1. BOLD fMRI

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 allowing functional 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
Create field gradients within/around vessels
What type of contrast would this generate?
Large signal changes: 30-50%
Delay in activation change until agent bolus passes through MR imaging volume
Width of activation change depends on delivery of bolus and vascular filtering
Degree of signal change depends on total blood volume of area

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

7. 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

8. from Mosley & Glover, 1995

9. Relation of BOLD Activity to Neuronal Activity

10. 1. Assumptions
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

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

12. 2. Measuring Deoxyhemoglobin
fMRI measurements are of amount of deoxyhemoglobin per voxel
We assume that relative oxygenation changes with amount of deoxygenated hemoglobin

13. 3. Different changes in 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
CMRO2 only increases slightly with activation
Note: A large CBF change may be needed to support a small change in CMRO2

14. History of BOLD fMRI

15. PET Studies of Brain Function
Injection of radioactive tracer
Measure presence of tracer during performance of task
Quantization of activity during single conditions
Advantages
Conceptually simple
Allows functional measurement
Disadvantages
Invasive contrast mechanism
Limited repeatability
Very low temporal resolution
Image from M. Raichle

16. 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:
Oxygenated blood in tube leads to little signal change, either on spin- or gradient-echo images
Deoxygenated blood leads to large susceptibility effects on gradient-echo images

17. 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

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. The Hemodynamic Response

22. 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

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

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

25. 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

26. 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

27. 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

28. 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

29. 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)
Short duration stimuli may not evidence
May remain for 10s of seconds

30. 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

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

32. 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

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

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

35. 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

36. Detection vs. Estimation
Detection power
The ability of a design to determine whether or not an area is active
Power: ability to detect an effect that is there (1-ß)
Alpha: odds that a detected effect is due to chance
Estimation efficiency
The ability of a design to characterize the form of the BOLD changes
With a priori knowledge of HDR timing, shape, etc., one can describe temporal properties of brain regions
We can think of these challenges as spatial and temporal, respectively.

37. Analyzing data using BIAC tools

38. Basic Steps of Analysis
Reconstruction of K-Space Data
Pre-processing Steps
Slice Timing Correction
Motion Correction
Coregistration, Normalization, Smoothing
Epoch averaging / Regression
Statistical comparison of data with convolved hemodynamic response