Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers.

MRI tractography is the mapping of neural fiber pathways based on diffusion MRI of tissue diffusion anisotropy. Tractography based on diffusion tensor imaging (DTI) cannot directly image multiple fiber orientations within a single voxel. To address this limitation, diffusion spectrum MRI (DSI) and related methods were developed to image complex distributions of intravoxel fiber orientation. Here we demonstrate that tractography based on DSI has the capacity to image crossing fibers in neural tissue. DSI was performed in formalin-fixed brains of adult macaque and in the brains of healthy human subjects. Fiber tract solutions were constructed by a streamline procedure, following directions of maximum diffusion at every point, and analyzed in an interactive visualization environment (TrackVis). We report that DSI tractography accurately shows the known anatomic fiber crossings in optic chiasm, centrum semiovale, and brainstem; fiber intersections in gray matter, including cerebellar folia and the caudate nucleus; and radial fiber architecture in cerebral cortex. In contrast, none of these examples of fiber crossing and complex structure was identified by DTI analysis of the same data sets. These findings indicate that DSI tractography is able to image crossing fibers in neural tissue, an essential step toward non-invasive imaging of connectional neuroanatomy.

Long-term monitoring of post-stroke plasticity after transient cerebral ischemia in mice using in vivo and ex vivo diffusion tensor MRI.

WE USED A MURINE MODEL OF TRANSIENT FOCAL CEREBRAL ISCHEMIA TO STUDY: 1) in vivo DTI long-term temporal evolution of the apparent diffusion coefficient (ADC) and diffusion fractional anisotropy (FA) at days 4, 10, 15 and 21 after stroke 2) ex vivo distribution of a plasticity-related protein (GAP-43) and its relationship with the ex vivo DTI characteristics of the striato-thalamic pathway (21 days). All animals recovered motor function. In vivo ADC within the infarct was significantly increased after stroke. In the stroke group, GAP-43 expression and FA values were significantly higher in the ipsilateral (IL) striatum and contralateral (CL) hippocampus compared to the shams. DTI tractography showed fiber trajectories connecting the CL striatum to the stroke region, where increased GAP43 and FA were observed and fiber tracts from the CL striatum terminating in the IL hippocampus.Our data demonstrate that DTI changes parallel histological remodeling and recovery of function.

A comparison of CH3-DTPA-GD (NMS60) and GD-DTPA for evaluation of acute myocardial ischemia.

PURPOSE: Our objective was to evaluate the use of a new medium weight MRI contrast agent, NMS60 (a synthetic oligomeric Gd-complex containing three Gd(3+) atoms, molecular weight 2158 Da) compared to gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) in a pig myocardial ischemia model. MATERIALS: We used 13 male white hybrid pigs. Animals were scanned in the acute phase 2-3 h after the onset of myocardial ischemia. Scans were acquired on a 1.5T GE Signa with dynamic T1-weighted imaging during a bolus injection of 0.1 mmol(gd)/kg of either NMS60 or Gd-DTPA, 2D CINE at 5 min after injection, and T1-weighted spin-echo imaging up to 60 min. RESULTS: The postcontrast CINE scans showed improved contrast-to-noise ratio after NMS60 injection, compared to Gd-DTPA. There was significantly greater enhancement with NMS60 in both normal myocardium and in the ischemic lesion on T1-weighted spin-echo scans up to 60 min after injection. The dose ranging study shows a 24% greater enhancement with NMS60 compared to Gd-DTPA. DISCUSSION: This new medium weighted contrast agent offers improved enhancement for cardiac MRI, compared to Gd-DTPA, with similar washout kinetics and lower toxicity, and may prove useful for better detection of myocardial ischemia as well as delayed or hyperenhancement after reperfusion.

Near-infrared frequency-domain optical spectroscopy and magnetic resonance imaging: a combined approach to studying cerebral maturation in neonatal rabbits.

