The success of diffusion magnetic resonance imaging (MRI) is deeply rooted in the powerful concept that during their random, diffusion-driven displacements molecules probe tissue structure at a microscopic scale well beyond the usual image resolution. As diffusion is truly a three-dimensional process, molecular mobility in tissues may be anisotropic, as in brain white matter. With diffusion tensor imaging (DTI), diffusion anisotropy effects can be fully extracted, characterized, and exploited, providing even more exquisite details on tissue microstructure. The most advanced application is certainly that of fiber tracking in the brain, which, in combination with functional MRI, might open a window on the important issue of connectivity. DTI has also been used to demonstrate subtle abnormalities in a variety of diseases (including stroke, multiple sclerosis, dyslexia, and schizophrenia) and is currently becoming part of many routine clinical protocols. The aim of this article is to review the concepts behind DTI and to present potential applications.

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Diffusion tensor imaging: Concepts and applications

Brain injury, subarachnoid hemorrhage and the subsequent delayed ischemic stroke show spreading depolarization of neurons in the tissue at risk, where it leads to spreading ischemia, vasoconstriction and brain electrical silencing, exacerbating damage and thwarting recovery. Jens Dreier reviews the underlying molecular mechanisms and the potential use for clinical diagnosis and therapies aimed at blocking spreading depolarization and boosting vasodilation to treat neurological disease.

The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease

l-Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) and mediates its actions via activation of both ionotropic and metabotropic receptor families. The development of selective ligands, including competitive agonists and antagonists and positive and negative allosteric modulators, has enabled investigation of the functional roles of glutamate receptor family members. In this review we describe the subunit structure and composition of the ionotropic and metabotropic glutamate receptors and discuss their pharmacology, particularly with respect to selective tools useful for investigation of their function in the CNS. A large number of ligands are now available that are selective either for glutamate receptor subfamilies or for particular receptor subtypes. Such ligands have enabled considerable advances in the elucidation of the physiological and pathophysiological roles of receptor family members. Furthermore, efficacy in animal models of neurological and psychiatric disorders has supported the progression of several glutamatergic ligands into clinical studies. These include ionotropic glutamate receptor antagonists, which have entered clinical trials for disorders including epilepsy and ischaemic stroke, α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor positive allosteric modulators which are under evaluation as cognitive enhancers, and metabotropic glutamate receptor 2 (mGluR2) agonists which are undergoing clinical evaluation as anxiolytics. Furthermore, preclinical studies have illustrated therapeutic potential for ligands selective for other receptor subtypes in various disorders. These include mGluR1 antagonists in pain, mGluR5 antagonists in anxiety, pain and drug abuse and mGluR5 positive allosteric modulators in schizophrenia. Selective pharmacological tools have enabled the study of glutamate receptors. However, pharmacological coverage of the family is incomplete and considerable scope remains for the development of novel ligands, particularly those with in vivo utility, and for the their use together with existing tools for the further investigation of the roles of receptor family members in CNS function and as potentially novel therapeutics.

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Ionotropic and metabotropic glutamate receptor structure and pharmacology

At-a-glance The kynurenine pathway is the main pathway for tryptophan metabolism. It generates compounds that can modulate activity at glutamate receptors and possibly nicotinic receptors, in addition to some as-yet-unidentified sites. The pathway is in a unique position to regulate other aspects of the metabolism of tryptophan to neuroactive compounds, and also seems to be a key factor in the communication between the nervous and immune systems. It also has potentially important roles in the regulation of cell proliferation and tissue function in the periphery. As a result, the pathway presents a multitude of potential sites for drug discovery in neuroscience, oncology and visceral pathology.

Endogenous kynurenines as targets for drug discovery and development

Ischemic stroke is a devastating disease with a complex pathophysiology. Animal modeling of ischemic stroke serves as an indispensable tool first to investigate mechanisms of ischemic cerebral injury, secondly to develop novel antiischemic regimens. Most of the stroke models are carried on rodents. Each model has its particular strengths and weaknesses. Mimicking all aspects of human stroke in one animal model is not possible since ischemic stroke is itself a very heterogeneous disorder. Experimental ischemic stroke models contribute to our understanding of the events occurring in ischemic and reperfused brain. Major approaches developed to treat acute ischemic stroke fall into two categories, thrombolysis and neuroprotection. Trials aimed to evaluate effectiveness of recombinant tissue-type plasminogen activator in longer time windows with finer selection of patients based on magnetic resonance imaging tools and trials of novel recanalization methods are ongoing. Despite the failure of most neuroprotective drugs during the last two decades, there are good chances to soon have effective neuroprotectives with the help of improved preclinical testing and clinical trial design. In this article, we focus on various rodent animal models, pathogenic mechanisms, and promising therapeutic approaches of ischemic stroke.

Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia.

This study investigated the role of spontaneous and induced spreading depression (SD) on the evolution of focal ischemia in vivo. We induced focal ischemia in 12 rats using the middle cerebral artery suture occlusion (MCAO) method. Chemical stimulation of nonischemic ipsilateral cortex by potassium chloride application (KCl group; n = 7) and saline (NaCl group; n = 5) was performed at 15, 30, 45, and 60 minutes following MCAO, and SD was detected electrophysiologically. Ischemic lesion volumes assessed over 15-minute intervals, evaluated by continuous apparent diffusion coefficient (ADC) of water mapping, demonstrated that the ischemic region increased significantly during 15-minute time epochs with a single SD episode (36.5 +/- 12.9 mm3, mean +/- SD) or multiple SD episodes (39.8 +/- 22.3) compared with those without SD (13.9 +/- 11.5) (p = 0.0009). Infarct volume at postmortem 24 hours after MCAO was significantly larger in the KCl group, with more total SDs (237.8 +/- 13.8) than the NaCl group (190.5 +/- 12.6) (p = 0.0001). This study demonstrates that ischemia-related and induced SDs increase significantly ischemic lesion volume in vivo, supporting the hypothesis for a causative role of SD in extending focal ischemic injury.

The role of spreading depression in focal ischemia evaluated by diffusion mapping.

A method is demonstrated for the noninvasive detection and study of spreading cortical depression. Spreading depression (SD) was elicited in rats by topical application of potassium chloride to the exposed cortex. The apparent diffusion coefficient (Dapp) of water in a region of the cortex, measured using a PFG-NMR spin echo sequence with an observation time of 40 ms, declines 35% within 30 s and recovers to the normal value within the next 30 s. The region of decreased Dapp was shown to be 2 mm in size and to move in the cortex, away from the point of application, with a uniform velocity of 3.3 +/- 0.5 mm/min. The behavior of the affected region is consistent with other reports of the behavior of SD as monitored by electrophysiological means. The technique can be implemented on currently available MRI equipment and makes possible the noninvasive study of SD in animal models of neurological disorders, their therapeutic intervention, and possibly the study of SD in humans.

Spreading waves of decreased diffusion coefficient after cortical stimulation in the rat brain.

Background and Purpose The aim of this study was to determine the effects of temporary severe hypoglycemia on the apparent diffusion coefficient (ADC) acquired by diffusion-weighted MRI of brain water with the use of serial multislice ADC mapping in rats. Severe hypoglycemia reduces the extracellular space volume, as does ischemia. Demonstrating a reduction of ADC with hypoglycemia should increase our understanding of the mechanisms underlying ADC changes in ischemia and other conditions. Methods Fasted rats were given regular insulin (15 IU/kg IP). Rats were subjected to 15 minutes (n=5) and 50 minutes (n=5) of temporary severe hypoglycemia, causing a transiently isoelectric electroencephalogram (EEG). ADC mapping was performed every 30 seconds beginning at the onset of isoelectricity for 8.5 minutes. ADC maps were also obtained later during the isoelectric EEG period and 10, 20, 30, and 40 minutes after glucose infusion. Control images were obtained from a separate group of animals suffering cardiac arr...

Severe Transient Hypoglycemia Causes Reversible Change in the Apparent Diffusion Coefficient of Water

Background and Purpose The glycine site on the N-methyl-d-aspartate (NMDA) receptor complex offers a therapeutic target for acute focal ischemia, potentially devoid of most side effects associated with competitive and noncompetitive NMDA antagonists. Methods A novel glycine receptor antagonist, ZD9379, was studied in 70 Sprague-Dawley rats using the suture occlusion model of permanent middle cerebral artery occlusion (MCAO). In the first experiment, 20 rats received an initial bolus of vehicle or 10 mg/kg ZD9379 (n=10 in each group) 30 minutes after MCAO, followed by a continuous infusion of the same dose per hour for 4 hours. Diffusion-weighted MRI with echo-planar acquisition was used to generate maps of the apparent diffusion coefficient (ADC) of water. In a second experiment, 50 rats were assigned to five groups: vehicle and 10, 5, 2.5, and 1 mg/kg ZD9379 (n=10 in each group) with the same dosing protocol but no imaging. In both experiments, infarct volume was determined by 2,3,5-triphenyltetrazolium ...

James E. Formato

Papers

The role of spreading depression in focal ischemia evaluated by diffusion mapping.

Spreading waves of decreased diffusion coefficient after cortical stimulation in the rat brain.

Severe Transient Hypoglycemia Causes Reversible Change in the Apparent Diffusion Coefficient of Water

Glycine Site Antagonist Attenuates Infarct Size in Experimental Focal Ischemia Postmortem and Diffusion Mapping Studies