# Presentation: 927909

## Peter A. Bandettini, Ph.D

Unit on Functional Imaging Methods
&
3T Neuroimaging Core Facility

Laboratory of Brain and Cognition
National Institute of Mental Health

- Unit on Functional Imaging Methods
- &
- 3T Neuroimaging Core Facility
- Laboratory of Brain and Cognition
- National Institute of Mental Health

**fMRI: Past, Present, and Future****Limits of Spatial Resolution,**
**Temporal Resolution **
**and Interpretation**

## Technology

**Interpretation**

**Methodology**

**Applications**

## Methodology

**Interpretation**

**Applications**

**Technology**

**Physicists**

**Statisticians**

**Mathematicians**

**Physiologists**

**Neuroscientists**

**Clinicians**

**Engineers**

## Methodology

- 02

- 01

- 00

- 99

- 98

- 97

- 96

- 95

- 94

- 93

- 92

- 91

- 90

- 89

- 88

- 82

**Methodology**

- Hemoglobin

- Blood T2

- IVIM

- Baseline Volume

**Interpretation**

**Applications**

- Volume-V1

- BOLD

- Correlation Analysis

- Linear Regression

- Event-related

- BOLD -V1, M1, A1

- TE dep

- Veins

- IV vs EV

- BOLD models

- ASL

- Deconvolution

- Phase Mapping

- V1, V2..mapping

- Language

- Memory

- Presurgical

- Attention

- PSF of BOLD

- Pre-undershoot

- Ocular Dominance

- Mental Chronometry

- Electrophys. correlation

- 1.5T,3T, 4T

- 7T

- SE vs. GE

- Performance prediction

- Emotion

- Real time fMRI

- Balloon Model

- Post-undershoot

- Inflow

- PET correlation

- CO2 effect

-  CO2 Calibration

- Drug effects

- Optical Im. Correlation

- Imagery

- Clinical Populations

- Plasticity

- Complex motor

- Motor learning

- Venography

- Face recognition

- Children

- Simultaneous ASL and BOLD

- Surface Mapping

- Linearity

- Mg+

- Dynamic IV volume

- Bo dep.

- Diff. tensor

- Volume - Stroke

- Z-shim

- Free-behavior Designs

- Extended Stim.

- Local Human Head Gradient Coils

- NIRS Correlation

- SENSE

- Baseline Susceptibility

- Metab. Correlation

- Fluctuations

- Priming/Learning

- Resolution Dep.

- Tumor vasc.

**Technology**

- EPI on Clin. Syst.

- EPI

- Quant. ASL

- Multi-shot fMRI

- Parametric Design

- Current Imaging?

- Multi-Modal Mapping

- Nav. pulses

- Motion Correction

- MRI

- Spiral EPI

- ASL vs. BOLD

- >8 channels

- Multi-variate Mapping

- ICA

- Fuzzy Clustering

## Thulborn, K. R., J. C. Waterton, et al.  (1982).“Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field.” Biochim. Biophys. Acta. 714: 265-270.

**Thulborn, K. R., J. C. Waterton, et al.  (1982).“Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field.” Biochim. Biophys. Acta. ****71****4: 265-270.**

**L. Pauling, C. D. Coryell, (1936) “The magnetic properties and structure of hemoglobin, oxyhemoglobin, and carbonmonoxyhemoglobin.” Proc.Natl. Acad. Sci. USA***** *****22, 210-216.**

**S. Ogawa, T. M. Lee, A. R. Kay, D. W. Tank, (1990) “Brain magnetic resonance imaging with contrast dependent on blood oxygenation.” Proc. Natl. Acad. Sci. USA 87, 9868-9872.**

**R. Turner, D. LeBihan, C. T. W. Moonen, D. Despres, J. Frank, (1991). Echo-planar time course MRI of cat brain oxygenation changes. Magn. Reson. Med. 27, 159-166.**

