A. de Crespigny

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.

Serial MRI After Transient Focal Cerebral Ischemia in Rats: Dynamics of Tissue Injury, Blood-Brain Barrier Damage, and Edema Formation

BACKGROUND AND PURPOSE With the advent of thrombolytic therapy for acute stroke, reperfusion-associated mechanisms of tissue injury have assumed greater importance. In this experimental study, we used several MRI techniques to monitor the dynamics of secondary ischemic damage, blood-brain barrier (BBB) disturbances, and the development of vasogenic edema during the reperfusion phase after focal cerebral ischemia in rats. METHODS Nineteen Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion of 30 minutes, 60 minutes, or 2.5 hours with the suture occlusion model. MRI, including diffusion-weighted imaging (DWI), T2-weighted imaging, perfusion-weighted imaging, and T1-weighted imaging, was performed 5 to 15 minutes before reperfusion, as well as 0.5, 1.5, and 2.5 hours and 1, 2, and 7 days after withdrawal of the suture. Final infarct size was determined histologically at 7 days. RESULTS In the 30-minute ischemia group (and partially also after 60 minutes), DWI abnormalities reversed transiently during the early reperfusion period but recurred after 1 day, probably due to secondary ischemic damage. After 2.5 hours of ischemia, DWI abnormalities no longer reversed, and signal intensity on both DWI and T2-weighted images increased rapidly in the previously ischemic region due to BBB damage (enhancement on postcontrast T1-weighted images) and edema formation. Early BBB damage during reperfusion was found to be predictive of relatively pronounced edema at subacute time points and was probably related to the increased mortality rates in this experimental group (3 of 7). CONCLUSIONS Reperfusion after short periods of ischemia (30 to 60 minutes) appears to be mainly complicated by secondary ischemic damage as shown by the delayed recurrence of the DWI lesions, whereas BBB damage associated with vasogenic edema becomes a dominant factor with longer occlusion times (2.5 hours).

Evaluation of early reperfusion and IV tPA therapy using diffusion- and perfusion-weighted MRI

Objective: To characterize the effects of recombinant tissue plasminogen activator (rt-PA) therapy and early reperfusion on diffusion-weighted (DWI) and perfusion-weighted imaging (PWI) changes observed following acute ischemic injury. Methods: Twelve patients were evaluated prospectively using echo planar DWI and bolus tracking PWI. Six patients received IV rt-PA 0.9 mg/kg and were compared with six patients who did not. Patients receiving rt-PA were initially imaged (T1) 3 to 5 hours postictus (mean, 4 hours 20 minutes) whereas those not treated with tissue plasminogen activator (tPA) were imaged 4 to 7 hours postictus (mean, 5 hours, 25 minutes). Follow-up imaging was performed 3 to 6 hours (T2), 24 to 36 hours (T3), 5 to 7 days (T4), and 30 days (T5) after the first scan in all patients. Lesion volumes were measured on both DWI and time-to-peak maps constructed from PW images. Results: PWI was performed successfully at T1 and T3 in 11 of 12 patients. In the group that received IV tPA, initial PWI volumes were less than DWI volumes in five of six patients (83%), whereas only one of five patients (20%) not receiving tPA had PWI < DWI volume (p = 0.08). PWI normalized by 24 to 36 hours (T3) in 6 of 11 patients (early reperfusers), with 5 of 6 of these early reperfusers having received tPA. The aggregate apparent diffusion coefficient (ADC) values for the early reperfusers were consistently higher at T2 (p = 0.04), T3 (p = 0.002), and T4 (p = 0.0005). Five of six patients with early reperfusion demonstrated regions of elevated ADC within the ischemic zone (mean ipsilateral ADC/contralateral ADC, 1.46 ± 0.19) by 24 to 36 hours, whereas none of the nonearly reperfusers showed these regions of elevated ADC (p = 0.015). Conclusion: Early reperfusion is seen more frequently with IV tPA therapy. In addition, the study showed that ADC may undergo early increases that are tied closely to reperfusion, and marked ADC heterogeneity may exist within the same lesion. Early reperfusion is seen more frequently with IV tPA therapy.

Topography of connections between human prefrontal cortex and mediodorsal thalamus studied with diffusion tractography.

