BOLD fMRI

1. BOLD fMRI FMRI Undergraduate Course (PSY 181F) FMRI Graduate Course (NBIO 381, PSY 362) Dr. Scott Huettel, Course Director FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

2. Why do we need to know physics/physiology of fMRI? • To understand the implications of our results • Interpreting activation extent, timing, etc. • Determining the strength of our conclusions • Exploring new and unexpected findings • To understand limitations of our method • Choosing appropriate experimental design • Combining information across techniques to overcome limitations • To take advantage of new developments • Evaluating others’ approaches to problems • Employing new pulse sequences or protocols FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

3. Contrast Agents • Defined: Substances that alter magnetic susceptibility of tissue or blood, leading to changes in MR signal • Affects local magnetic homogeneity: decrease in T2* • Two types • Exogenous: Externally applied, non-biological compounds (e.g., Gd-DTPA) • Endogenous: Internally generated biological compound (e.g., deoxyhemoglobin, dHb) FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

4. External Contrast Agents • Most common are Gadolinium-based compounds introduced into bloodstream • Very large magnetic moments, but do not cross blood-brain barrier • Create field gradients within/around vessels • Reduces T1 values in blood (can help visualize tumor, etc.) • Changes local magnetic fields • Large signal changes • Delay until agent bolus passes through MR imaging volume • Width of response depends on delivery of bolus and vascular filtering • Degree of signal change depends on total blood volume of area • Issues • Potential toxicity of agents (short-term toxicity, long-term accumulation) • Cause headaches, nausea, pain at injection FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

5. Common Contrast Agents FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

6. Belliveau et al., 1990 Slice Location NMR intensity change (CBV) CBV Maps (+24%) FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

7. Potential for Endogenous Contrast through Hemodynamics FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

8. FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

9. Blood Deoxygenation affects T2* Decay Thulborn et al., 1982 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

10. Ogawa et al., 1990a • Subjects: 1) Mice and Rats, 2) Test tubes • Equipment: High-field MR (7+ T) • Results 1: • Contrast on gradient-echo images influenced by proportion of oxygen in breathing gas • Increasing oxygen content  reduced contrast • No vascular contrast seen on spin-echo images • Results 2: • Examined signal from tubes of oxygenated and deoxygenated blood as measured using gradient-echo and spin-echo images FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

11. Gradient Echo Spin Echo ? ? Oxyhemoglobin ? ? Deoxyhemoglobin Ogawa 1990 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

12. Gradient Echo Spin Echo Oxyhemoglobin Deoxyhemoglobin Ogawa 1990 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

13. Ogawa et al., 1990b 100% O2 Under anesthesia, rats breathing pure oxygen have some BOLD contrast (black lines). Breathing a mix including CO2 results in increased blood flow, in turn increasing blood oxygenation. There is no increased metabolic load (no task). Therefore, BOLD contrast is reduced. 90% O2, 10% CO2 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

14. BOLD does not simply reflect blood flow or neuronal activity… 0.75% Halothane, 0.25cm/s (BOLD contrast) 3% Halothane, 0.12cm/s (reduced BOLD) 100% N2 (enormous BOLD) Ogawa 1990 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

15. BOLD Endogenous Contrast • Blood Oxyenation Level Dependent Contrast • Deoxyhemoglobin is paramagnetic • Magnetic susceptibility of blood increases linearly with increasing oxygenation • Oxygen is extracted during passage through capillary bed • Brain arteries are fully oxygenated • Venous (and capillary) blood has increased proportion of deoxyhemoglobin • Difference between oxy and deoxy states is greater for veins  BOLD sensitive to venous changes FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

16. MR Signal MR Signal T2 Decay T1 Recovery Effects of TE and TR on T2* Contrast 50 ms 1 s TE TR FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

17. Kwong et al., 1992  VISUAL   MOTOR  FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

18. Ogawa et al., 1992 • High-field (4T) in humans • Patterned visual stimulation at 10 Hz • Gradient-echo (GRE) pulse sequence used • Surface coil recorded • Significant image intensity changes in visual cortex • Image signal intensity changed with TE change • What form of contrast? FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

19. Blamire et al., 1992 This was the first event-related fMRI study. It used both blocks and pulses of visual stimulation. Gray Matter Hemodynamic response to long stimulus durations. White matter Hemodynamic response to short stimulus durations. Outside Head FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

20. Relation of BOLD Activity to Neuronal Activity FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

21. 1. Information processing reflects collected neuronal activity • Possibility #1: fMRI response varies with pooled neuronal activity in a brain region • Behavior/cognition determined by pooled activity • Possibility #2: Single neurons govern behavior, making fMRI activation epiphenomenal FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

22. BOLD response reflects pooled local field potential activity (e.g., Logothetis et al, 2001) FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

23. 2. Co-localization • BOLD response reflects activity of neurons that are spatially co-localized • Based on what you know, is this true? FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

24. FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

25. 3. Measuring Deoxyhemoglobin • fMRI measurements are of amount of deoxyhemoglobin per voxel • We assume that amount of deoxygenated hemoglobin is predictive of neuronal activity FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

