as a “Failure of Function” as a Tool for Delirium Research: • An acute state of confusion that affects cognitive functions – Attention, Declarative Memory, Karin Schon, Ph.D. Perception, Executive Function Assistant Professor Department of Anatomy & Neurobiology Boston University School of Medicine [email protected]

Functional Neuroimaggging critical to elucidate acute functional brain changes associated with delirium

Image source: http://upload.wikimedia.org/wikipedia/en/f/f4/The_Scream.jpg

Overview

• Structural Neuroimaging (Charles Guttmann) • Functional Neuroimaging Methods: Brief discussion of invasive and non-invasive methods: – Positron Emission Tomoggpy(raphy(PET ) – Single Photon Emission Computed Tomography (SPECT) – Arterial Spin Labeling (ASL) In-depth discussion of non-invasive methods: – Cognitive fMRI (task-related) – Resting-state fMRI O()Other techniques (not discussed): – Magnetoencephalography (MEG) – (EEG) – Transcrani alM l Magne tic Stimu la tion (TMS)

Image source: Blow (2009) Nature Image source: Huettel et al. (2008) Functional Magnetic Resonance Imaging. 2nd Edition.

Single Photon Emission Computed SPECT Tomography (SPECT) and • N = 1 published study with N > 1 subjects Positron Emission Tomography (PET) with delirium • To examine regional cerebral blood flow (rCBF), metabolism, • Functional neuropharmacology neuroimaging during and after delirium • Invasive: need for radioactive tracer – PET: Positron emitting isotopes (e.g. 15O for blood flow) • Qualitative analysis – SPECT: J-emitting isotopes (e.g. 99mTc for blood flow) • Statistical Parametric • Examination of neurotransmitters Mapping (SPM) – e.g. 18F-dopa PET • Poor temporal and spatial resolution • Functional neuroimaging during and bef/ffore/after delirium • Decreased CBF in left inferior frontal, right temporal, right occipital, and pontine regions in 11 of 22 delirium patients • SPM: ppgpppgerfusion changes in parietal areas in 3 or 6 participants during compared to after delirium

Fong et al. (2006) J Gerontol Ser A–Biol Sci Med Sci (Inouye) PET HC Arterial Sppg()ggin Labeling(ASL) MR Imaging •[11C]Pittsburgh Compound-B (PiB) • What is it good for? AD imaging to visualize - Relative Cerebral Blood Flow (rCBF) amylidbtloid beta (AE) • ASL characteristics: deposition in - Requires specialized pulse sequences (“EPISTAR”, “FAIR”) Alzheimer’s disease HC - Noninvasive! • In-vivo amylidiloid imag ing - Arterial blood water is magnetically labeled • PiB imaging not yet AD 1. Tag inflowing arterial blood done in delirium by magnetic inversion 2. Acquire the tag image in slice • Can also be used to of interest examine 3. Repeat image without tag – glucose metabolism 4. Acquire the control image (FDG-PET) – 15 activity [ O] H2O PET)

Klunk et al. (2004) Annals of Neurology (top); Buckner et al. (2005) J Neurosci (bottom) Image source: http://fmri.research.umich.edu/research/main_topics/asl.php

Arterial Sppg()ggin Labeling(ASL) MR Imaging Functional MRI (()fMRI)

• Cognitive (task-related) vs. resting state fMRI

• A: Statistical pppgyppparametric maps of significant hypoperfusion in posterior cingulate, inferior parietal, and frontal regions in AD compared to HC - B: Same analysis as in A, after accounting for global perfusion - C: Same as in A, with data corrected for gray matter atrophy and after accounting for gllblobal per fus ion • Similar to FDG-PET and HMAO SPECT, but noninvasive Johnson et al. (2005) Radiology Image source: http://culhamlab.ssc.uwo.ca/fmri4newbies/Tutorials.html

