Low-intensity (400 mW/cm2, 500 kHz) pulsed transcranial ultrasound preconditioning may mitigate focal cerebral ischemia in rats

BACKGROUND Preconditioning methods, which could increase tolerance of brain to subsequent ischemic injuries with a small dose of non-injury stimuli, have gained attention. Capitalizing on noninvasiveness and safety of ultrasound modality, the pulsed transcranial ultrasound stimulation (pTUS) approach may provide a novel treatment for patients with high risk of stroke. OBJECTIVE This study's goal was to investigate whether the risk of stroke could be minimized or eliminated by prior exposure to low-intensity, pulsed transcranial ultrasound stimulation (pTUS). METHODS Rats were randomly assigned to control (n = 12) and pTUS preconditioning (pTUS-PC) groups (n = 14). The animals in pTUS-PC group were exposed to transcranial ultrasound stimulation before the induction of photothrombotic stroke, whereas control animals were handled identically but without the ultrasound stimulation. Cerebral blood flow was monitored using laser speckle imaging in both groups during stroke induction, as well as 24 and 48 h after stroke, respectively. Also, infarct volumes and edema were measured at 48 h after stroke. RESULTS pTUS-PC rats had smaller ischemic areas during stroke induction, and 24 and 48 h after the stroke, and smaller infarct volume (1.770 ± 0.169%) than the controls (3.215 ± 0.401%) (p < 0.01). Moreover, the pTUS-PC group experienced lower volume of brain edema than the control group (pTUS-PC rats: 6.658 ± 1.183%; control rats: 12.48 ± 1.386%, p < 0.01). CONCLUSION These results support the hypothesis that transcranial ultrasound stimulation applied before photothrombosis could provide neuroprotection by increasing the brain's tolerance to subsequently induced focal ischemic injury.

[1]  J D Briers,et al.  Laser speckle contrast analysis (LASCA): a nonscanning, full-field technique for monitoring capillary blood flow. , 1996, Journal of biomedical optics.

[2]  H. C. Han,et al.  Anti-inflammatory effect of low intensity ultrasound (LIUS) on complete Freund's adjuvant-induced arthritis synovium. , 2012, Osteoarthritis and cartilage.

[3]  K. Kitagawa,et al.  Metabolic Downregulation: A Key to Successful Neuroprotection? , 2008, Stroke.

[4]  H. Diener,et al.  Respiratory Chain Inhibition Induces Tolerance to Focal Cerebral Ischemia , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  A. Williams,et al.  Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans , 2014, Nature Neuroscience.

[6]  J. Greenberg,et al.  The effect of right vagus nerve stimulation on focal cerebral ischemia: an experimental study in the rat , 2012, Brain Stimulation.

[7]  S. Shoham,et al.  Cell-Type-Selective Effects of Intramembrane Cavitation as a Unifying Theoretical Framework for Ultrasonic Neuromodulation123 , 2016, eNeuro.

[8]  M. Endres,et al.  Atorvastatin Upregulates Type III Nitric Oxide Synthase in Thrombocytes, Decreases Platelet Activation, and Protects From Cerebral Ischemia in Normocholesterolemic Mice , 2000, Stroke.

[9]  P. A. Snegur,et al.  Anti-inflammatory action of therapeutic and low-frequency ultrasound on the inflammatory process model on rats , 2013 .

[10]  W. Harvey,et al.  The anti-inflammatory effects of dexamethasone and therapeutic ultrasound in oral surgery. , 1985, The British journal of oral & maxillofacial surgery.

[11]  John H. Zhang,et al.  Changes in Brain Swelling and Infarction Volume over Four Days After Hypoxia Ischemia in Neonatal Rats. , 2016, Acta neurochirurgica. Supplement.

[12]  Byoung-Kyong Min,et al.  Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity , 2011, BMC Neuroscience.

[13]  A. Shah,et al.  Nitric Oxide Mediates Cerebral Ischemic Tolerance in a Neonatal Rat Model of Hypoxic Preconditioning , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[14]  Antoine M. Hakim.  Ischemic penumbra , 1998, Neurology.

[15]  D. Boas,et al.  Laser speckle contrast imaging in biomedical optics. , 2010, Journal of biomedical optics.

[16]  John H. Zhang,et al.  Correcting for Brain Swelling’s Effects on Infarct Volume Calculation After Middle Cerebral Artery Occlusion in Rats , 2015, Translational Stroke Research.

[17]  M. Stenzel-Poore,et al.  Toll-like receptors and ischemic brain injury. , 2014, Journal of neuropathology and experimental neurology.

[18]  R. Busto,et al.  Induction of reproducible brain infarction by photochemically initiated thrombosis , 1985, Annals of neurology.

[19]  A. D. Ammar,et al.  The Incidence of Ischemic Stroke versus Intracerebral Hemorrhage after Carotid Endarterectomy: A Review of 2452 Cases , 2005, Annals of vascular surgery.

[20]  Jaykaran Charan,et al.  How to calculate sample size in animal studies? , 2013, Journal of pharmacology & pharmacotherapeutics.

[21]  H Zhao,et al.  Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation , 2015, Scientific Reports.

