1. BOLD Imaging An Introduction to MRI Physics and Analysis Michael Jay Schillaci, PhD Monday, February 25, 2008

2. Overview Neurophysiology  The brain’s vascular system  Neurons, dendrites and pumps  Energy in the brain BOLD Imaging  Source of BOLD Signal  The Hemodynamic response  BOLD Artifacts

3. Neurophysiology

4. Duvernoy, H. M., Delon, S., & Vannson, J. L. (1981). Cortical blood vessels of the human brain. Brain Research Bulletin, 7(5), 519-579. Arteries (1-25mm) Arterioles (10 - 300 microns) precapillary sphincters Capillaries (5-10 microns) Venules (8-50 microns) Veins

6. (anastomosis of internal carotids and basilar artery)

7. ACA – Medial cortex MCA – Anterolateral cortex PCA – Posterior temporal and occipital lobes

8. Sinus. n. An separation of the dura mater in which blood drains into the venous system.

9. Distribution of vascularization - occurs across cortical layers

10. Capillary structure

11. Oxygen (via hemoglobin) Glucose

12. Facts about energy supply to brain 30-50 μmol/g/min of ATP for awake brain 10 μmol/g/min of ATP for comatose brain Information processing accounts for >75% of ATP consumption 54mL/min of blood for each 100 g of brain tissue Brain is ~3% of body weight, but demands 15-20% of blood flow and ~20% of blood oxygen

14. There are two primary types of information flow in the CNS: 1) Signaling via action potentials (axonal activity) and 2) Integration via dendritic activity

15. Action potential Depolarization opens CA 2+ channels Vesicles fuse with presynaptic membrane Neurotransmitter release Neurotransmitters open ion channels on postsynaptic membrane Change in potential IPSP or EPSP

16. Energy Demands of Integration/Signaling Following activity, neurons require energy to restore concentration gradients of key ions. Sodium-Potassium pump takes sodium out of the cell while bringing potassium into the cell. Note that for action potentials, the movement of ions is along gradients. Key concept: activity of neurons does not itself require energy; restoring membrane potentials afterward does.

17. BOLD Imaging

18. BOLD - Endogenous Contrast Blood Oxyenation Level Dependent Contrast  dHb is paramagnetic, Hb is less  Susceptibility of blood increases linearly with oxygenation  BOLD subject to T2* criteria Oxygen is extracted from capillaries  Arteries are fully oxygenated  Venous blood has increased proportion of dHb  Difference between Hb and dHb states is greater for veins  Therefore BOLD is result of venous blood changes

19. Sources of the BOLD Signal Neuronal activity Metabolism Blood flow Blood volume [dHb] BOLD signal BOLD is a very indirect measure of activity…

20. Facts about blood flow Aorta peak flow: 90 cm/s Internal carotid flow: ~ 40 cm/s Smaller arteries: ~10-250 mm/s Capillaries: ~ 1 mm/s Venules and small veins: ~10-250 mm/s

21. Change in arteriole dilation as a function of distance from active neurons Iadecola, Nature Reviews Neuroscience, 2004

22. How does the vascular system respond to neuronal activity? Iadecola, Nature Reviews Neuroscience, 2004 Physiological data suggests that blood flow changes may be associated with preponderance of dendritic activity, but disconnections are possible.

23. Neuronal Origins of BOLD Adapted from Logothetis et al. (2002) BOLD response predicted by dendritic activity (LFPs) Increased neuronal activity results in increased MR (T2*) signal LFP=Local Field Potential; MUA=Multi-Unit Activity; SDF=Spike-Density Function

24. BASELINE ACTIVE

25. Hemoglobin and Magnetism The Hemoglobin (Hb) Molecule  An organic molecule containing four heme groups (with iron in each) and globular protein (globin). Oxygen Characteristics  Oxygen bound - oxyhemoglobin (Hb)  No oxygen bound - deoxyhemoglobin (dHb) Magnetic Properties  Hb is diamagnetic - no dipole  dHb is paramagnetic - slight dipole

26. Oxygen and Field Strength Apply magnetic field to brain Blood oxygen level differs dHb is paramagnetic  Local field increased Hb diamagnetic  Local field decreased

27. Blamire et al., 1992 This was the first event-related fMRI study. It used both blocks and pulses of visual stimulation. Hemodynamic response to long stimulus durations. Hemodynamic response to short stimulus durations. Gray Matter White matter Outside Head

28. fMRI and Contrast Endogenous Mechanism  Blood deoxygenation affects T 2 Recovery Increasing Blood Oxygenation Level Decreasing Relaxation Time T2 T1

29. Basic Form of Hemodynamic Response

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

31. Early Evidence for the Initial Dip C AB Menon et al, 1995

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

33. Yacoub et al., 2001

34. Negative BOLD response caused by impaired oxygen supply 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 Rother, et al., 2002

36. The Hemodynamic Response Lags Neural Activity Experimental Design Convolving HDR Time-shifted Epochs Introduction of Gaps

37. The fMRI Linear Transform

38. Boynton et al., 1996 Varied contrast of checkerboard bars as well as their interval (B) and duration (C).

39. Boynton, et al, 1996

40. Refractory Periods Definition: a change in the responsiveness to an event based upon the presence or absence of a similar preceding event  Neuronal refractory period  Vascular refractory period

41. Dale & Buckner, 1997 Responses to consecutive presentations of a stimulus add in a “roughly linear” fashion Subtle departures from linearity are evident

42. Intra-Pair Interval (IPI) Inter-Trial Interval (16-20 seconds) 6 sec IPI 4 sec IPI 2 sec IPI 1 sec IPI Single- Stimulus Huettel & McCarthy, 2000 500 ms duration

43. Hemodynamic Responses to Closely Spaced Stimuli

44. “Rough Linearity” Time since onset of second stimulus (sec) Signal Change over Baseline(%)

45. T2*: fMRI Signal is an Artifact

46. BOLD artifacts fMRI is a T2* image – we will have all the artifacts that a spin-echo sequence attempts to remove. Dephasing near air-tissue boundaries (e.g., sinuses) results in signal dropout. BOLD Non-BOLD

47. Neuro-Vascular coupling