## Anatomic

- time

- _Anatomic_

- _Functional_

## Single Shot EPI

**T2* decay**

**EPI Readout Window**

**≈ ****20 to 40 ms**

## Imaging System Components

**X**

**Y**

**Z**

**Gradient Power**
**Systems**

**RF Transmitter**

**Magnet**

**RF Receiver**

**Viewing Console**

**Scan Controller**

## Local gradients solved the problem

**August, 1991**

## 1991-1992

**1991-1992**

**1992-1999**

## Imaging System Components

**X**

**Y**

**Z**

**Gradient Power**
**Systems**

**RF Transmitter**

**Magnet**

**RF Receiver**

**Viewing Console**

**Scan Controller**

## General Electric 3 Tesla Scanner

**General Electric 3 Tesla Scanner**

## Functional MRI Methods

**Blood Volume Imaging**
**BOLD Contrast**
**Arterial Spin Labeling**

## Susceptibility Contrast agent bolus injection and time series collection of T2* or T2 - weighted images

**Blood Volume Imaging**

## Blood Volume

## Susceptibility Contrast

**Susceptibility Contrast**

**Faster**

**Slower**

## BOLD Contrast in the Detection of Neuronal Activity

**BOLD Contrast in the Detection of Neuronal Activity**

**Cerebral Tissue Activation**

**Local Vasodilation**

**Increase in Cerebral Blood**
**Flow and Volume**

**Oxygen Delivery Exceeds**
**Metabolic Need**

**Increase in Capillary and Venous Blood Oxygenation**

**Decrease in Deoxy-hemoglobin**

***Deoxy-hemoglobin: paramagnetic***
***Oxy-hemoglobin: ******	******diamagnetic***

**Decrease in susceptibility-related**
**intravoxel dephasing**

**Increase in T2 and T2***

**Local Signal Increase in T2 and T2* - weighted sequences**

## The BOLD Signal

- _B_lood _O_xygenation _L_evel _D_ependent (BOLD)  signal changes

*task*

*task*

## Alternating Left and Right Finger Tapping 

**Alternating Left and Right Finger Tapping **

**~**** ****1992**

**K. K. Kwong, et al, (1992) “Dynamic magnetic resonance imaging of human brain activity during primary sensory stimulation.” Proc. Natl. Acad. Sci. USA. 89, 5675-5679.**
**S. Ogawa, et al., (1992) “Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging. Proc. Natl. Acad. Sci. USA.” 89, 5951-5955.**
**P. A. Bandettini, et al., (1992) “Time course EPI of human brain function during task activation.”  Magn. Reson. Med 25, 390-397.**
**Blamire, A. M., et al. (1992). “Dynamic mapping of the human visual cortex by high-speed magnetic resonance imaging.” Proc. Natl. Acad. Sci. USA 89: 11069-11073.**

## X

**ON**

**ON**

**ON**

**ON**

**ON**

- Signal Time Course

- Reference Function

- =

**Creating a Functional Image**

- P. A. Bandettini, A. Jesmanowicz, E. C. Wong, J. S. Hyde, Processing strategies for time-course data sets in functional MRI of the human brain. *Magn. Reson. Med.* **30, 161-173 (1993). **

## Cross Correlation Image

- _Cross Correlation Image_
- Anatomical Image

**P. A. Bandettini, A. Jesmanowicz, E. C. Wong, J. S. Hyde, Processing strategies for time-course data sets in functional MRI of the human brain. *****Magn. Reson. Med.***** 30, 161-173 (1993). **

## Correlation analysis, Fourier analysis, t-test, f-test...

**Correlation analysis, Fourier analysis, t-test, f-test...**
**SPM, AFNI, brain voyager, FIASCO, FSL, free surfer...**

***Quality of results and importance of the findings depends on***
***type of question asked, experimental method, and analysis method... ***

## Blood Perfusion

**EPISTAR**

** **

** **

** **

** **

**FAIR**

** **

** **

** **

**. . .**

**. . .**

**Perfusion**
**Time Series**

**-**

**-**

**-**

**-**

## FAIR

**FAIR**

**EPISTAR**

## Williams, D. S., Detre, J. A., Leigh, J. S. & Koretsky, A. S. (1992) “Magnetic resonance imaging of perfusion using 

- Williams, D. S., Detre, J. A., Leigh, J. S. & Koretsky, A. S. (1992) “Magnetic resonance imaging of perfusion using
- spin-inversion of arterial water.” Proc. Natl. Acad. Sci. USA 89, 212-216.
- Edelman, R., Siewert, B. & Darby, D. (1994) “Qualitative mapping of cerebral blood flow and functional localization
- with echo planar MR imaging ans signal targeting with alternating radiofrequency (EPISTAR).” Radiology
**192**, 1-8.
- Kim, S.-G. (1995) “Quantification of relative cerebral blood flow change by flow-sensitive alternating inversion
- recovery (FAIR) technique: application to functional mapping.” Magn. Reson. Med. **34**, 293-301.
- Kwong, K. K. et al. (1995) “MR perfusion studies with T1-weighted echo planar imaging.”Magn. Reson. Med. **34**,
- 878-887.