Studies in monkeys show clear anatomical and functional distinctions among networks connecting with subregions within the prefrontal cortex. Three such networks are centered on lateral orbitofrontal cortex, medial frontal and cingulate cortex, and lateral prefrontal cortex and all have been identified with distinct cognitive roles. Although these areas differ in a number of their cortical connections, some of the first anatomical evidence for these networks came from tracer studies demonstrating their distinct patterns of connectivity with the mediodorsal (MD) nucleus of the thalamus. Here, we present evidence for a similar topography of MD thalamus prefrontal connections, using non-invasive imaging and diffusion tractography (DWI–DT) in human and macaque. DWI–DT suggested that there was a high probability of interconnection between medial MD and lateral orbitofrontal cortex, between caudodorsal MD and medial frontal/cingulate cortex, and between lateral MD and lateral prefrontal cortex, in both species. Within the lateral prefrontal cortex a dorsolateral region (the principal sulcus in the macaque and middle frontal gyrus in the human) was found to have a high probability of interconnection with the MD region between the regions with a high probability of interconnection with other parts of the lateral prefrontal cortex and with the lateral orbitofrontal cortex. In addition to suggesting that the thalamic connectivity in the macaque is a good guide to human prefrontal cortex, and therefore that there are likely to be similarities in the cognitive roles played by the prefrontal areas in both species, the present results are also the first to provide insight into the topography of projections of an individual thalamic nucleus in the human brain.

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.

Multilocal magnetic resonance perfusion mapping comparing the cerebral hemodynamic effects of decompressive craniectomy versus reperfusion in experimental acute hemispheric stroke in rats

This study examined the hemodynamic effects of craniectomy compared to reperfusion on the temporal evolution of cerebral perfusion in different brain regions in a rat model of focal cerebral ischemia. Three groups were investigated: no treatment, reperfusion or craniectomy at 1 h. Perfusion-weighted magnetic resonance imaging (PWI) was performed serially from 0.5 to 6 h. Relative regional cerebral blood flow was calculated for different regions and infarct volume was assessed by histology at 24 h. As conclusion, both, craniectomy and reperfusion increased cerebral perfusion in the acute phase of cerebral ischemia. While reperfusion resulted in a homogeneous improvement of perfusion in the cortex and basal ganglia, craniectomy improved only cortical perfusion in areas directly under the craniectomy site. PWI is well suited to non-invasively monitor perfusion alterations after aggressive therapeutical approaches in stroke.

Serial MRI After Transient Focal Cerebral Ischemia in Rats : Dynamics of Tissue Injury, Blood-Brain Barrier Damage, and Edema Formation Editorial Comment: Dynamics of Tissue Injury, Blood-Brain Barrier Damage, and Edema Formation

BACKGROUND AND PURPOSE With the advent of thrombolytic therapy for acute stroke, reperfusion-associated mechanisms of tissue injury have assumed greater importance. In this experimental study, we used several MRI techniques to monitor the dynamics of secondary ischemic damage, blood-brain barrier (BBB) disturbances, and the development of vasogenic edema during the reperfusion phase after focal cerebral ischemia in rats. METHODS Nineteen Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion of 30 minutes, 60 minutes, or 2.5 hours with the suture occlusion model. MRI, including diffusion-weighted imaging (DWI), T2-weighted imaging, perfusion-weighted imaging, and T1-weighted imaging, was performed 5 to 15 minutes before reperfusion, as well as 0.5, 1.5, and 2.5 hours and 1, 2, and 7 days after withdrawal of the suture. Final infarct size was determined histologically at 7 days. RESULTS In the 30-minute ischemia group (and partially also after 60 minutes), DWI abnormalities reversed transiently during the early reperfusion period but recurred after 1 day, probably due to secondary ischemic damage. After 2.5 hours of ischemia, DWI abnormalities no longer reversed, and signal intensity on both DWI and T2-weighted images increased rapidly in the previously ischemic region due to BBB damage (enhancement on postcontrast T1-weighted images) and edema formation. Early BBB damage during reperfusion was found to be predictive of relatively pronounced edema at subacute time points and was probably related to the increased mortality rates in this experimental group (3 of 7). CONCLUSIONS Reperfusion after short periods of ischemia (30 to 60 minutes) appears to be mainly complicated by secondary ischemic damage as shown by the delayed recurrence of the DWI lesions, whereas BBB damage associated with vasogenic edema becomes a dominant factor with longer occlusion times (2.5 hours).

MRI of focal cerebral ischemia using 17O-labeled water

This work presents a novel approach for quantifying low concentrations of H217O in vivo and explores its utility for assessing cerebral ischemia. Oxygen‐17 enriched water acts as a T2 shortening contrast agent whose effect can be suppressed by decoupling at the 17O frequency during TE interval in a spin‐echo MR image. Serial T2‐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 H217O 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 H217O in rat brain were generated. The transverse relaxivity of H217O in brain was estimated, R2 = 2.4 ± 0.5 s−1(atom%)−1. After bolus injection of 1 ml of 10 atom% H217O, brain H217O concentration was estimated at 0.06 ± 0.01 atom%. In the rat focal ischemia model, 17O 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.