1. BIAC Graduate fMRI Course October 5, 2005
BOLD fMRI
BIAC Graduate fMRI Course
October 5, 2005

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

3. Developments for BOLD MRI
Echoplanar imaging methods
Proposed by Mansfield in 1977
Ready availability of high-field scanners
Technological developments
Clinical applicability  insurance reimbursement  clinical prevalence
Discovery of BOLD contrast mechanism

4. 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., dHb)

5. External Contrast Agents
Most common are Gadolinium-based compounds introduced into bloodstream
Very large magnetic moments
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: 30-50%
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

6. Belliveau et al., 1990 Slice Location NMR intensity change (CBV)
CBV Maps (+24%)

7. Common Contrast Agents
Compound
Longitudinal Relaxivity
Transverse Relaxivity
Magnetic Susceptibility
GdCl2 1
MnCl2
0.96
3.83
0.51
GdDTPA
0.52
0.5
DyDTPA
0.03
0.04
1.78
GDTPA albumin
1.6 -
Iron oxide particle (3nm)
0.41
0.63
40.7
Iron oxide particle (253nm)
4.4
15.5
148

8. Potential for Endogenous Contrast through Hemodynamics

10. Blood Deoxygenation affects T2 Recovery
Decreasing Relaxation Time T1
Increasing Blood Oxygenation
Thulborn et al., 1982

11. 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

12. ? ? ? ? Gradient Echo Spin Echo Ogawa 1990 Oxyhemoglobin
Deoxyhemoglobin
Ogawa 1990

13. Gradient Echo
Spin Echo
Oxyhemoglobin
Deoxyhemoglobin
Ogawa 1990

14. 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

15. BOLD does not simply reflect blood flow…
0.75% Halothane
(BOLD contrast)
3% Halothane
(reduced BOLD)
100% N2
(enormous BOLD)
Ogawa 1990

16. BOLD Endogenous Contrast
Blood Oxyenation Level Dependent Contrast
Deoxyhemoglobin is paramagnetic, oxyhemoglobin is less so.
Magnetic susceptibility of blood increases linearly with increasing oxygenation
Oxygen is extracted during passage through capillary bed
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

17. Effects of TE and TR on T2* Contrast
T2 Decay MR
Signal
T1 Recovery MR
Signal
50 ms
1 s TE TR

18. Kwong et al., 1992
 VISUAL 
 MOTOR 

19. 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?

20. 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

21. Relation of BOLD Activity to Neuronal Activity

22. 1. Information processing reflects collected neuronal activity
fMRI response varies with pooled neuronal activity in a brain region
Behavior/cognitive ability determined by pooled activity
Alternatively, if single neurons governed behavior, fMRI activation may be epiphenomenal

23. BOLD response reflects pooled local field potential activity
BOLD response reflects pooled local field potential activity (Logothetis et al, 2001)

24. fMRI Hemodynamic Response
1500ms
500ms
100ms
Calcarine Sulci
Fusiform Gyri

25. Calcarine
1500ms
500ms *
Fusiform
100ms

26. 2. Co-localization
BOLD response reflects activity of neurons that are spatially co-localized
Based on what you know, is this true?

28. 3. Measuring Deoxyhemoglobin
fMRI measurements are of amount of deoxyhemoglobin per voxel
We assume that amount of deoxygenated hemoglobin is predictive of neuronal activity

29. 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 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

30. The Hemodynamic Response

31. 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

32. Basic Form of Hemodynamic Response
Peak
Rise
Initial Dip
Baseline
Undershoot
Sustained Response

33. fmri-fig jpg

34. 7.14 Summary of BOLD signal generation. (Part 1)
fmri-fig jpg

35. 7.14 Summary of BOLD signal generation. (Part 2)
fmri-fig jpg

36. Baseline Period Why include a baseline period in epoch?
Corrects for scanner drift across time

37. 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

38. Early Evidence for the Initial DipB
Menon et al, 1995

39. 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

40. Yacoub et al., 2001

41. 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

42. Rise (Hyperoxic Phase)
Results from vasodilation of arterioles, resulting in a large increase in cerebral blood flow
Inflection point can be used to index onset of processing

43. Peak – Overshoot Over-compensatory response
More pronounced in BOLD signal measures than flow measures
Overshoot found in blocked designs with extended intervals
Signal saturates after ~10s of stimulation

44. Sustained Response
Blocked design analyses rest upon presence of sustained response
Comparison of sustained activity vs. baseline
Statistically simple, powerful
Problems
Difficulty in identifying magnitude of activation
Little ability to describe form of hemodynamic response
May require detrending of raw time course

45. Undershoot
Cerebral blood flow more locked to stimuli than cerebral blood volume
Increased blood volume with baseline flow leads to decrease in MR signal
More frequently observed for longer-duration stimuli (>10s)
May not be present for short duration stimuli
May remain for 10s of seconds

46. fmri-fig jpg

47. Issues in HDR Analysis Delay in the HDR Amplitude of the HDR
Hemodynamic activity lags neuronal activity
Amplitude of the HDR
Variability in the HDR
HDR as a relative measure

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

49. Percent Signal Change Peak / mean(baseline)
Often used as a basic measure of “amount of processing”
Amplitude variable across subjects, age groups, etc.
505 1%
500
205
200

50. Amplitude of the HDR Peak signal change dependent on: Brain region
Task parameters 
Voxel size
Field Strength
Kwong et al, 1992

51. fmri-fig jpg

52. fmri-fig jpg

53. Variability in the Hemodynamic Response
Across Subjects
Across Sessions in a Single Subject
Across Brain Regions
Across Stimuli

54. 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