## Comparison with Positron Emission Tomography

- PET: H215O

- MRI: ASL

## Rest		Activation

*Rest**	**	**Activation*

**Perfusion**

## +				-

**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**

## Methodology

- 02

- 01

- 00

- 99

- 98

- 97

- 96

- 95

- 94

- 93

- 92

- 91

- 90

- 89

- 88

- 82

**Methodology**

- Hemoglobin

- Blood T2

- IVIM

- Baseline Volume

**Interpretation**

**Applications**

- Volume-V1

- BOLD

- Correlation Analysis

- Linear Regression

- Event-related

- BOLD -V1, M1, A1

- TE dep

- Veins

- IV vs EV

- BOLD models

- ASL

- Deconvolution

- Phase Mapping

- V1, V2..mapping

- Language

- Memory

- Presurgical

- Attention

- PSF of BOLD

- Pre-undershoot

- Ocular Dominance

- Mental Chronometry

- Electrophys. correlation

- 1.5T,3T, 4T

- 7T

- SE vs. GE

- Performance prediction

- Emotion

- Real time fMRI

- Balloon Model

- Post-undershoot

- Inflow

- PET correlation

- CO2 effect

-  CO2 Calibration

- Drug effects

- Optical Im. Correlation

- Imagery

- Clinical Populations

- Plasticity

- Complex motor

- Motor learning

- Venography

- Face recognition

- Children

- Simultaneous ASL and BOLD

- Surface Mapping

- Linearity

- Mg+

- Dynamic IV volume

- Bo dep.

- Diff. tensor

- Volume - Stroke

- Z-shim

- Free-behavior Designs

- Extended Stim.

- Local Human Head Gradient Coils

- NIRS Correlation

- SENSE

- Baseline Susceptibility

- Metab. Correlation

- Fluctuations

- Priming/Learning

- Resolution Dep.

- Tumor vasc.

**Technology**

- EPI on Clin. Syst.

- EPI

- Quant. ASL

- Multi-shot fMRI

- Parametric Design

- Current Imaging?

- Multi-Modal Mapping

- Nav. pulses

- Motion Correction

- MRI

- Spiral EPI

- ASL vs. BOLD

- >8 channels

- Multi-variate Mapping

- ICA

- Fuzzy Clustering

## Refinements

**BOLD Contrast Interpretation**
**Dynamics**
**Paradigm Design and Processing**

## Refinements

**BOLD Contrast Interpretation**
**Dynamics**
**Paradigm Design and Processing**

## The Neuroscientists’ Challenge:

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

## The use of fMRI for the Investigation 

- The use of fMRI for the Investigation
- of Brain Function and Physiology

**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*****: limited time and signal to noise, motion, acoustic noise)**
**How much more information can we obtain?**

## ?

**?**

**?**

**?**

## Spin-echo vs. Gradient-echo

## Spin-Echo EPI

**Spin-Echo EPI**

**Gradient-Echo EPI**

## Slide 37

**Gradient - Echo**

**Spin - Echo**

## GE

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

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

## 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

## Effect of diffusion weighting

## Slide 42

## no diffusion weighting

**no diffusion weighting**

**diffusion weighting**

## Slide 44

**b = 0**

**b = 160**

**b = 50**

**b = 10**

## Spin-Echo EPI

**Spin-Echo EPI**

**Gradient-Echo EPI**

**Echo time dependence**

## Slide 47

## Slide 48

## Slide 49

## Perfusion localization vs. BOLD localization

**Perfusion localization vs. BOLD localization**

## T1 - weighted

**T1 - weighted**

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

**T2* weighted**

- P. A. Bandettini, E. C. Wong, Echo - planar magnetic resonance imaging of human brain activation, *in*  "Echo Planar Imaging: Theory, Technique, and Application" (F. Schmitt, M. Stehling, R. Turner, Eds.), p.493-530, Springer - Verlag, Berlin, 1997

***Flow weighted***

***BOLD weighted***

***Flow and BOLD weighted***

## BOLD

**BOLD**

*Rest**	**	**Activation*

**P. A. Bandettini, E. C. Wong, Magnetic resonance imaging of human brain function: principles, practicalities, and possibilities, *****in*****  "Neurosurgery Clinics of North America: Functional Imaging" (M. Haglund, Ed.), p.345-371, W. B. Saunders Co., 1997. **