The neonatal rabbit brain shows prolonged postnatal development both structurally and physiologically. We use noninvasive near-IR frequency-domain optical spectroscopy (NIRS) and magnetic resonance imaging (MRI) to follow early developmental changes in cerebral oxygenation and anatomy, respectively. Four groups of animals are measured: NIRS in normals, MRI in normals, and both NIRS and MRI with hypoxia-ischemia (HI) (diffusion MRI staging). NIRS and/or MRI are performed from P3 (postnatal day=P) up to P76. NIRS is performed on awake animals with a frequency-domain tissue photometer. Absolute values of oxyhemoglobin concentration ([HbO2]), deoxyhemoglobin concentration ([HbR]), total hemoglobin concentration (HbT), and hemoglobin saturation (StO2) are calculated. The brains of all animals appeared to be maturing as shown in the diffusion tensor MRI. Mean optical coefficients (reduced scattering) remained unchanged in all animals throughout. StO2 increased in all animals (40% at P9 to 65% at P43) and there are no differences between normal, HI controls, and HI brains. The measured increase in StO2 is in agreement with the reported increase in blood flow during the first 2 months of life in rabbits. HbT, which reflects blood volume, peaked at postnatal day P17, as expected since the capillary density increases up to P17 when the microvasculature matures.

A comparative evaluation of CH3-DTPA-Gd (NMS60) for contrast-enhanced magnetic resonance angiography.

In a canine model the signal dynamics of a new oligomer-based MR contrast agent (NMS60, 2158 Da) were compared to Gd-DTPA to investigate the agents' potential for magnetic resonance angiography (MRA). Twelve male mongrel dogs were imaged sequentially under anesthesia with two different MRA sequences (Tlw 3DSPGR). Initial enhancement was measured every 9 s for eight points in time. Thereafter, spatial highly resolved MRAs were obtained at 5, 10, 15, 20, 30, 45, and 60 min post-injection of two different dosages. Over the first 20 s following bolus administration the average arterial enhancement of 0.1 mmol(Gd)kg NMS60 was 44% greater than Gd-DTPA. Twenty minutes post-injection the relative signal intensity of NMS60 was as high as the peak signal intensity with Gd-DTPA at the same dosage level (0.1 mmol(Gd)/kg). In the animals that received NMS60 injections the vascular conspicuity was overly superior to those who received Gd-DTPA. No significant toxicity effects were noted for either dosage level. The intermediate weight contrast agent NMS60 offers greater vascular enhancement and retention time than Gd-DTPA. For a given set of optimized imaging parameters this offers improved spatial details, less arterial/venous overlap, and better vascular contrast.

Evolution of apparent diffusion coefficient, diffusion-weighted, and T2-weighted signal intensity of acute stroke.

BACKGROUND AND PURPOSE: Serial study of such MR parameters as diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), ADC with fluid-attenuated inversion recovery (ADC(FLAIR)), and T2-weighted imaging may provide information on the pathophysiological mechanisms of acute ischemic stroke. Our goals were to establish the natural evolution of MR signal intensity characteristics of acute ischemic lesions and to assess the potential of using specific MR parameters to estimate lesion age. METHODS: Five serial echo-planar DWI studies with and without an inversion recovery pulse were performed in 27 patients with acute stroke. The following lesion characteristics were studied: 1) conventional ADC (ADC(CONV)); 2) ADC(FLAIR); 3) DWI signal intensity (SI(DWI)); 4) T2-weighted signal intensity (SI(T2)), and 5) FLAIR signal intensity (SI(FLAIR)). RESULTS: The lesion ADC(CONV) gradually increased from low values during the first week to pseudonormal during the second week to supranormal thereafter. The lesion ADC(FLAIR) showed the same pattern of evolution but with lower absolute values. A low ADC value indicated, with good sensitivity (88%) and specificity (90%), that a lesion was less than 10 days old. All signal intensities remained high throughout follow-up. SI(DWI) showed no significant change during the first week but decreased thereafter. SI(T2) initially increased, decreased slightly during week 2, and again increased after 14 days. SI(FLAIR) showed the same initial increase as the SI(T2) but remained relatively stable thereafter. CONCLUSION: Our findings further clarify the time course of stroke evolution on MR parameters and indicate that the ADC map may be useful for estimating lesion age. Application of an inversion recovery pulse results in lower, potentially more accurate, absolute ADC values.

