Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations.
Peri-infarct depolarizations (PIDs) are seemingly spontaneous spreading depression-like waves that negatively impact tissue outcome in both experimental and human stroke. Factors triggering PIDs are unknown. Here, we show that somatosensory activation of peri-infarct cortex triggers PIDs when the activated cortex is within a critical range of ischemia. We show that the mechanism involves increased oxygen utilization within the activated cortex, worsening the supply-demand mismatch. We support the concept by clinical data showing that mismatch predisposes stroke patients to PIDs as well. Conversely, transient worsening of mismatch by episodic hypoxemia or hypotension also reproducibly triggers PIDs. Therefore, PIDs are triggered upon supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. Based on the data, we propose that minimizing sensory stimulation and hypoxic or hypotensive transients in stroke and brain injury would reduce PID incidence and their adverse impact on outcome.
Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA; Department of Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Center for Stroke Research, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Daniel
D
von Bornstädt
Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA; Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, the Netherlands.
Thijs
T
Houben
Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA.
Jessica L
JL
Seidel
Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA.
Yi
Y
Zheng
Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA; Department of Pharmacology, Gazi University Faculty of Medicine, Besevler Campus, 06560 Ankara, Turkey.
Ergin
E
Dilekoz
Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA.
Tao
T
Qin
Department of Neurosurgery, Charité - Universitätsmedizin Augustenburger Platz 1, 13353 Berlin, Germany; Center for Stroke Research, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Nora
N
Sandow
Optics Division, MHG/MIT/HMS Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA.
Sreekanth
S
Kura
Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA.
Katharina
K
Eikermann-Haerter
Department of Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Center for Stroke Research, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE), Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; German Centre for Cardiovascular Research (DZHK), Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Matthias
M
Endres
Optics Division, MHG/MIT/HMS Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA.
David A
DA
Boas
Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA.
Michael A
MA
Moskowitz
Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA.
Eng H
EH
Lo
Department of Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Center for Stroke Research, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Jens P
JP
Dreier
Department of Neurosurgery, Charité - Universitätsmedizin Augustenburger Platz 1, 13353 Berlin, Germany; Center for Stroke Research, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Johannes
J
Woitzik
Optics Division, MHG/MIT/HMS Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA.
Sava
S
Sakadžić
Neurovascular Research Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, 6408, Charlestown, MA 02129, USA; Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. Electronic address: cayata@partners.org.
Cenk
C
Ayata
D000328:Adult; D000368:Aged; D000818:Animals; D002544:Cerebral Infarction / Q000378:metabolism* / Q000473:pathology; D013181:Cortical Spreading Depression / Q000502:physiology*; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D013003:Somatosensory Cortex / Q000378:metabolism* / Q000473:pathology