**Perfusion**

## Anatomy

**Anatomy**

**BOLD**

**Perfusion**

**P. A. Bandettini, E. C. Wong, Magnetic resonance imaging of human brain function: principles, practicalities, and possibilities, *****in*****  "Neurosurgery Clinics of North America: Functional Imaging" (M. Haglund, Ed.), p.345-371, W. B. Saunders Co., 1997. **

## 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**

## Frank Ye, et al.

**BOLD image**

**Perfusion image**

**BOLD signal change**

**Perfusion signal change**

- Simultaneous perfusion and BOLD imaging (10 min, 1.5x1.5x4mm3)

## What Changes with Field Strength?

- Tissue Relaxation Characteristics
- Functional Contrast
- Signal to Noise Ratio
- Bo Inhomogeneity Effects
- RF Power Deposition
- Mechanical Force on Gradient Coil

## Slide 58

## Slide 59

## Whole Brain Anatomy 

- <date/time>

- Whole Brain Anatomy

**T1-SE**                 **T2-FSE**            **FLAIR**

**1.5T**
**3.0T**

**UIC**
**Thulborn**

## 3.0T:   3D TOF MRA 

**15 y.o. female patient****	****57 y.o. male patient**

**Longer T1 at 3.0T enhances flow effects and improves **
**background suppression as well as allows higher spatial resolution**

**UIC**
**Thulborn**

## Slide 62

## Venograms (3T)

**Venograms (3T)**

## Slide 64

## Slide 65

## Slide 66

## Spin-Echo EPI

**Spin-Echo EPI**

**Gradient-Echo EPI**

## Gradient - Echo

**Gradient - Echo**

**Asymmetric**
**Spin - Echo**

## Gradient - Echo

**Gradient - Echo**

**Asymmetric**
**Spin - Echo**

## Gradient - Echo

**Gradient - Echo**

**Asymmetric**
**Spin - Echo**

## Slide 71

## Slide 72

## Slide 73

## Contrast depends on:

- T2*

- T2*

- activation-induced changes in T2* *and* resting T2*

## Slide 75

## Slide 76

## Contrast depends on:

- T2*

- T2*

- activation-induced changes in T2* *and* resting T2*

## Gradient echo Signal Loss

- 100%

- 0%

- 50%

- Signal loss map

- 3 Tesla, 6464, TE=30ms, thk=6mm

## Slide 79

## Slide 80

## Pulse Sequence

*Venous inflow*
*(for ASL, w/ no VN***)**

*Arterial inflow*
*(BOLD TR < 500 ms)*

- Sensitivity

- Spatial
- Heterogeneity

## A few slides about 

**Image Resolution and Noise...**

## Multishot Imaging

**T2* decay**

**EPI Window 2**

## Multi Shot EPI

**Excitations****	****1****	****	****2****	****	****4****	****	****8****	**
**Matrix Size****	****64 x 64****	****128 x 128****	****256 x 128 ****	****256 x 256**

**Multi Shot EPI**

## Partial k-space imaging

## Partial k-space imaging

**Jesmanowicz, P. A. Bandettini, J. S. Hyde, (1998) “Single shot half k-space high resolution EPI for**
**fMRI at 3T.” *****Magn. Reson. Med.***** 40, 754-762.**

## Temporal vs. Spatial SNR- 3T

**26ms**

**49ms**

**SPIRAL**

**EPI**

**27ms**

**50ms**

**26ms**

**49ms**

**27ms**

**50ms**

## 0.25 Hz Breathing at 3T

**Image**

**Respiration map**

**0                      0.25                      0.5  ****Hz**

**0.25 Hz Breathing at 3T**

**3ms**

**26ms**

**49ms**

## 0.68 Hz Cardiac rate at 3T

**3ms**

**26ms**

**49ms**

**0         0.68 (aliased)                 0.5  Hz**

**0.68 Hz Cardiac rate at 3T**

**Power Spectra**

**Image**

**Cardiac map**

## Temporal  S/N vs. Image S/N

- <date/time>

**1400**
**1200**
**1000**
**800**
**600**
**400**
**200**

**0      200       400       600       800      1000     1200     1400**

**PHANTOMS**

**Image S/N**

**Temporal S/N**

***	******	******	******	******	******           ******	******	*****N. Petridou **

**Image S/N**

**Temporal S/N**

**SUBJECTS**

**Temporal  S/N vs. Image S/N**

## Slide 91

## Human data

**Human data**

**Temporal vs. Image S/N**
**Optimal Resolution Study**

**Petridou et al**

## Phantom data

**Phantom data**

**Temporal vs. Image S/N**
**Optimal Resolution Study**

**Petridou et al**

## Signal / Thermal Noise

- Signal / Physiologic Noise

- Resolution, Speed, Surface Coils, Field Strength, etc..