Comparison of diffusion, blood oxygenation, and blood volume changes during global ischemia in rats.

Rapid diffusion, blood oxygenation, and blood volume weighted echo planar imaging was used to monitor global cerebral ischemia by cardiac arrest in rats. Serial CBV measurements used intravascular iron oxide contrast media (iron dextran). ADC dropped by 5% within 20 sec of cardiac arrest, then continued to decay slowly until a larger rapid drop after 2 min. After iron oxide injection, the initial 5% drop was not observed. The transverse relaxation rate (R(2), R(*)(2) no iron injection) increased rapidly after cardiac arrest, peaking at about 30 sec, then declining towards baseline. The CBV dropped by about 50% within 20 sec. The initial 5% ADC drop may be a vascular artifact. The rapidity of the CBV-weighted signal drop suggests a flow-mediated contribution to the iron oxide contrast mechanism. Magn Reson Med 45:10-16, 2001.

MRI of focal cerebral ischemia using (17)O-labeled water.

This work presents a novel approach for quantifying low concentrations of H(2)(17)O in vivo and explores its utility for assessing cerebral ischemia. Oxygen-17 enriched water acts as a T(2) shortening contrast agent whose effect can be suppressed by decoupling at the (17)O frequency during TE interval in a spin-echo MR image. Serial T(2)-weighted echo planar images were acquired in phantoms and rat brain with decoupler power alternated every eight images. The resulting periodic signal change (proportional to H(2)(17)O concentration) was detected by cross-correlating the square-wave decoupler power timecourse with the signal intensity in each voxel. Natural abundance (0.037 atom%) images of H(2)(17)O in rat brain were generated. The transverse relaxivity of H(2)(17)O in brain was estimated, R(2) = 2.4+/-0.5 s(-1)(atom%)(-1). After bolus injection of 1 ml of 10 atom% H(2)(17)O, brain H(2)(17)O concentration was estimated at 0.06+/-0.01 atom%. In the rat focal ischemia model, (17)O cross-correlation maps compared well with diffusion and Gd-DTPA perfusion images to indicate infarct location. Magn Reson Med 43:876-883, 2000.

Dynamic contrast-enhanced MRI of Implanted VX2 tumors in rabbit muscle: comparison of Gd-DTPA and NMS60.

We studied the dynamics of injected contrast enhancement in implanted VX2 tumors in rabbit thigh muscle. We compared two contrast agents Gd-DTPA and NMS60, a novel gadolinium containing trimer of molecular weight 2.1 kd. T1-weighted spin echo images were acquired preinjection and at 5-60 min after i.v. injection of 0.1 mmol/kg of agent. Dynamic T1-weighted SPGR images (1.9 s/image) were acquired during the bolus injection. Male NZW rabbits (n = 13) were implanted with approximately 2 x 10(6) VX2 tumor cells and grew tumors of 28+/-27 mL over 12 to 21 days. NMS60 showed significantly greater peak enhancement in muscle, tumor rim, and core compared to DTPA in both T1-weighted and SPGR images. NMS60 also showed delayed peak enhancement in the dynamic scans (compared to Gd-DTPA) and significantly reduced leakage rate constant into the extravascular space for tumor rim (K21 = 5.1 min(-1) vs. 11.5 min(-1) based on a 2 compartment kinetic model). The intermediate weight contrast agent NMS60 offers greater tumor enhancement than Gd-DTPA and may offer improved regional differentiation on the basis of vascular permeability in tumors.

Rapid monitoring of diffusion, DC potential, and blood oxygenation changes during global ischemia. Effects of hypoglycemia, hyperglycemia, and TTX.