26. 4. Uncoupling of CBF & CMRO2 • Cerebral Blood Flow (CBF) and Cerebral Metabolic Rate of Oxygen (CMRO2) are coupled under baseline conditions • PET measures CBF well, CMRO2 poorly • fMRI measures CMRO2 well, CBF poorly • CBF about .5 ml/g/min under baseline conditions • Increases to max of about .7-.8 ml/g/min under activation conditions (+ 30%) • CMRO2 only increases slightly with activation • May only increase by 10-15% or less • Note: A large CBF change may be needed to support a small change in CMRO2 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

27. The Hemodynamic Response FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

28. Under normal conditions, oxygen is extracted from red blood cells within the capillaries. But when neurons are active, more oxygenated blood is supplied than needed. This reduces the local quantity of deoxygenated hemoglobin. FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

29. Basic Form of Hemodynamic Response FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

30. Initial Dip (Hypo-oxic Phase) • Transient increase in oxygen consumption, before change in blood flow • Menon et al., 1995; Hu, et al., 1997 • Shown by optical imaging studies • Malonek & Grinvald, 1996 • Smaller amplitude than main BOLD signal • 10% of peak amplitude (e.g., 0.1% signal change) • Potentially more spatially specific • Oxygen utilization may be more closely associated with neuronal activity than perfusion response FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

31. Early Evidence for the Initial Dip C A B Menon et al, 1995 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

32. Why is the initial dip controversial? • Not seen in most studies • Spatially localized to Minnesota • May require high field • Increasing field strength increases proportion of signal drawn from small vessels • Of small amplitude/SNR; may require more signal • Yacoub and Hu (1999) reported at 1.5T • May be obscured with large voxels or ROI analyses • May be selective for particular cortical regions • Yacoub et al., 2001, report visual and motor activity • Mechanism unknown • Probably represents increase in activity in advance of flow • But could result from flow decrease or volume increase FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

33. Yacoub et al., 2001 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

34. Subject: 74y male with transient ischemic attack (6m prior) Revealed to have arterial occlusion in left hemisphere Tested in bimanual motor task Found negative bold in LH, earlier than positive in right Negative BOLD response caused by impaired oxygen supply Rother, et al., 2002 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

35. FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

36. Why does the hemodynamic response matter? • Delay in the hemodynamic response (HDR) • Hemodynamic activity lags neuronal activity • Amplitude of the HDR • Variability in the HDR • Linearity of the HDR • HDR as a relative measure FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

37. Convolving HDR Time-shifted Epochs Introduction of Gaps The Hemodynamic Response Lags Neural Activity Experimental Design FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

38. Amplitude of the HDR • Peak signal change dependent on: • Brain region • Task parameters  • Voxel size • Field Strength Kwong et al, 1992 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

39. 1% 1% Percent Signal Change • Peak / mean(baseline) • Often used as a basic measure of “amount of processing” • Amplitude variable across subjects, age groups, etc. 505 500 205 200 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

40. FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

41. FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

42. Relative vs. Absolute Measures • fMRI provides relative change over time • Signal measured in “arbitrary MR units” • Percent signal change over baseline • PET provides absolute signal • Measures biological quantity in real units • CBF: cerebral blood flow • CMRGlc: Cerebral Metabolic Rate of Glucose • CMRO2: Cerebral Metabolic Rate of Oxygen • CBV: Cerebral Blood Volume FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

43. Linearity of the Hemodynamic Response FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

44. Impulse-Response Systems • Impulse: single event that evokes changes in a system • Assumed to be of infinitely short duration • Response: Resulting change in system Impulses Convolution Response = Output FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

45. Linear Systems • Scaling • The ratio of inputs determines the ratio of outputs • Example: if Input1 is twice as large as Input2, Output1 will be twice as large as Output2 • Superposition • The response to a sum of inputs is equivalent to the sum of the response to individual inputs • Example: Output1+2+3 = Output1+Output2+Output3 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

46. Scaling (top) and Superposition (bottom) A B FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

47. fMRI Hemodynamic Response 1500ms 500ms 100ms Calcarine Sulci Fusiform Gyri FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

48. Linear and Non-linear Systems A B C D FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

49. Possible Sources of Nonlinearity • Stimulus time course  neural activity • Activity not uniform across stimulus (for any stimulus) • Neural activity  Vascular changes • Different activity durations may lead to different blood flow or oxygen extraction • Minimum bolus size? • Minimum activity necessary to trigger? • Vascular changes  BOLD measurement • Saturation of BOLD response necessitates nonlinearity • Vascular measures combining to generate BOLD have different time courses From Buxton, 2001 FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University

50. Effects of Stimulus Duration • Short stimulus durations evoke BOLD responses • Amplitude of BOLD response often depends on duration • Stimuli < 100ms evoke measurable BOLD responses • Form of response changes with duration • Latency to peak increases with increasing duration • Onset of rise does not change with duration • Rate of rise increases with duration • Key issue: deconfounding duration of stimulus with duration of neuronal activity FMRI – Week 6 – BOLD fMRI Scott Huettel, Duke University