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.

/pdf/diffusion-tensor-imaging-concepts-and-applications-40utq0zjun.pdf

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

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.

Cortical spreading depolarization (CSD) is an electrophysiologic phenomenon found mostly in the setting of neurologic injury resulting in the disturbance of ion homeostasis and leading to changes in the local vascular response. The bioelectric etiology of CSD shares similarities to those in epileptic disorders, yet the relationship between seizures and CSD is unclear, with several studies observing cortical depression before, during, and after seizure activity, thus obscuring our understanding of whether CSD activity potentiates or limits seizures and vice versa. Cortical sampling has exhibited how the redistribution of ion concentrations in the intra- and extracellular environments interplay between the excitation of seizures and the electrical depression of CSD. Modeling of both environments has suggested that CSD synchronizes the affected tissue, creating a favorable environment for seizure activity; however, other studies have demonstrated the opposite: epileptiform activity initiating waves of CSD. Further studies have underscored the role of the vascular response and subsequent ischemia in CSD that contributes to epileptogenesis. Investigations in migraine, traumatic brain injury, and other neurologic injuries suggest that several drugs may target CSD. Manipulations in the occurrence and nature of CSD can potentially alter the threshold for seizure activity, and perhaps minimize immediate and long-term sequelae associated with epilepsy.

/pdf/interplay-between-cortical-spreading-depolarization-and-48r5csh4hz.pdf

Interplay between Cortical Spreading Depolarization and Seizures

Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2010.191

Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury:

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.

Using echo planar diffusion-weighted magnetic resonance imaging, we measured three-dimensional changes in the apparent diffusion coefficient (ADC) of water in eight contiguous coronal slices, encompassing the entire rat brain, before and after local cortical stimulation. We applied chemical (potassium chloride application; n = 6) and mechanical (needle stab; n = 4) stimulations to the right posterior parietal rat cortex. In all animals in which potassium chloride or the needle stab was applied, a region of decreased ADC values to a mean of 0.45 ± 0.03 × 10−5cm2/s occurred. These reduced ADC levels appeared in the posterior parietal cortex within 1 min after cortical stimulation and the change recovered within 1 min. Then a ripple-like movement of similar changes developed across the unilateral cortex. This change was localized to the cortex and no significant ADC changes occurred in subcortical structures. The propagating speed of this movement was 3.4 ± 0.5 mm/min. These findings are compatible with spre...

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1995.23

Yasuhiro Hasegawa

Papers

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

Spreading Waves of a Reduced Diffusion Coefficient of Water in Normal and Ischemic Rat Brain