy showed the extract composition to be in agreement with myelin’s known chemical make-up. The 400-MHz 1H spectrum of the myelin extract, at 20 °C (room temperature) and 37 °C, consists of a narrow water resonance superimposed on a broad envelope shifted ∼3.5 ppm upfield, suggestive of long-chain methylene protons. Superimposed on this signal are narrow components resulting from functional groups matching the chemical shifts of the constituents making up myelin lipids. The spectrum could be modeled as a sum of super-Lorentzians with a T2* distribution covering a wide range of values (0.008–26 ms). Overall, there was a high degree of similarity between the spectral properties of extracted myelin lipids and those found in neural tissue. The normalized difference spectrum had the hallmarks of membrane proteins, not present in the myelin extract. Using 3D radially ramp-sampled proton MRI, with a combination of adiabatic inversion and echo subtraction, the feasibility of direct myelin imaging in situ is demonstrated. Last, the integrated signal from myelin suspensions is shown, both spectroscopically and by imaging, to scale with concentration, suggesting the potential for quantitative determination of myelin density.