Functional MRI (fMRI): What Happens fMRI: Keyyp Concepts whNhen Neurons are AtiActive? 50% 50% • Blood-Oxygen-Level Dependent A. More deoxygenated (BOLD) contrast: hemoglobin with • The difference in signal as a increased neuronal ftifthfunction ofthe amount tf of activity? deoxygenated hemoglobin B. More oxygenated • Paramagnetic substances distort hemoglobin with the local magnetic field increased neuronal Æ greater MR s igna l w here bloo ddi is hig hly oxygena te d activity? . ob. og... m ogl Æ reduced MR signal where blood is highly deoxygenated m he ed nated he t ge na yge ox e or More deoxy M Functional MRI: Hemodyypnamic Response Functional MRI: Hemodyypnamic Response

Positive BOLD response Positive BOLD response

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2 2 Overshoot Overshoot Post-stimulus Post-stimulus esponse esponse l change l change 1 Initial Undershoot 1 Initial Undershoot aa aa RR Dip RR Dip 0 Time 0 Time BOLD BOLD (% sign (% sign Stimulus Stimulus

• Hemodynamic Response: “The change in MR signal • Initial dip: transient increase in oxygen consumption following local neuronal activity and the subsequent • Overshoot: over-compensation, mostly found in blocked decrease in the amount of deoxygenated hemoglobin” design • Undershoot: due to increase in blood volume (mostly observed with long-duration stimuli) Image source: http://culhamlab.ssc.uwo.ca/fmri4newbies/Tutorials.html Image source: http://culhamlab.ssc.uwo.ca/fmri4newbies/Tutorials.html

Preprocessing Steps Is it Possible to Prevent Head Motion in Delirium Patients? • Tell your subjects how to be good subjects – “Don’t move” is too vague • Make sure the subject is comfy going in • Emphasize importance of not moving at all during beeping – do not change posture; if possible, do not swallow • Discourage any movements that would displace the head between scans • Use comfortable “memory foam” padding

• Can you tell this to delirium patients??? – Scan as short as possible – Study patients with mild delirium – Allow spouse in scanner room for comfort to reduce patients from tensing up at start of scan – Patients may need to be sedated to prevent motion artifacts

Image source: Huettel et al. (2008) Functional Magnetic Resonance Imaging. 2nd Edition. Slide adapted from: http://culhamlab.ssc.uwo.ca/fmri4newbies/Tutorials.html

Variability from Event to Event Cogg()nitive (Task) fMRI

• Best used for hypothesis testing • Univariate analysis (subtraction method) – what brain areas are activated • Neural network (functional connectivity) analysis – hdbihow do brain areas itttinteractto suppor t cogn itive functions • Very challenging for delirium patients: – Scan only patients with mild delirium – Use simple cognitive tasks requiring minimal interaction – Use eye-tracking in scanner

•Demonstrates importance of signal averaging 17 •Scan as long as possible

Image source: Huettel et al. (2008) Functional Magnetic Resonance Imaging. 2nd Edition. Challenges and Limitations of Resting-State fMRI Functional Neuroimaging in Delirium “Default Mode Network” (DMN) Correlation between resting state - Just one of many RSNs activity, age, and cognition in normal • Best to scan before, during, and after delirium, aging but scanning during delirium difficult • Multimodal neuroimaging needed to distinguish r = -0.58 r = -0.60 between chronic and acute brain changes • Nee ddt to inc lu de as many su bjec ts as poss ible, but poor retention due to hospital discharge • Need to scan as long as possible for cognitive fMRI, b u t as sh or t as possibl e w hen exam in ing patients • Subject compliance (task, head motion)

Greicius et al. (2003) PNAS (left); Damoiseaux et al. (2007) Cereb Cortex (right)

Summary

• The st ud y ofth f the path oph ysi o logy of delirium requires noninvasive functional brain imaging techniques. • Given the challenges and limitations of functional neuroimaging techniques in delirium patients, resting state fMRI, ASL, and PET appear most promising.