[22]  J. Loscalzo.  Nitric oxide insufficiency, platelet activation, and arterial thrombosis. , 2001, Circulation research.

[23]  S. Tillery,et al.  Transcranial Pulsed Ultrasound Stimulates Intact Brain Circuits , 2010, Neuron.

[24]  Hongyang Lu,et al.  Pulsed Transcranial Ultrasound Stimulation Immediately After The Ischemic Brain Injury is Neuroprotective , 2015, IEEE Transactions on Biomedical Engineering.

[25]  J. Gidday.  Cerebral preconditioning and ischaemic tolerance , 2006, Nature Reviews Neuroscience.

[26]  Brian N. Pasley,et al.  Analysis of oxygen metabolism implies a neural origin for the negative BOLD response in human visual cortex , 2007, NeuroImage.

[27]  T. Sick,et al.  Rapid Preconditioning Protects Rats against Ischemic Neuronal Damage after 3 but Not 7 Days of Reperfusion following Global Cerebral Ischemia , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[28]  A. Luft,et al.  3-Nitropropionic Acid-Induced Ischemia Tolerance in the Rat Brain is Mediated by Reduced Metabolic Activity and Cerebral Blood Flow , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[29]  R. Kelley.  Stroke in the postoperative period. , 2001, The Medical clinics of North America.

[30]  Guy M McKhann,et al.  Stroke and encephalopathy after cardiac surgery: an update. , 2006, Stroke.

[31]  Joseph P Desimone,et al.  Perioperative stroke and long-term survival after coronary bypass graft surgery. , 2005, The Annals of thoracic surgery.

[32]  Liping Huang,et al.  Ultrasound prevents renal ischemia-reperfusion injury by stimulating the splenic cholinergic anti-inflammatory pathway. , 2013, Journal of the American Society of Nephrology : JASN.

[33]  R. Traystman,et al.  Inhalational anesthetics as preconditioning agents in ischemic brain. , 2008, Current opinion in pharmacology.

[34]  Andreas R. Luft,et al.  Imaging the development of an ischemic core following photochemically induced cortical infarction in rats using Laser Speckle Contrast Analysis (LASCA) , 2006, NeuroImage.

[35]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[36]  Jong-Hwan Lee,et al.  Focused ultrasound modulates region-specific brain activity , 2011, NeuroImage.

[37]  E. Picano,et al.  Effects of diagnostic cardiac ultrasound on oxygen free radical production and microvascular perfusion during ischemia reperfusion. , 2004, Ultrasound in medicine & biology.

[38]  H. Nawashiro,et al.  TNF-α Pretreatment Induces Protective Effects against Focal Cerebral Ischemia in Mice , 1997 .

[39]  A. Hakim,et al.  Cortical Spreading Depression Protects against Subsequent Focal Cerebral Ischemia in Rats , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[40]  M. Dereski,et al.  Transient hyperthermia protects against subsequent forebrain ischemic cell damage in the rat , 1989, Neurology.

[41]  S. Kobayashi,et al.  Journal of Cerebral Blood Flow and Metabolism Spreading Depression Induces Tolerance of Cortical Neurons to Ischemia in Rat Brain , 2022 .

[42]  Jürgen Götz,et al.  Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model , 2015, Science Translational Medicine.

[43]  S. L. Stevens,et al.  Reprogramming the Response to Stroke by Preconditioning , 2014, Stroke.

[44]  Zhi-ming Yang,et al.  Angiogenesis effect of therapeutic ultrasound on ischemic hind limb in mice. , 2014, American journal of translational research.

[45]  S. Kaul,et al.  Ultrasound stimulates formation and release of vasoactive compounds in brain endothelial cells. , 2015, American journal of physiology. Heart and circulatory physiology.

[46]  W. Balfour,et al.  PROLONGED ANOXIC SURVIVAL DUE TO ANOXIA PRE-EXPOSURE: BRAIN ATP, LACTATE, AND PYRUVATE. , 1964, The American journal of physiology.

[47]  Shanbao Tong,et al.  Predicting the ischemic infarct volume at the first minute after occlusion in rodent stroke model by laser speckle imaging of cerebral blood flow , 2013, Journal of biomedical optics.

[48]  Joel H Greenberg,et al.  Cortical Spreading Depression Causes a Long-Lasting Decrease in Cerebral Blood Flow and Induces Tolerance to Permanent Focal Ischemia in Rat Brain , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[49]  K. Plaschke,et al.  Permanent cerebral hypoperfusion: `preconditioning-like' effects on rat energy metabolism towards acute systemic hypotension , 2000, Brain Research.

[50]  S. Tong,et al.  Intraoperative cerebral blood flow imaging of rodents. , 2014, The Review of scientific instruments.

[51]  S. Moncada,et al.  ENDOGENOUS NITRIC OXIDE INHIBITS HUMAN PLATELET ADHESION TO VASCULAR ENDOTHELIUM , 1987, The Lancet.

[52]  U. Dirnagl,et al.  Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use , 2009, The Lancet Neurology.

[53]  H. Hasegawa,et al.  Low-Intensity Pulsed Ultrasound Induces Angiogenesis and Ameliorates Left Ventricular Dysfunction in a Porcine Model of Chronic Myocardial Ischemia , 2012, PloS one.