- Optimal for fMRI

- Signal to Noise Ratio

## Slide 95

## Ocular Dominance Column Mapping using fMRI

**calcarine**

**Menon, R. S., S. Ogawa, et al. (1997). “Ocular dominance in human V1 demonstrated by functional magnetic resonance imaging.” **_**J Neurophysiol**_** 77(5): 2780-7.**

**R. D. Frostig et. al, PNAS 87: 6082-6086, (1990).**

**Ocular Dominance Column Mapping using fMRI**

**Optical Imaging**

## Slide 97

## Ziad Saad, et al (Submitted)

- Continuously Growing
- Activation Area

- Inflection Point

- CC Histogram

**Notes:**
(perhaps show only six and keep going up till 22).
This is a plot of the number of activated voxels detected versus the number of averaged scans.
This data is from the 3T.
The red data represents positive responses and the green data represents negative responses. 
Different dots at any one number of average scans represents the estimates from the different permutations.
The curves represent linear fits to the average number of activated voxels versus Navg.
Note the dramatic increase in the number of activated voxels with Navg. This function fits a linear curve with a correlation of ~92-97%. 
Note also the very large scatter of the number of activated voxels for voxels in a single rep. (perhaps put the subject performance and the number of voxels versus repno here ...)

## Refinements

**BOLD Contrast Interpretation**
**Dynamics**
**Paradigm Design and Processing**

## P. A. Bandettini, Functional MRI temporal resolution in  "Functional MRI" (C. Moonen, and P. Bandettini., Eds.), p. 205-220, Springer - Verlag,. 1999. 

**P. A. Bandettini, Functional MRI temporal resolution *****in*****  "Functional MRI" (C. Moonen, and P. Bandettini., Eds.), p. 205-220, Springer - Verlag,. 1999. **

**P. A. Bandettini, K. K. Kwong, T. L. Davis, R. B. H. Tootell, E. C. Wong, P. T. Fox, J. W. Belliveau, R. M. Weisskoff, B. R. Rosen, (1997). “Characterization of cerebral blood oxygenation and flow changes during prolonged brain activation.” *****Human Brain Mapping***** 5, 93-109.**

## Motor Cortex

**Motor Cortex**

**Auditory Cortex**

**S. M. Rao et al, (1996) “Relationship between finger movement rate and functional magnetic resonance signal change in human primary motor cortex.” *****J. Cereb. Blood Flow and Met.***** 16, 1250-1254.**

**J. R. Binder, et al, (1994). “Effects of stimulus rate on signal response during functional magnetic resonance imaging of auditory cortex.” *****Cogn. Brain Res.***** 2, 31-38**

## Logothetis et al. (2001) “Neurophysiological investigation of the basis of the fMRI signal” Nature, 412, 150-157

**S. M. Rao et al, (1996) “Relationship between finger movement rate and functional magnetic resonance signal change in human primary motor cortex.” *****J. Cereb. Blood Flow and Met.***** 16, 1250-1254.**

## First Event-related fMRI Results

**Blamire, A. M., et al. (1992). “Dynamic mapping of the human visual cortex by high-speed magnetic resonance imaging.” Proc. Natl. Acad. Sci. USA 89: 11069-11073.**

**First Event-related fMRI Results**

## R. L. Savoy, et al., Pushing the temporal resolution of fMRI: studies of very brief visual stimuli, onset variability and asynchrony, and stimulus-correlated changes in noise [oral], 3'rd Proc. Soc. Magn. Reson., Nice, p. 450. (1995). 

- R. L. Savoy, et al., Pushing the temporal resolution of fMRI: studies of very brief visual stimuli, onset variability and asynchrony, and stimulus-correlated changes in noise [oral], 3'rd Proc. Soc. Magn. Reson., Nice, p. 450. (1995).

