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Basis of the BOLD Signal Christoph Korn Andrea Dantas Slide 2 Outline fMRI Physics fMRI Physics fMRI - Magnetic fields & spins fMRI - Magnetic fields & spins fMRI - Radio pulse & relaxation times fMRI - Radio pulse & relaxation times fMRI - Tissue contrasts fMRI - Tissue contrasts fMRI - BOLD & T2* fMRI - BOLD & T2* BOLD Signal BOLD Signal Brain Metabolism Brain Metabolism Neural Basis of BOLD signal Neural Basis of BOLD signal Technique & Protocols Technique & Protocols Advantages & Disadvantages Advantages & Disadvantages Areas for future research Areas for future research Slide 3 What do we want to understand? Singer et al., 2006 Slide 4 Which magnetic fields do we know? 1 Tesla = 20,000x Earths magnetic field Slide 5 Where is the magnetic field in the scanner? B0 = constant magnetic field Along z-axis For fMRI 1.5T or 3T Z Slide 6 Where are our compass needles? Protons have a spin and therefore a magnetic dipole moment MDM They can align to external magnetic fields in two ways: parallel or anti-parallel Slide 7 Outside scanner What happens in the scanner? Slide 8 Inside scanner (B0) What happens in the scanner? The protons of the H 2 O molecules in our body align along B0 Slide 9 Are there more up-spins than down-spins? [T] Yes and the excess spins create a new magnetic field M which we can measure Slide 10 Do the spinning tops tumble? Precession and Larmor frequency z-axis = B0 Larmor frequency gyromagnetic constant B0 static magnetic field e.g. 1.5 T = 64 MHz Slide 11 How do we measure spins? We have to disturb them How? With a radiofrequency pulse with Larmor frequency Slide 12 What happens if spins fall down? z axis x-y plane Slide 13 What happens if spins fall down? z axis x-y plane z axis x-y plane 90 High frequency pulse beforeafter Slide 14 What is the T1 relaxation? Recovery in z-axis = longitudinal relaxation = spin-lattice relaxation Supplied energy lost Spins re-align with B0 T1 Slide 15 What is the T2 relaxation? 90 pulseT2 relaxation Dephasing in x-y plane = horizontal relaxation = spin-spin relaxation Slide 16 Why does this happen and what is T2*? Two reasons for dephasing in x-y plane Spin-spin interaction T2 Local magnetic field inhomogeneities T2* T2(*) time constant Magnetic field inhomogeneities Slide 17 And? How can we use this for imaging? Different tissues have different relaxation times Lets look at T1 Fat White matter Grey matter CSF Slide 18 And T2? Different tissues have different relaxation times Fat White matter Grey matter CSF Slide 19 How do the T1 & T2 contrasts look like How do the T1 & T2 contrasts look like? Fat White matter Grey matter CSF Slide 20 How do we get these contrasts? How do we get a 3D-image? Too much to explain here Different times between high frequency pulses Different gradients along magnetic field Slide 21 Finally, what is BOLD? Blood Oxygen Level Dependent signal O 2 is transported by haemoglobin (Hb) Slide 22 What is the difference between deoxyHb and oxyHb? Remember T2* and field inhomogeneities? DeoxyHb paramagnetic strong field inhomogeneities OxyHb diamagnetic weak field inhomogeneities Fast dephasing Fast T2* Slower dephasing slower T2* Slide 23 Better? Singer et al., 2006 Slide 24 Outline fMRI Physics fMRI Physics fMRI - Magnetic fields & spins fMRI - Magnetic fields & spins fMRI - Radio pulse & relaxation times fMRI - Radio pulse & relaxation times fMRI - Tissue contrasts fMRI - Tissue contrasts fMRI - BOLD & T2* fMRI - BOLD & T2* BOLD Signal BOLD Signal Brain Metabolism Brain Metabolism Neural Basis of BOLD signal Neural Basis of BOLD signal Technique & Protocols Technique & Protocols Advantages & Disadvantages Advantages & Disadvantages Areas for future research Areas for future research Slide 25 Brain Metabolism Review Basic Facts Basic Facts 54ml of blood / 100g of brain tissue 54ml of blood / 100g of brain tissue Brain: Brain: 2-3% of body weight 2-3% of body weight 20% of O 2 consumption 20% of O 2 consumption For imaging purposes, the main vasculature concerned are the capillaries networks where glucose and O 2 exchanges happen For imaging purposes, the main vasculature concerned are the capillaries networks where glucose and O 2 exchanges happen Slide 26 Principles of BOLD BOLD contrast depends on the balance between O 2 supply and consumption by the neural tissues Deoxy DeoxyHb is paramagnetic as its proportion decreases, the MR signal increases and generates what is referred to as the BOLD signal Slide 27 Neural Basis of BOLD Energy Consumption Theory Initial thoughts were that increase of blood flow was due to the increase in energy requirements of the active tissue Most of the energy is spent maintaining action potentials and in post-synaptic signalling Inhibitory synapses use less energy than excitatory ones controversy around whether these generate a BOLD signal at all!! Attwell, D., Iadecola, C. 2002. The neural basis of functional brain imaging signals. Trends in Neuroscience. 