The Physiological Basis of the Haemodynamic Response

Transcription

1 The Physiological Basis of the Haemodynamic Response The Primate Visual System Bi/CNS 184 1

2 Four Bold Questions What is BOLD? How BOLD is generated physiologically? How BOLD is imaged using fmri? What does BOLD represent? i.e. what are the neural correlates of BOLD? 2

3 What is BOLD? Blood Oxygen Level Dependent Discovered by Ogawa in 1990 A surrogate signal potentially underlying neural activity Depends on hemodynamics: Blood flow Blood volume Blood oxygenation Changes in haemodynamics lead to a change in the local magnetic properties 3

4 Terms Perfusion: process of nutritive delivery of arterial blood to a capillary bed Capillary: tiny blood vessel (~10 micro meter) CMRO2: cerebral metabolic rate of O2 [O2]: O2 concentration in the blood CBF: Cerebral blood flow OEF: fraction of delivered O2 that is extracted and matebolized CMRO2 = OEF x CBF x [O2] 4

5 How BOLD is generated physiologically? The Cartoon Version (I) Oxygenated Hemoglobin (diamagnetic) Draining Vein Oxygen and glucose Capillary bed Blood flow Aretry Blood vessel Glucose Tissue Converting ADP to ATP (Generating energy using Glucose and O2) CO2 & Water Deoxygenated Hemoglobin (paramagnetic) 5

6 ATP ADP Adenosine Triphosphate (ATP) Contains three phosphate groups (P3) Free energy is released when the third P group is removed by insertion of a water molecule. This is called HYDROLYSIS ATP can be produced from many substrates, among them glucose. The energy provided by ATP supports many aspects of brain physiology Synthesis of proteins, packaging of neurotransmitters, and Restoring unequal distribution of ions following EPSPs and IPSPs and action potentials 6

7 Glucose Glucose is stored in the form of glycogen Little glycogen is in the brain A continuous supply of glucose and oxygen is needed via the vascular system ATP is generated from glucose in three steps Glycolysis TCA Cycle Electron transport chain 7

8 The Cartoon Version (II) The Relative concentration of oxygenated and deoxygenated hemoglobin determines the local magnetic susceptibility Increase of Blood flow => More Fresh blood => oxygenated hemoglobin) Increase in MR Signal Brain Activation => increase of deoxygenated Hemoglobin Decrease in MR Signal 8

9 BOLD measures the magnetic properties of water molecules Which reflect changes in the concentration of paramagnetic dexoyhemoglobin The concentration of dexoyhemoglobin is a physiological indicator of oxygen consumption Which reflects change in neural activity evoked by sensory/motor/cognitive processes Local brain regions require EXTERNAL sources of energy to support metabolic process, and much of this energy facilitates the restoration of the concentration gradients following changes in membrane potential. 9

10 Blood flow and energy metabolism are tightly linked to local neuronal activity This means that neuronal activity can be inferred from maps of Local blood flow Glucose consumption Oxygen consumption 10

11 Where is the energy spent? Maintaining electrochemical membrane potentials Sodium ions that enter during depolarization must be pumped out of the cell against the electrochemical gradient to restore resting membrane potential. Release of chemical neurotransmitters Both involve work coupled to ion transport across the membrane During excitation, local increase in metabolism can exceed 100% of the metabolism during resting state. 11

12 The Neurovascular Unit Who controls and increases CBF when there is neural activity? Pre Synaptic Neuron Action Potential Neurotransmitter (Glu) Arteriole (Small artery) Ionic Channel Astrocyte Ca2+ Increase K+ Post synaptic neuron Receptor Smooth muscle dilation 12

13 How to Image BOLD with fmri? Early studies of Ogawa (1990) with rats External manipulation of blood oxygenation 100% Oxygen 100 % Oxygen 90% O2, 10% CO2 Normal Air 13

14 Deoxy decreases MR signal in T2* Oxygenated Hemoglobin Deoxygenated Hemoglobin Spin Echo Gradient Echo Spin Echo Gradient Echo 14

15 Two Years Later 15

16 The Cartoon Version (II) The Relative concentration of oxygenated and deoxygenated hemoglobin determines the local magnetic susceptibility Increase of Blood flow => More Fresh blood => oxygenated hemoglobin) Increase in MR Signal Brain Activation => increase of deoxygenated Hemoglobin Decrease in MR Signal 16

