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BOLD fMRI

BOLD fMRI. BIAC Graduate fMRI Course October 1, 2003. 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

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BOLD fMRI

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  1. BOLD fMRI BIAC Graduate fMRI Course October 1, 2003

  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. Common Contrast Agents

  8. Hemodynamic Measures of Blood Flow

  9. Does blood flow serve function? “These facts seem to us to indicate the existence of an automatic mechanism by which the blood supply of any part of the cerebral tissue is varied in accordance with the activity of the chemical changes which underlie the functional action of that part. Bearing in mind that strong evidence exists of localisation of function in the brain, we are of opinion that an automatic mechanism, of the kind just referred to, is well fitted to provide for a local variation of the blood supply in accordance with local variations of the functional activity.” - Roy and Sherrington (1890)

  10. Apparatus of Angelo Mosso, as described by James (1890)

  11. PET Imaging

  12. 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

  13. History of BOLD fMRI

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

  15. 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

  16. 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

  17. Gradient Echo Spin Echo Oxyhemoglobin Deoxyhemoglobin Ogawa 1990b

  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. 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

  22. from Mosley & Glover, 1995

  23. MR Signal MR Signal T2 Decay T1 Recovery T2* and T2 Contrast 1 s 50 ms

  24. Discarded and Deleted Acquisitions (DISDAQs) Raw MR Signal (arbitrary units) Images (TRs)

  25. Relation of BOLD Activity to Neuronal Activity

  26. 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

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

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

  29. * Calcarine 1500ms 500ms 100ms Fusiform

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

  31. 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 .7-.8 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

  32. The Hemodynamic Response

  33. 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

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

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

  36. 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

  37. Early Evidence for the Initial Dip C A B Menon et al, 1995

  38. 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

  39. 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

  40. 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

  41. 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

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

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

  44. 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

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

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

  47. 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

  48. 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.

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