# Presentation: 759319

## The Spatial, Temporal and Interpretive Limits of Functional MRI

- Peter A. Bandettini, Ph.D
- Unit on Functional Imaging Methods
- Laboratory of Brain and Cognition
- National Institute of Mental Health

## Categories of Questions 

**Categories of Questions **
**Asked with fMRI**

**Where?**
**When?**
**How much?**
**---**
**How to get the brain to do what we want it to **
**do in the context of an fMRI experiment?**
**(*****limitations*****: time, motion, acoustic noise....)**

## A Primary Challenge:

**...to make progressively more precise inferences using fMRI **
**without making too many assumptions about non-neuronal**
**physiologic factors.**

## Blood Volume
Contrast agent injection and time series collection of T2* or T2 - weighted images
BOLD
Time series collection of T2* or T2 - weighted images
Perfusion
T1 weighting
Arterial spin labeling	

**Blood Volume**
**Contrast agent injection and time series collection of T2* or T2 - weighted images**
**BOLD**
**Time series collection of T2* or T2 - weighted images**
**Perfusion**
**T1 weighting**
**Arterial spin labeling****	**

**Contrast in Functional MRI**

## Resting		   Active

**Resting****	****	****   ****Active**

## Slide 6

## Slide 7

## Slide 8

## Slide 9

## Slide 10

## Slide 11

## -

**EPISTAR**

** **

** **

** **

** **

**FAIR**

** **

** **

** **

**. . .**

**. . .**

**Perfusion**
**Time Series**

**-**

**-**

**-**

**-**

**Perfusion / Flow  Imaging**

## FAIR

**FAIR**

**EPISTAR**

## +				-

**BOLD**
**Perfusion**

**+****	****	****	****	****-**

**• ****unique information**
**• ****baseline information**
**• ****multislice trivial**

**• ****highest C / N**
**• ****easy to implement**
**• ****multislice trivial**
**• ****non invasive**
**• ****highest temp. res.**

**• ****unique information**
**• ****control over ves. size**
**• ****baseline information**
**• ****non invasive**

**• ****invasive**
**• ****low C / N for func.**

**• ****complicated signal**
**• ****no baseline info.**

**• ****multislice non trivial**
**• ****lower temp. res.**
**• ****low C / N**

## ?

**Neuronal**

**Activation**

**Hemodynamics**

**Measured**

**fMRI**

**Signal**

**?**

**?**

**Physiologic Factors**

## Physiologic Factors that Influence BOLD Contrast

- Blood oxygenation
- Blood volume
- Blood pressure
- Hematocrit
- Vessel size

**Coupling:**
**Flow & CMRO****2**

## Slide 17

## Where and When?

**The resolution is determined by **
**the cerebral hemodynamics.**
**• ****Know the vasculature at which **
**you are looking.**
**(or)**
**• ****Normalize to the spatial variation **
**in the vasculature.**
**(or)**
**• ****Make several assumptions.**

## Single Shot Imaging

**T2* decay**

**EPI Readout Window**

**≈ ****20 to 40 ms**

## Multishot Imaging

**T2* decay**

**EPI Window 2**

## Partial k-space imaging

## Slide 22

## Slide 23

## Slide 24

## Slide 25

## Pulse sequence based methods for increasing spatial and temporal resolution

**Spin-echo**
**ASL**
**Diffusion weighting**
**Threshold based on magnitude**

## Slide 27

## compartment 

**compartment**** **
**     ****radius:****	****    ****  ****	****   < ****3 μm    3 to 15 μm     > 15  μm**

**Spin echo vs. Gradient echo**

## GE

**GE**
** ****TE = 30 ms**

**SE**
** ****TE = 110 ms**

## ∆R2* /∆R2

***average ∆R2* / ∆R2  ≈ 3 to 4***

**1.5**

**1.5 to 3**
**extravascular**

**1.5**
**intravascular**

**3 to ∞ **
**extravascular**

**1.5**
**intravascular**

**∆****R2* /∆R2**

- Spin-echo??

