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(Stroke. 2008;39:439.)
© 2008 American Heart Association, Inc.

Original Contributions

Functional MRI of Delayed Chronic Lithium Treatment in Rat Focal Cerebral Ischemia

Young R. Kim, PhD; Maurits P.A. van Meer, MD; Emiri Tejima, MD, PhD; Yoshi Murata, MD; Joseph B. Mandeville, PhD; George Dai, PhD; De-Maw Chuang, PhD; Bruce R. Rosen, MD, PhD Eng H. Lo, PhD

From the Athinoula Martinos Center for Biomedical Imaging/Massachusetts General Hospital (Y.R.K., M.P.A.v.M., J.B.M., G.D., B.R.R.), Charleston, Mass; Neuroprotection Research Laboratory/Massachusetts General Hospital (Y.R.K., M.P.A.v.M., E.T., Y.M., E.H.L.), Charlestown, Mass; Image Sciences Institute (M.P.A.v.M.), University Medical Center Utrecht, Utrecht, The Netherlands; and the Molecular Neurobiology Section (D.M.C.), National Institute of Mental Health, National Institutes of Health, Bethesda, Md.

Correspondence to Young R. Kim, PhD, Athinoula Martinos Center for Biomedical Imaging/Massachusetts General Hospital, 149 13th Street, Room 2301, Charlestown, MA 02129. E-mail spmn{at}nmr.mgh.harvard.edu

Background and Purpose— The use of lithium as a neuroprotective agent has been demonstrated using various models in which improvements in infarct size, DNA damage, and neurological function were reported. We further investigated neurohemodynamic aspects of the treatment-associated recovery by assessing the therapeutic efficacy of delayed chronic lithium treatment using functional MRI.

Methods— Ipsilesional functional MRI activations in the somatosensory cortex, acquired 2 weeks after the 90-minute transient middle cerebral artery occlusion, were compared between lithium- and saline-treated rats. Specifically, MRI signal changes based on blood oxygenation level dependence and functional cerebral blood volume responses were examined using electrical stimulation of forelimbs. Additional immunohistochemical assays were performed.

Results— The ratio of ipsilesional to contralesional blood oxygenation level dependence response magnitudes significantly improved with lithium treatments. In contrast, the increase of the functional cerebral blood volume response magnitude ratio was not statistically significant. Nonetheless, the lithium treatment induced significant enhancements of total functional MRI activation (defined as a product of activation volume and response magnitude) for both blood oxygenation level dependence and functional cerebral blood volume methods. Increased cerebral blood volume in periinfarct tissues suggests a possible stroke-induced vascular transformation in both saline- and lithium-treated rats; however, other MRI-derived vascular parameters (vascular size index and microvascular volume) and immunohistochemical staining (CD31, glia fibrillary-associated protein, and matrix metalloproteinase-9) may imply that the neoformation of vasculature was differently affected by the lithium treatment.

Conclusions— The delayed chronic lithium treatment enhanced the blood oxygenation level dependence functional MRI response magnitude in the absence of neurological improvement and influenced vascular formation in poststroke animal models.

Key Words: BOLD • CBV • fMRI • focal ischemia • neuroprotective agents • rat • treatment