BACKGROUND AND PURPOSE: The increasing interest in diffusion-weighted MRI (MRI) for diagnosis and monitoring of acute stroke in humans calls for a sound understanding of the underlying mechanisms of this image contrast in acute cerebral ischemia. The present study aimed to show that a rapid decrease in brain-water apparent diffusion coefficient (ADC) occurs coincident with anoxic depolarization and that this change is delayed by hyperglycemia and sodium channel blockade but accelerated by hypoglycemia. METHODS: Rats were divided into groups: normoglycemic, hypoglycemic, and hyperglycemic, and those given local tetrodotoxin (TTX) application. Cardiac arrest was effected by intravenous KCl injection during serial high-speed diffusion and blood oxygenation-sensitive gradient-recalled echo MRI. Brain DC potential was recorded simultaneously. Serial ADC maps were calculated from the diffusion-weighted data and fitted to a model function to measure the delay between cardiac arrest and rapid ADC decrease. RESULTS: The time of anoxic depolarization indicated by DC change agreed well with the rapid drop in ADC in all groups; both were accelerated with hypoglycemia and delayed by hyperglycemia. A more gradual ADC decline occurred before anoxic depolarization, which was more pronounced in hyperglycemic animals and less pronounced in hypoglycemic animals. Rapid drop in ADC was also delayed by local TTX application. Changes in gradient-recalled echo image intensity were not significantly different among groups. CONCLUSIONS: While much of the ADC decrease in ischemia occurs during anoxic depolarization, significant but gradual ADC changes occur earlier that may not be due to a massive loss in ion homeostasis.

High-resolution mapping of discrete representational areas in rat somatosensory cortex using blood volume-dependent functional MRI.

The present study documents the use of an iron oxide-based blood-pool contrast agent in functional magnetic resonance imaging to monitor activity-related changes in cerebral blood volume (CBV) resulting from peripheral sensory stimulation and the application of this technique to generate high-resolution functional maps. Rats, anesthetized with alpha-chloralose, were imaged during electrical stimulation (3 ms, 3 Hz, 3 V) of forelimb or hindlimb. Activation maps were generated by cross-correlation of the measured signal response and a square-wave function representative of the stimulus for each image pixel. Multislice imaging produced functional maps consistent with the known functional anatomy of rat primary somatosensory (S-I) cortex. Imaging with improved temporal resolution demonstrated rapid (<6 s) CBV increases which were sustained and relatively stable (coefficient of variation = 0.17 +/- 0.02) for forelimb stimulation periods of up to 5 min. Enabled by this sustained response we generated high-resolution (approximately 100 micrometer in-plane) functional maps showing discrete forelimb and hindlimb activation. This technique offers many advantages over other methods for the study of brain activity in the rat and has resolution sufficient to be useful in reorganization studies.

High-resolution functional magnetic resonance imaging of the rat brain: mapping changes in cerebral blood volume using iron oxide contrast media.

Contrast-enhanced magnetic resonance imaging was used to produce high-resolution activation maps reflecting local changes in cerebral blood volume after a simple sensory stimulus. Activation of the forelimb region of the somatosensory cortex was performed in alpha-chloralose-anaesthetized rats with an electrical stimulus (5 V, 3 Hz) delivered through needle electrodes placed subcutaneously on the left forelimb. A gradient echo magnetic resonance imaging sequence, sensitive to changes in the relative amount of deoxyhemoglobin within the cerebral vasculature, produced a 4.05%+/-1.69% increase in signal intensity. This effect was enhanced with an injection of an intravascular iron oxide contrast agent (Combidex, Advanced Magnetics), resulting in a 9.11%+/-1.52% decrease in signal intensity.

Diffusion and perfusion magnetic resonance imaging of the evolution of hypoxic ischemic encephalopathy in the neonatal rabbit.

Hypoxic-ischemic encephalopathy (HIE) can result from neonatal asphyxia, the pathophysiology of which is poorly understood. We studied the acute evolution of this disease, using magnetic resonance imaging in an established animal model. HIE was induced in neonatal rabbits by a combination of common carotid artery (CCA) ligation and hypoxia. Serial diffusion and perfusion-weighted magnetic resonance images were acquired before, during, and after the hypoxic interval. Focal areas of decreased apparent diffusion coefficient (ADC) were detected initially in the cortex ipsilateral to CCA ligation within 62 +/- 48 min from the onset of hypoxia. Subsequently, these areas of decreased ADC spread to the subcortical white matter, basal ganglia (ipsilateral side), and then to the contralateral side. Corresponding perfusion-weighted images showed relative cerebral blood volume deficits which closely matched those regions of ADC change. Our results show that MRI diffusion and perfusion-weighted imaging can detect acute cell swelling post-hypoxia in this HIE model.