25 (12) 621-625 Slide 28 Neural Basis of BOLD Blood Flow Increase Energy use does not directly increase blood flowso how does the brain cope with the increase in glucose and O 2 demands? Glutamate-generated Calcium influx at post-synaptic level releases potent vasodilators: Nitric Oxide Adenosine Arachidonic Acid metabolites Blood flow is increased over an area larger than the one with neuronal activity Global blood flow changes also associated with dopamine, noradrenaline and serotonin Not related with regional energy utilisation at all!! Attwell, D., Iadecola, C. 2002. The neural basis of functional brain imaging signals. Trends in Neuroscience. 25 (12) 621-625 Energy utilisation and increase in blood flow are processes that occur in parallel and are not causally related Slide 29 How can we (can we?) predict neural activity from fMRI signals? 90.000 to 100.000 neurons per 1mm 3 of brain tissue 10 9 synapses, depending on cortical thickness Slide 30 What is in a Voxel? Volume of 55mm 3 Using a 9-16 mm 2 plane resolution and slice thickness of 5-7 mm Only 3% of vessels and the rest are.(be prepared!!) 5.5 million neurons 2.2-5.5 x 10 10 synapses 22km of dendrites 220km of axons Slide 31 What are we actually measuring? Inputs or Outputs? Inputs or Outputs? BOLD responses correspond to intra-cortical processing and inputs, not outputs Aligned with previous findings related to high activity and energy expenditure in processing and modulation Excitation or inhibition circuits? Excitation or inhibition circuits? Excitation increases blood flow, but inhibition might too ambiguous data Neuronal deactivation is associated with vasoconstriction and reduction in blood flow (hence reduction in BOLD signal) And what about the awake, but resting brain? And what about the awake, but resting brain? Challenges in interpreting BOLD signal Presence of the signal without neuronal spiking Logothetis, N. K. 2008, "What we can and cannot do with fMRI", Nature, vol. 453, pp. 869-877 Slide 32 fMRI Study Designs Main types of study design: Block design Consecutive tasks in pre-defined time intervals (also referred to as epochs) Event-related Stimuli (events or trials) are presented Higher image acquisition rates (1/sec) 5 minutes of scanning can result in over 80 MB of data! Slide 33 Example of fMRI Protocol Initial Dip decrease in BOLD signal due to O 2 consumption Delay between the stimulus and the vascular changes might take up to 6 secs Slide 34 fMRI Image ProcessingStages fMRI Image Processing Stages 1. 1. Images are re-aligned 2. 2. Spatial normalisation of images to a standard brain space 3. 3. Smooth and normalise the data 4. 4. Combine statistical maps with anatomical information Result is a superposition of a statistical map on a raw image Slide 35 Sample fMRI Images Slide 36 Advantages of BOLD Advantages over other methods: EEG / MEG Poor spatial localisation, high number of electrodes needed PET Invasive and need to use potentially toxic contrast Non-invasive Increasing availability High spatial and temporal resolution Enables demonstration of entire network brain areas engaged in specific activities Logothetis, N. K. 2008, "What we can and cannot do with fMRI", Nature, vol. 453, pp. 869-877 Slide 37 Disadvantages of BOLD Surrogate signal of haemodynamic activity which has physical and biological constraints Neuronal mass activity and not activity of specific neuronal units Circuitry and functional organisation of the brain not fully understood Difficult to differentiate between excitation/inhibition and neuromodulation Signal intensity does not accurately differentiate between: Different brain regions Different tasks within the same region Logothetis, N. K. 2008, "What we can and cannot do with fMRI", Nature, vol. 453, pp. 869-877 Slide 38 Future Development Areas Multimodal approach is the way forward!!! Coupling of electrophysiological studies with BOLD Further improvements to fMRI technology Expansion of human and animal experimentation, enhancing the comprehension of the neural basis of haemodynamic responses New smart contrast agents that do not rely on haemoglobin Slide 39 References Logothetis, N. K. 2008, "What we can and cannot do with fMRI", Nature, vol. 453, pp. 869-877 Attwell, D., Iadecola, C. 2002. The neural basis of functional brain imaging signals Trends in Neuroscience. 25 (12) 621-625 Huettel, S. C., A. W. Song, and G. McCarthy. Functional Magnetic Resonance Imaging. 2 nd ed. Sinauer Associates Inc., 2004 McRobbie, D.W., Moore, E.A., Graves, M.J., and Prince, M.R. MRI From Picture to Proton. 2 nd ed. Cambridge University Press, 2007 SIEMENS. Magnets, Spins and Resonance. 2003. 25-10-2008. Ref Type: Report