## TR = ∞

**Spin-Echo**
**TE = 105 ms**
**TR = ****∞**

**Gradient-Echo**
**TE = 50 ms**

**Gradient-Echo**
**functional**
**TE = 50 ms**

**Spin-Echo**
**functional**
**TE = 105 ms**

- 3T

## no diffusion weighting

**no diffusion weighting**

**diffusion weighting**

## Slide 33

**b = 0**

**b = 160**

**b = 50**

**b = 10**

## BOLD

**BOLD**

**Perfusion**
*Rest**	**	**Activation*

## Anatomy

**Anatomy**

**BOLD**

**Perfusion**

## Simultaneous Flow and BOLD

**Simultaneous Flow and BOLD**

**Mz(blood)**

**t**

**Mz(tissue)**

**t**

**Flow**

**BOLD**

**blood**

**tissue**

**Mz(blood)**

**t**

**Mz(blood)**

**tag**

**t**

**Mz(blood)**

**-**

**Mz(tissue)**

**t**

**Mz(tissue)**

**t**

**-**

**Mz(tissue)**

**t**

**blood**

**tissue**

**Mz(blood)**

**tag**

**t**

**Mz(blood)**

**t**

**+**

**Mz(tissue)**

**t**

**Mz(tissue)**

**t**

**+**

**t**

**control**

**control**

## BOLD

**BOLD**

**Perfusion**

**Simultaneous BOLD and Perfusion**

## perfusion

**perfusion**
**BOLD**

**Simultaneous BOLD and Perfusion**

## Angiogram

**Angiogram**
**Perfusion**
**BOLD**

## Spatial Normalization

**Hypercapnia**

**Spatial Normalization**

## T1 - weighted

**T1 - weighted**

**T1 and T2***
**weighted**

**T2* weighted**

## Vascular Sensitization

**Vascular Sensitization**

## Problems with pulse sequence - based methods for increasing resolution

**Spin-echo ****(sensitivity, specificity)**
**Arterial spin-labeling ****(sensitivity, time, range)**
**Diffusion weighting ****(sensitivity, specificity)**
**Threshold based on magnitude ****(sensitivity, specificity)**

## Slide 45

## ,

**Finger **
**Movement**

**5% CO2**

**12% O2**

**Anatomical**

## Slide 47

## %

**%**

**=**

## Hoge et al

**Hoge et al**

## Hoge et al

**Hoge et al**

## Mapping CMRO2 using CO2 Calibration

**Hoge et al**

**Mapping CMRO****2**** using CO****2**** Calibration**

## Slide 52

## Types of Temporal Resolution

**1. ****	****Maximum on-off switching rate.**
**2. ****	****Minimum detectable activation duration.**
**3. ****	****Minimum detectable difference in activation ****	****duration or onset in same region.**
**4. ****	****Minimum detectable activation interval across ****	****separate brain regions.**
**5. ****	****Maximum image acquisition rate.**

## Slide 54

## S = k t 8.6 e - t / 0.547

**Cohen, Neuroimage 6, 93-103 (1997)**

## Slide 56

## Latency

**Latency**

**Magnitude**

**+ 2 sec**

**- 2 sec**

## Temporal Normalization

**Relative Timing**

**Temporal Normalization**

## Regions of Interest Used for Hemi-Field Experiment

- <date/time>

- Regions of Interest Used for Hemi-Field Experiment

**Right Hemisphere**

**Left Hemisphere**

## Slide 60

## Hemi-field with 500 msec asynchrony

- <date/time>

**Percent**

**MR**

**Signal**

**Strength**

**Time (seconds)**

**Average of 6 runs     Standard Deviations Shown**

## Percent

- <date/time>

**Percent**

**MR**

**Signal**

**Strength**

**Time (seconds)**

**Average of 6 runs     Smoothed Data**

## =

**+ 2.5 s**

**- 2.5 s**

**0 s**

**500 ms**

**500 ms**

**Right**** ****Hemifield**

**Left Hemifield**

**-**

## =

**+ 2.5 s**

**- 2.5 s**

**0 s**

**250 ms**

**250 ms**

**Right**** ****Hemifield**

**Left Hemifield**

**-**

## How Much?

**Central Issue:**
**Spatial and temporal neuronal firing integration **
**to create an fMRI signal change.**
***- is the hemodynamic response a linear system?***
***-what is the dynamic range?***

## Motor Cortex

**Motor Cortex**

**Auditory Cortex**

## DeYoe et al.

**DeYoe et al.**

## Slide 68

## Time (sec)

**Time (sec)**

## Stimululs - Duration Dependent Deviation 

- Stimululs - Duration Dependent Deviation
- from Linearity of the fMRI Response
- (Hemodynamic or Neuronal?)