Experimental cerebral venous thrombosis: evaluation using magnetic resonance imaging.

Diffusion-weighted (DWI), dynamic contrast-enhanced (perfusion imaging), and conventional spin-echo magnetic resonance imaging (MRI) were applied to characterize the pathophysiology of cerebral venous thrombosis (CVT) in the rat. We induced CVT by rostral and caudal ligation of the superior sagittal sinus (SSS) and injection of a thrombogenic cephalin suspension. The resulting pathology was monitored in an acute and long-term study group. Evans blue and hematoxylin-eosin staining was performed for comparison with MRI data. A subgroup of animals was treated with i.v. tissue plasminogen activator (t-PA). Successful thrombosis of the SSS was confirmed by macropathology or histopathology in all rats. Parenchymal lesions as shown by MRI, however, were present only in animals with additional involvement of cortical cerebral veins (11 of 18 rats). The early pathology was clearly detected with the DWI. The apparent diffusion coefficient declined to 56 +/- 7% of control value at 0.5 h and slowly increased to 84 +/- 8% by 48 h. Perfusion imaging showed parasagittal perfusion deficits. Treatment with t-PA partially resolved the hyperintensity on DWI. Evidence of blood-brain-barrier disruption was observed 2 to 3 h after induction of CVT. In conclusion, experimental CVT is characterized by early cytotoxic edema closely followed by vasogenic edema. The t-PA treatment partially reversed the DWI signal changes consistent with regional tissue recovery, as shown by histopathology. These results encourage the use of cytoprotective drugs in addition to anticoagulant or thrombolytic therapy.

Recovery of apparent diffusion coefficient after ischemia-induced spreading depression relates to cerebral perfusion gradient.

BACKGROUND AND PURPOSE: Transient decreases of the apparent diffusion coefficient (ADC) of water as measured by fast diffusion-weighted imaging (DWI) in the ischemic border zone are thought to reflect cellular swelling associated with spreading depression. DWI and dynamic contrast-enhanced MRI were applied to study the characteristics of spreading depression and the correlation between ADC recovery time and tissue perfusion in focal ischemia. METHODS: Serial DWI was performed during remote middle cerebral artery occlusion in rats (n = 5) with an echo-planar imaging technique. ADC maps were calculated and ADC values displayed as a function of time in user-defined regions of interest with a time resolution of 12 to 16 seconds. Dynamic contrast-enhanced MRI was performed for qualitative correlation of ADC changes with tissue perfusion. RESULTS: Recovery time of transient ADC decreases correlated with the degree of the perfusion deficit (r = .81, P < .001). Slowly recovering ADC declines were found close to the ischemic core and correlated with severe perfusion deficit, while short-lasting ADC declines were typically found in moderately malperfused or normal tissue. Transient ADC decreases originated in the subcortical and cortical ischemic border zones and propagated along the cortex with a velocity of 2.9 +/- 0.9 mm/min. CONCLUSIONS: The variation in the recovery time of transient ADC decreases in the ischemic periphery reflects the gradient of the tissue perfusion. Severely delayed recovery time after spreading depression is thought to represent the ischemic penumbra.

MR detection of cortical spreading depression immediately after focal ischemia in the rat.

