Complex models for the complexity of cerebral ischemia

*Corresponding Author:

David S. Liebeskind, M.D
UCLA Stroke Center, 710 Westwood Plaza, Los Angeles, CA 90095
Tel: (310) 794-6379
Fax: (310) 267-2063
E-mail: davidliebeskind@yahoo.com

Abstract

The recent series of articles in the journal devoted to building a dynamic network model of cerebral ischemia provides a refreshing perspective in the field of acute stroke. Several points raised in these articles merit further commentary.

Keywords

Stroke, ischemia, model, collateral circulation, hemodynamics

Letters to the editor

The recent series of articles in the journal devoted to building a dynamic network model of cerebral ische-mia provides a refreshing perspective in the field of acute stroke.(DeGracia 2010a; DeGracia 2010b; DeGracia 2010c; DeGracia 2010d) The complexity of this model may be so advanced that few may appre-ciate the details yet this conceptual approach is truly innovative, providing a great example of what may be currently lacking in the field. The author takes an in-trospective viewpoint on the chronicle of colossal ef-forts that have aimed to extend effective therapies for acute ischemic stroke. Altogether the articles evoke a key question on progress in translating stroke re-search to the bedside: Are the answers to combating cerebral ischemia buried amidst the tremendous data amassed in prior studies and trials to date, yet we have failed to recognize the solutions?

Several points raised in these articles merit further commentary. The author daringly, yet appropriately questions the concepts of the ischemic cascade sug-gesting that this approach may be misleading and overly simplistic. The pivotal role of collaterals and hemodynamics as a primary stress response involv-ing various segments of the cerebral circulation are duly accentuated despite little attention to date.(Liebeskind 2003) The concept of vasoprotec-tion and endothelial events is raised, underscoring the impact of ischemia on the entire neurovascular unit beyond neuroprotection. This point should prompt researchers to avoid prior errors in the past where vascular processes and targets such as endo-thelium have been ignored due to the overwhelming focus on the tissue consequences of ischemia at the neuronal and glial level alone. The proposed integral concept of ischemia may be difficult to follow, but there are clear correlates already recognized such as the compensatory role of collaterals. Collateral circulation is a key element of the vasoprotective stress response operating at the tissue level with influences on numerous facets at the cellular level. This sug-gested multiscale nature of ischemia overcomes the exclusive focus of the ischemic cascade concept largely limited to intracellular molecular events. A li-near concept of time is brain is also appropriately questioned, noting that such a model is implausible from a functional perspective.(Liebeskind 2009) In animals and man, it is well established that arterial occlusion rarely results in the same decrement of downstream perfusion and ischemic severity. The time course of ischemic evolution is also known to be highly variable. This point is important when one con-siders use of thresholds in imaging analyses of stroke. Heterogeneity in ischemia and perfusion abnormali-ties and variable topography remain unaccounted in most stroke imaging studies. The dynamic concept proposed in these articles also challenges the use of cerebral blood flow alone, as the sole perfusion pa-rameter of interest. The evolution of ischemia due to hemodynamics driven by venous steal and other me-chanisms stresses the potential value of multipara-metric perfusion analyses.(Pranevicius and Pranevi-cius 2002) Multiparametric imaging analyses may also reveal regional gradients or variation in stages of ischemia, providing estimates of potential vulnerabili-ty to lesion expansion. Such embedded temporal and spatial data are important as they provide the basis for understanding a variety of post-ischemic state spaces and potential translational therapies for acute to chronic ischemia. In sum, stroke imaging holds the potential to test the innovative concepts advanced in these articles.(DeGracia 2010a; DeGracia 2010b; DeGracia 2010c; DeGracia 2010d)

The complexity of cerebral ischemia will undoubtedly require use of complex models and detailed imaging approaches to disclose potential breakthroughs. The articles are solely the first steps in re-examining some entrenched and unfortunately unfruitful con-cepts in stroke. The onus now rests with other re-searchers to test such complex models, yet it is clear-ly time to move beyond simplistic models of a se-quential cascade, rigid thresholds and linear time course of ischemia in the brain.

Acknowledgement

This work has been supported by funding from NIH-NINDS Awards K23 NS054084 and P50 NS044378. There are no other disclosures relevant to this work.

Conflict of interest

None

References

1. DeGracia DJ. (2010a) Towards a dynamical network view of brain ischemia and relierfusion. liart I: background and lireliminaries. Journal of Exlierimental Stroke &amli; Translational Medicine 3:59-71
2. DeGracia DJ. (2010b) Towards a dynamical network view of brain ischemia and relierfusion. liart II: a liost-ischemic neuronal state sliace. Journal of Exlierimen-tal Stroke &amli; Translational Medicine 3:72-89
3. DeGracia DJ. (2010c) Towards a dynamical network view of brain ischemia and relierfusion. liart III: theralieutic imlilications. Journal of Exlierimental Stroke &amli; Transla-tional Medicine 3:90-103
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