- >linear

- linear

## Spatial Distribution of the Hemodynamic Response Linearity

**Spatial Distribution of the Hemodynamic Response Linearity**

## Neuronal Activation Input Strategies

**1. Block Design**
**2. Frequency Encoding**
**3. Phase Encoding**
**4. Single Event**
**5. Orthogonal Block Design**
**6. Free behavior Design.**

## Spatial: 0.5 mm

- Spatial: 0.5 mm
- Temporal: 100 ms
- Interpretability...too early to tell, but hopeful

- Ultimate Limits?

## Neuronal Input Strategies

- Peter A. Bandettini, Ph.D
- Unit on Functional Imaging Methods
- Laboratory of Brain and Cognition
- National Institute of Mental Health

## How to get the brain to do what we want it to 

**do in the context of an fMRI experiment?**

**"Interesting"**
** ****Aspects of**
**MR Signal**

**Noise **
**&**
**Artifact**

## Neuronal Activation Input Strategies

**1. Block Design**
**2. Frequency Encoding**
**3. Phase Encoding**
**4. Single Event**
**5. Orthogonal Block Design**
**6. Free behavior Design.**

## Neuronal Activation Input Strategies

**1. Block Design**
**2. Frequency Encoding**
**3. Phase Encoding**
**4. Single Event**
**5. Orthogonal Block Design**
**6. Free behavior Design.**

## Neuronal Activation Input Strategies

**1. Block Design**
**2. Frequency Encoding**
**3. Phase Encoding**
**4. Single Event**
**5. Orthogonal Block Design**
**6. Free behavior Design.**

## Slide 80

**0.08 Hz          0.05 Hz**

**spectral**
**density**

**c.c. > 0.5**
**with spectra**

## Neuronal Activation Input Strategies

**1. Block Design**
**2. Frequency Encoding**
**3. Phase Encoding**
**4. Single Event**
**5. Orthogonal Block Design**
**6. Free behavior Design.**

## Slide 83

## Slide 84

## Neuronal Activation Input Strategies

**1. Block Design**
**2. Frequency Encoding**
**3. Phase Encoding**
**4. Single Event**
**5. Orthogonal Block Design**
**6. Free behavior Design.**

## Slide 86

## Slide 87

## Slide 88

## Slide 89

## 2

- 3

- 4

- 5

- 6

- 7

- 8

- 9

- 10

- 11

- 12

- 13

- Overt Word Production

## Tongue Movement

- Jaw Clenching

## Event-Related fMRI Questions:

**1. What is the optimal ISI?**
**2. How does functional contrast **
** ****compare with “blocked” timing?**
***(Is the hemodynamic response a linear system?)***

## Contrast in Event Related fMRI

**Dependency on:**
**•****Inter-stimulus Interval (ISI)**
**•****Stimulus Duration (SD)**
**Comparison with:**
**•****Blocked strategies**
**•****Synthesized responses created using**
** ****convolution**

## Issues:

**1. ISI Issue**** **
**•****Shorter ISI provides more trials per unit time.**
**•****Shorter ISI causes overlap in hemodynamic **
**response, reducing dynamic range.**
**2. Contrast Issue**
**• ****Does signal behave like a linear system with **
**brief SD?**

## Experimental Methods

**•****Two imaging planes containing motor and **
**visual cortex.**
**•****EPI, 3.75 x 3.75 x 7 mm, TE = 40 ms, TR = 1 sec.**
**•****Time series duration = 360 images (6 minutes).**
**•****10 series compared:**
**Single Trial:**** SD = 2, ISI =  24, 20, 16, 12, 10, 8, 6, 4, 2.**
**Blocked: ****SD = 20, ISI = 20.**
**•****Subjects instructed to tap fingers when GRASS **
**goggles were on.**