The suture model for middle cerebral artery occlusion (MCAO) was used to induce acute ischemia in rats remotely within a magnetic resonance (MRI) scanner. Serial MR diffusion weighted imaging (DWI) was performed during remote MCAO using an echo planar imaging technique. MR perfusion imaging was performed before and after occlusion using the bolus tracking technique. Transient apparent diffusion coefficient (ADC) changes were detected in six of seven rats as early as 2.7 +/- 1.5 min post MCAO. ADC values declined transiently to 70.1 +/- 6.0% of control and recovered to 95.5 +/- 6.8% of control within 3.3 +/- 2.9 min. These ADC changes propagated bidirectionally away from the ischemic core with a speed of 3.0 +/- 1.1 mm/min. Transient ADC decreases only occurred in ischemic areas characterized by moderately decreased tissue perfusion. Propagation toward cortical regions with severe tissue perfusion deficits was not detected. DWI can detect the earliest dynamic, reversible ADC changes in the ischemic tissue. The speed of propagation of the decreasing ADC wave, the waveform characteristics, and the occurrence in moderately perturbated tissue are compatible with cortical spreading depression.

Navigated diffusion imaging of normal and ischemic human brain.

The principal barrier to clinical application of diffusion-weighted MR imaging is the severe image degradation caused by patient motion. One way to compensate for motion effects is the use of a "navigator echo" phase correction scheme. In this work, a modification of this technique is introduced, in which the phase correction step is performed in the frequency domain (i.e., after the readout Fourier transform). This significantly improves the robustness of the navigator echo approach and, when combined with cardiac gating, allows diagnostic quality diffusion-weighted images of the brain to be routinely obtained on standard clinical scanner hardware. The technique was evaluated in phantom studies and in 23 humans (3 normal volunteers and 20 patients). Diffusion anisotropy and apparent diffusion coefficient maps were generated from the image data and showed decreased apparent diffusion in acute stroke lesions and, in several cases, increased apparent diffusion in chronic stroke lesions.

Early detection of regional cerebral ischemia using high-speed MRI.

BACKGROUND AND PURPOSE: Diffusion-weighted magnetic resonance imaging (MRI) has been shown to be effective in detailing regions of cerebral ischemia in which water proton translations or motions have been slowed. The corresponding perfusion patterns, however, have not been correlated. Further, the hemodynamics of normal and ischemic tissues and the changes due to mild insults are also not clear. This study describes high-speed MRI techniques and observations found in the early detection of regional cerebral ischemia in the cat. METHODS: Gradient-echo and spin-echo-planar MRI was used with middle cerebral artery balloon occluders to induce transient ischemia and reperfusion. RESULTS: Apparent diffusion fell within minutes after middle cerebral artery occlusion and correlated with near-total or total perfusion deficits. Reactive hyperemia, apnea, and vasodilatation appeared to be changed in ischemic and normal brain. CONCLUSIONS: Characterization of early ischemic events is dramatically improved when the motions of water (apparent diffusion), delivery of water (perfusion), and response to hemodynamic perturbations (regulatory response) are measured. All can be accomplished with high-speed MRI techniques described herein.

Perfusion and diffusion MR imaging of thromboembolic stroke.

A carotid embolic stroke model in rats was studied with a combination of diffusion- and perfusion-sensitive magnetic resonance (MR) imaging at 4.7 T. Capillary blood deoxygenation changes were monitored during formation of focal ischemia by acquiring multisection magnetic susceptibility-weighted echo-planar images. A signal intensity decrease of 7% +/- 3 in ischemic brain (1% +/- 2 in normal brain) was attributable to a T2* decrease due to increased blood deoxygenation, which correlated well with subsequently measured decreases in the apparent diffusion coefficient. The same multisection methods were used to track the first-pass transit of a bolus of dysprosium-DTPA-BMA [diethylenetriaminepentaacetic acid-bis(methylamide)] to assess relative tissue perfusion before and after stroke and after treatment with a thrombolytic agent. Analysis of contrast agent transit profiles suggested a total perfusion deficit in ischemic tissue and essentially unchanged perfusion in normal brain tissue after stroke.

Improved sensitivity to magnetic susceptibility contrast.

Changes in the local magnetic susceptibility of brain tissue due to injected paramagnetic contrast agent are manifest as both a line-broadening and frequency shift of the water resonance. By combining these two effects, the sensitivity of gradient recalled echo images to such changes can be increased.