1. What are we measuring in fMRI? Caroline Catmur Jack Kelly

2. In BOLD fMRI, we are measuring:  the inhomogeneities introduced into the magnetic field of the scanner…  as a result of the changing ratio of oxygenated:deoxygenated blood…  via their effect on the rates of dephasing of hydrogen nuclei. Ehhh???

3. Physics: underlying principles Hydrogen nuclei ( 1 H): positively charged particles which spin around their axes, producing a (small) magnetic field. MDM: magnetic dipole moment: vector of the magnetic field of the nucleus. When placed in a uniform magnetic field, (conventionally indicated by the z axis), the particles’ MDMs align with or against the field. A small percentage more align with the field than against, proportional to the strength of the field, giving the particles a net magnetization.

4. The MDMs also precess around the axis of the field, at a resonant frequency dependent on the strength of field and type of nucleus, eg 64MHz for 1 H in a 1.5T field.

5. So what goes on in the scanner? Place the nuclei (ie the brain) in a uniform magnetic field (the scanner). The next step: apply an RF pulse, frequency equal to frequency of precession of the nuclei, normally at 90° to the magnetic field. This ‘tips’ the MDMs of those nuclei which have this frequency of precession, ie we only ‘tip’ the 1 H nuclei. So, the MDMs of the 1 H nuclei are now at 90° to the main field, ie in the x/y plane.

6. Terminate the RF pulse and the nuclei relax: their MDMs return to the original orientation in the z dimension, and the energy released during relaxation is what is measured by the receiver coil. Three different relaxation times of interest in MRI: T1, T2 and T2*.

7. Phase Before the RF pulse, all the MDMs precess at the same frequency but not in phase. After they’re tipped, all precess in phase. Can think of it as all MDMs moving together: this produces a strong signal in the x/y plane. Once the RF pulse ends, begin to dephase: start to cancel each other out and the signal decays.

8. Two reasons for this dephasing: inhomogeneities in the magnetic field, and ‘spin-spin’ interactions between neighbouring nuclei. Possible to correct for dephasing due to inhomogeneities in the field by applying another RF pulse at 180° to the initial pulse. Known as a spin-echo sequence.

9. Back to those relaxation times T1 relaxation: time course for the MDMs to return to their original (z) orientation. T2 relaxation: time course of the breakdown of the magnetization in the x/y plane due to spin-spin interactions.

10. T2* relaxation: time course of the breakdown of the magnetization in the x/y plane due to variations in the magnetic field. The T2* processes can be refocused using a 180° spin-echo sequence, though the T2 processes will still remain. Different tissues have different T1 and T2 relaxation rates. T1-weighted scan: measure signal at time when relative difference (between tissue types) in amplitudes of MDMs in z dimension is maximum. T2-weighted scan: measure at time when relative difference in amplitudes of MDMs in x/y plane is maximum. To get these different scans, change time between RF- pulse and measurement (TE), and between successive RF pulses (TR).

11. But why do we need to know all this? BOLD (blood oxygenation level dependent) contrast: measures inhomogeneities in the magnetic field due to changes in the level of oxygen in the blood. So it’s a T2* contrast. Oxygenated blood contains oxyhaemoglobin: red blood cells with O 2 molecule attached. Not magnetic. Deoxygenated blood: deoxyhaemoglobin: red blood cells without O 2. Magnetic.

12. So if ratio deoxygenated:oxygenated blood is high, increases inhomogeneities in the magnetic field  faster breakdown of magnetism in x/y plane (T2* relaxation)  decrease in fMRI signal. If ratio oxygenated:deoxygenated is high, slower T2* relaxation  less decrease in signal. So we can use the change in fMRI signal to infer the relative oxygenation of the blood.

13. So how do we get the actual information? Spatial localisation: ‘gradients’. Small magnetic field gradients (eg 30 mT/m) superimposed onto the main static magnetic field. Remember that the resonant frequency for a nucleus in a magnetic field depends on the field strength. So, differences in the resonance frequencies encode the positions of the nuclei along the gradient field. Switching the small gradients on and off is noisy! Receiving the information: the RF coil both transmits and receives. A volume coil images any part of the brain; a surface coil gives better images, but only for the nearest part of the brain, due to distortions. A phased array coil is a series of surface coils.

14. fMRI – neurophysiology

15. fMRI Outline: What is BOLD? Correlation of BOLD with electrophys. How neurons cause CBF increases Localising BOLD Summation of BOLD Implications for cognitive studies

16. BOLD and MRI BOLD = Blood Oxygenation Level Dependent functional Magnetic Resonance Imaging Deoxyhemoglobin is paramagnetic and produces a reduced signal, oxyhemoglobin is weakly dimagnetic and doesn’t reduce the signal.

17. BOLD and Cerebral Blood Flow

18. BOLD and electro-physiology: correlation Same area in V1 of cat, Kim DS (2004)

19. BOLD and electro-physiology: correlation Single unit recording, cat V1, Kim 2004

20. What causes BOLD? The purpose of the increase in blood oxygenation is to feed neurons… …so, what makes a neuron hungry? (neurons can’t store much energy)

21. Vascular density Vascular density is proportional to synaptic density, not soma density

22. Hungry brains White matter uses ¼ the energy of grey matter per unit volume Attwell & Iadecola 2002 62% of mitochondria are in dendrites

23. Regulation of blood flow

24. Is it feedback or feed forward? ActivityUses energy Vascular system must supply more energy Activity Directly commands more blood flow

25. Regulation of blood flow Feedforward! Activity Directly commands more blood flow Energy use does not directly increase blood flow… …so how does tell CBF to increase?

26. Feed forward pro-active control

27. Monoamines and blood flow DA, NA and 5HT = vasoconstriction Cholinergic axons from BF = vasodilation This complicates neuropsychiatric studies e.g. schizophrenia, PD, ADHD

28. Localising fMRI Cat scanner (!); Kim 2004

29. Correlation of BOLD and single unit Kim 2004

30. Summation of BOLD BOLD LFP Single unit

31. Comparing different areas Different vasculature Different neuromodulatory control Different circuitry BOLD [X] > BOLD [Y] does not mean NEURAL ACTIVITY [X] > ACTIVITY [Y]

32. Comparing different subjects

33. What BOLD does not measure The output of an area Comparisons of activity between areas GABA ??????

34. What does contribute to BOLD Synaptic activity Local processing Sub-threshold neuromodulatory inputs

35. What does a blob in area X mean? X has changed its local activity Change of modulatory inputs arriving at X Change of inputs arriving at X (beware: the areas giving rise to the inputs to X may not produce a BOLD signal if their local synaptic activity levels remain constant)

36. References Logothetis NK & Wandell BA (2004) Interpreting the BOLD signal Annu. Rev. Physiol 66:735-69 Attwell D & Iadecola C (2002) The neural basis of functional brain imaging signals Trends in Neurosciences 25:621-625 Kim DS et al (2004) Spatial relationship between neuronal activity and BOLD functional MRI NeuroImage 21:876-885