**Experimental Methods**

## Visual Cortex

**20, 20**

**ISI, SD**

**12, 2**

**10, 2**

**8, 2**

**6, 2**

**4, 2**

**2, 2**

**ISI, SD**

## Motor Cortex

**Motor Cortex**

**20, 20**

**ISI, SD**

**12, 2**

**10, 2**

**8, 2**

**6, 2**

**4, 2**

**2, 2**

**ISI, SD**

## Motor Cortex

**ISI**

**ISI**

**Visual Cortex**

## Motor Cortex

**ISI**

**ISI**

**Motor Cortex**

**Visual Cortex**

## Contrast to Noise Images

**( ISI, SD )**

**S1**

**S2**

**Contrast to Noise Images**

## 20, 20

**20, 20**

**2, 2**

**( ISI, SD )**

**Motor**

**Visual**

**Relative differences in activation intensities**
**may reflect spatial differences in hemodynamic responsivity. (draining veins vs. capillaries).**

## Functional Contrast

**Functional Contrast**

**( Block design = 1 )**

## *

*****

**Response Synthesis**

**S = k t ****8.6 ****e**** - t / 0.547**

**Cohen, Neuroimage 6, 93-103 (1997)**

## Synthesized Responses

**Synthesized Responses**

**20, 20**

**ISI, Dur**

**12, 2**

**10, 2**

**8, 2**

**6, 2**

**4, 2**

**2, 2**

**ISI, Dur**

## Convolution

**ISI**

**Convolution**

## Functional Contrast

**ISI (sec)**

**1**

**32**

**1**

**32**

**SD (sec)**

**Functional Contrast**

## Functional Contrast

**Functional Contrast**

**( Block design = 1 )**

## Slide 108

## Possible implications for interpretation of event-related

**Possible implications for interpretation of event-related**
**data using short, randomized ISI w/ deconvolution.****	**

**Dale AM, Buckner RL (1997), Human Brain Mapping, 5, 329-340.**

## BOLD response - constant ISI

- ISI = 2 s

- ISI = 4s

- ISI = 8 s

*Tasks can be performed faster by varying the ISI*

## Slide 111

## Slide 112

## Slide 113

## You can go

**You can go**
**even faster with**
**the assumption of **
**linearity...**

## If ISI is randomized,

**If ISI is randomized,**
**and if ON / OFF distribution**
**is 50%, the optimal average**
**ISI is as short as you can **
**make it.**

## BOLD response - varying ISI

- Event-related
- random ISI

- Blocked trial

- Event-related
- constant ISI

- BOLD response

- Stimulus

## fCNR vs. Average ISI

- <date/time>

## Conclusions

**The fMRI signal is able to be ****calibrated****. Physiologic, neuronal, and pulse sequence calibration techniques are just starting to develop to complement pulse sequence advances.**
**-****spatial resolution**** < 0.5 mm**
**-****temporal resolution**** < 100 ms**
**-****information content:**** quantitative flow, CMRO2...**
**A large amount of additional information exists in the fMRI signal (i.e. fluctuations..).**
**To aid the development of calibration, more work needs to be done using extremely well understood neuronal activation (across several temporal, spatial, and intensity scales) to better characterize of the fMRI signal.**

## Neuronal Activation Input Strategies

**1. Block Design**
**2. Frequency Encoding**
**3. Phase Encoding**
**4. Single Event**
**5. Orthogonal Block Design**
**6. Free behavior Design.**

## Neuronal Activation Input Strategies

**1. Block Design**
**2. Frequency Encoding**
**3. Phase Encoding**
**4. Single Event**
**5. Orthogonal Block Design**
**6. Free behavior Design**

## Free behavior Design:

**Free behavior Design:**
**Use the following as “reference functions”**
**Skin Conductance**
**EEG**
**Eye tracking**
**Task performance**
**Heart rate**
**Respiration rate**

## Basic

**Pulse sequences**

**Paradigms**

**Advanced**

**Processing**

**Phase and freq. encoding**

**Orthogonal multi-task encoding**

**Event - related fMRI**

**Parametric manipulation**

**Physiologic fluctuations**

**Motion correction**

**Embedded contrast**

**Effective connectivity mapping**

**<- CMRO****2**** mapping ->**

**Real time fMRI**

**<- Sub - second resolution ->**

**<- Sub - millimeter resolution ->**

**<- Multi - modal integration ->**

** ****Contrast comparisons**

**Shimming**

**RF coil arrays**

**Perfusion quantitation**

**Physiologic manipulations**

**Distortion / dropout correction**

## 1991-1992

**1991-1992**

**1992-1999**

## Slide 124