1. Histopathological and Radiological Validation of Continuous Wave (CW) Near Infrared Spectroscopy (NIRS) Recordings During Cerebral Intravascular Manipulations Daniel C. Lee, M.D. Cardiothoracic Surgery State University of New York Downstate Medical Center

2. Introduction Prevalent neurological complications associated with surgery Neurocognitive impairment in 50% of patients after coronary bypass procedure - declined quality of life 600,000 open heart procedures/year at $100,000 hospital cost per case Neuroprotection pertinent in improving quality of life and medical economics

3. Introduction Currently available intraoperative cerebral monitoring inadequate –Intracranial pressure, regional cerebral blood flow, jugular venous oxygen saturation monitoring – invasive –Sensitivity of transcranial Doppler limited by bony cranium –EEG requires trained neurologist, does not measure tissue oxygenation –Low-density NIRS oximetry neglects heterogeneity of cerebral perfusion

4. Introduction Clinical need of intraoperative cerebral monitoring tool –Real-time –Temporal and spatial specificity –Identify ischemia/hypoperfusion at a reversible stage to allow countermeasures ? NIRS tomography Controlled cerebral ischemia studies needed for validation

5. Study Aim Validate capability of NIRS tomography in cerebral monitoring using a non-human primate (NHP: Bonnet Macaque) model of acute cerebral ischemia

6. Methods NIRS Imager: Continuous-wave (CW), f-NIRS 3D Diffuse Optical Tomography (3D-DOT) Two wavelengths (760 and 830 nm) Time-series imaging: 8 Hz image framing rate 270-channel array (30 detector optodes, 9 coupled with light sources)

7. Methods Stroke model  2-3 hour unilateral microcatheter occlusion of the middle cerebral artery (MCA) of anesthetized NHP Continuous recordings of Hb total, Hb oxy, Hb deoxy concentration from each channel of the array –4×5 cm 2 area in the frontal-parietal region of the exposed monkey skull –3D image reconstruction Post-procedure MRI and post-mortem histopathology of brain performed

8. Monitored Events of Interest Intra-arterial Verapamil (vasodilator) injection Intra-arterial contrast (Omnipaque TM ) injection –Mimicking transient ischemia Localized acute cerebral ischemia Subarachnoid hemorrhage (SAH)

9. Lateral Digital Subtraction Angiogram Before Microcatheter Occlusion Normal cerebral vascular anatomy and the circle of Willis (red circle). before right MCA occlusion CCA–common carotid artery ECA – external carotid artery ICA –internal carotid artery MCA – middle cerebral artery ACA – anterior cerebral artery Elements of the fNIRS optode array mounted to the animal’s cranium also are visible. Right MCA Azygous ACA Left MCA Right ICA Right CCA Right ECA fNIRS array Optical fibers

10. Anteroposterior Digital Substraction Angiogram Image confirmation of occlusion of the right MCA Intra-arterial ICA catheter occluding right MCA fNIRS optode array Lateral Fluoroscopy

11. Right Hemisphere NIRS monitoring Optodes directly over confirmed stroke site Begin Occlusion End Occlusion

12. Left Hemisphere NIRS monitoring: optodes positioned over contralateral side Begin occlusion End occlusion

13. Lateral Digital Subtraction Angiogram Demonstrating Subarachnoid Hemorrhage: Internal Carotid Artery Perforation

14. Insertion of catheter in the right ICA Catheter moved from right ICA to the left ICA Contrast injection Beginning of subarachnoid hemorrhage Begin Left ICA/MCA occlusion End Left ICA/MCA occlusion Left Hemisphere NIRS monitoring: optodes positioned over site of acute cerebral ischemia

15. Verapamil injections Contrast injections Start of subarachnoid hemorrhage Begin Left ICA/MCA occlusion Insertion of catheter into the right ICA Catheter moved from the right ICA to the left CA End of left ICA/MCA occlusion Right Hemisphere NIRS monitoring optodes positioned over contralateral side

16. Right MCA Verapamil injection 3D DOT image reconstruction Before After Axial section Right Sagittal section

17. Right MCA Contrast injection 3D DOT image reconstruction Before After Animation Axial section Right Sagittal section

18. Acute Cerebral Ischemia of the right (NHP-1) and left (NHP-2) hemispheres Before [NHP-1] After Before [NHP-2] After Axial section Coronal section

19. Diffuse Bilateral Subarachnoid Hemorrhage (SAH) Before [NHP-1] After Before [NHP-2] After Axial section Coronal section

20. Diffuse Bilateral Subarachnoid Hemorrhage (SAH) Before After Animation Axial section

21. Coronal FLAIR MRI sequences (NHP-2) R L LR Confirmation of: 1) ischemia (dotted circle) in the left temporal and inferior frontal lobe; 2) the presence of SAH (arrow points).

22. Gross pathology and histologic findings for NHP-1. A) SAH present in the sulci. B) Hemorrhage in subarachnoid space (>) and vasculature ( ). C, D) Vacuolization of neuropil (  ) and shrunken neurons with hypereosinophilic cytoplasm (◄) indicate acute ischemic damage.

23. Gross pathology and histologic findings for NHP-2. A) Subarachnoid hemorrhage over the brainstem and Circle of Willis. B) Subarachnoid hemorrhage in the sulci. C) Photomicrograph of the hemorrhage in the subarachnoid space ( >)

24. Conclusions NIRS Tomography accurately captured cerebral ischemia, vasodilatation, and hemorrhage in an experimental primate model in real time, with spatial and temporal specificity Utilization for cerebral monitoring in a clinical setting (intraoperative, trauma/critical care) may be promising

25. Acknowledgments Surgery –Tigran Gevorgyan, John Kral Pathology –Douglas Pfeil, Harry Graber, Yong Xu, Jenny Libien, Randall Barbour Interventional Neuroradiology –Sundeep Mangla Neurology –Frank Barone Anesthesia –Jean Charchaflieh This research was supported by the National Institutes of Health under Grants nos. R21NS067278, R42NS050007 and R44NS049734; by the Defense Advanced Research Projects Agency (DARPA) project N66001-10-C-2008; and by New York State Department of Health ECRIP Grants to Randall Barbour and Daniel Lee.