17 The Cartoon Version (III) So why is there an increase (!) in BOLD for activated regions? Blood flow BOLD Metaboic rate of oxygen BOLD BOLD 17

18 Some Comments We obtain a 4D Data The signal is small and robust statistical methods are needed to detect it The metabolic activity producing the change in oxygenation lag behind the stimulus The response to an impulse stimulus is called hemodynamic response function (HRF) 18

19 The BOLD Response Noisy Initial Dip Delayed 19

20 HRF (a.k.a. HDR) Single Event Block of multiple events 20

21 Spatial Resolution? Voxel size (full brain coverage) In humans, typically, 3mm sec In monkeys, as low as 2 sec Can t we use smaller voxels? Less signal (in ½ voxel there is ½ less deoxy blood) Increase in acquisition time The limit is set not because of the method, but due to physiology. 21

22 Temporal Resolution 22

23 Linearity of the Response Linear Response Non Linear Response (Second BOLD response is smaller) 23

24 HRF / HDR

25 Properties of a Linear System Scaling Superposition 25

26 Testing Linearity Record responses for different contrast levels Divide each curve by the amount of contrast If the system is linear, you should get good overlap of all curves because they are just scaled version of each other Record responses for different stimulus length If you can predict the response of a long stimulus from the response of a short stimulus it indicates the system is linear 26

27 Linear Responses

28 Testing The Separability Hypothesis Are the curves just a scaled copies of each other? Dividing each curve by the contrast level used Basically, their claim was that this fit explains 85 99% of the variance, suggesting a good model fit

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30 The linear transform model f c, t f c, t f t stimulus noise ht* rct, fnoise t ht rctd, fnoise t The response can be considered as a sum of shifted and scaled (by neural activity) copies of the impulse response function

31 Time Contrast Separability r c, t g c r 1, t g(c) is the non linear function of contrast r(1,t) is the neural activity for a full contrast stimulus f stimulus c, t h t * r c, t h t * g c r 1, t g c h t * r 1, t The response is separable g(c) depends only on contrast, while the second part depends only on time

32 Another Prediction The response for a long duration should be the sum of two shifted copies of the short duration rs c, t r1 c, t r1 c, t fs ct, h t * rs ct, h t * r1 ct, r1 ct, h t * r ct, h t r ct, f ct, f ct,

33 The HRF Boynton proposed a simple parametric model for the temporal impulse function h(t): ht n 1 t e n 1! t

34 The linear model with fitted HRF predicted ~63% of the variance:

35 Some Comments Boynton states that the poor prediction for to the short pulse might be because in long durations there is neural adaptation, which is not well modeled by the square wave stimulus profile. At that time, it was unclear whether same HRFs would be found in extrastriate areas We now know that they do differ in their shape.

36 Event Related Analysis Building on the results of Boynton (block design), Dale and Buckner (1997) tested linearity by presenting clusters of 1,2 or 3 stimuli. 36

37 fmri Refractory Period? Some recent studies show that at short intertrial intervals there is a reduced BOLD amplitude 37

38 fmri Adaptation Grill Specktor and Malach,

39 What does BOLD represent? Input? Output? Local Processing? It is believed that input to an area is rather weak. The feedback is massive and local connectivity is composed of excitation and inhibition, where output is representing the balance between the two 39

40 EIN and BOLD Changes in excitation inhibition balance alter the fmri signal due since they affect the regional metabolic energy demands. Note that increase in inhibition may lead to increase in bold signal. 40

41 The three things picked up by an electrode Single unit (single neuron) Multi unit activity (MUA) Local field potential 41

42 Logothetis results 42

43 Neural Activity and BOLD 43

44 Estimating the HRF The impulse response (BOLD to stimulus) was recovered by cross correlating the BOLD and neural signal 44

45 Linear System Analysis Results from Logothetis Testing Different Contrasts Model fits nicely with the data 45

46 Main Results One of the remarkable findings was that BOLD can persist in cases where spiking was entirely absent despite a clear and strong stimulus included modulation of the LFP. In many cases, spikes do correlate with LFPs and will also correlate with BOLD. Spatially localized increase in the BOLD contrast directly and monotonically reflects an increase in neural activity Increase in LFPs during stimulation is significantly stronger than MUA, which quickly adapts to baseline. 46