## Slide 106

## Methods

- 16 s

- Stimulus Duration (SD)

- SD = 250 ms

- SD = 500 ms

- SD = 1000 ms

- SD = 2000 ms

- ...

- ...

- ...

- ...

- 20 s

- Blocked Trial

*Visual*

- SD = 500 ms

- SD = 1000 ms

- SD = 2000 ms

- SD = 4000 ms

*Motor*

- ...

## Different stimulus “ON” periods

- measured

- linear

- Signal

- 0.25 s

- 0.5 s

- 1 s

- 2 s

- 20 s

- Stimulus
- timing

- BOLD
- Response

*Brief stimuli produce larger responses than expected*

**Dynamic Nonlinearity Assessment**

**R. M. Birn, Z. Saad, P. A. Bandettini, (2001) “Spatial heterogeneity of the nonlinear dynamics in the fMRI BOLD response.” *****NeuroImage*****, 14: 817-826.**

## BOLD response is nonlinear

*Short duration stimuli produce larger responses than expected*

- Observed response

- Linear response

## Spatial Heterogeneity of BOLD Nonlinearity

**R. M. Birn, Z. Saad, P. A. Bandettini, (2001) “Spatial heterogeneity of the nonlinear dynamics in the fMRI BOLD response.” *****NeuroImage*****, 14: 817-826.**

**Spatial Heterogeneity of BOLD Nonlinearity**

## Results – visual task

- Nonlinearity

- Magnitude

- Latency

**R. M. Birn, Z. Saad, P. A. Bandettini, (2001) “Spatial heterogeneity of the nonlinear dynamics in the fMRI BOLD response.” *****NeuroImage*****, 14: 817-826.**

## Results – motor task

- 2

- 4

- 6

- 8

- 0

- 1

- 2

- 3

- 4

- 5

- Stimulus Duration

- f (SD)

## Results – motor task

- Nonlinearity

- Magnitude

- Latency

## Reproducibility

- Nonlinearity2

- Nonlinearity1

- Nonlinearity2

- Nonlinearity1

*Visual task*

*Motor task*

- Experiment 1

- Experiment 2

- Experiment 1

- Experiment 2

**Notes:**
Even though we find a large variation in nonlinearity that is not significantly correlated with either magnitude or latency, the spatial maps of nonlinearity are reproducible, shown here for the computed nonlinearities plotted for two separate runs at all the stimulus durations.  

## Different stimulus “ON” periods

- Stimulus
- timing

- BOLD
- Response

- measured

- linear

- Signal

- 2 s

- 3 s

- 4 s

- 8 s

- 16 s

*Brief stimulus OFF periods produce smaller decreases than expected*

## Sources of this Nonlinearity

- Neuronal
- Hemodynamic
- Oxygen extraction
- Blood volume dynamics

- Volume

- Flow In

- Flow Out

- Oxygen Extraction

## BOLD Correlation with Neuronal Activity

**Logothetis et al. (2001) “****Neurophysiological investigation of the basis of the fMRI signal” ****Nature, 412, 150-157.**

**P. A. Bandettini and L. G. Ungerleider, (2001) “From neuron to BOLD: new connections.” Nature Neuroscience, 4:  864-866.**

## Results – constant gratings

- Results – constant gratings

- 0

- 1000

- 2000

- 3000

- 0

- 1

- 2

- 3

- Measured Amplitudes

- Stimulus Duration (ms)

- Amplitude (%)

- Estimated
- Neuronal
- activity

**a** = initial slope

**b** = final slope

- 200

*Simulation*

**Notes:**
Averaged over ROI (entire activated region) and across 5 subjects.  (Each subject showed a similar response, but noisier.)

What can be seen: 

## Slide 119

## Refinements

**BOLD Contrast Interpretation**
**Dynamics**
**Paradigm Design and Processing**

## Slide 121

## Slide 122

## Neuronal Activation Input Strategies

**Block Design**
**2. Parametric Design**
**3. Frequency Encoding**
**4. Phase Encoding**
**5. Event Related**
**6. Orthogonal Design**
**7.**** ****Free Behavior Design**

## Neuronal Activation Input Strategies

**Block Design**
**2. Parametric Design**
**3. Frequency Encoding**
**4. Phase Encoding**
**5. Event Related**
**6. Orthogonal Design**
**7. Free Behavior Design**

## E. A. DeYoe, P. A. Bandettini, J. Nietz, D. Miller, P. Winas, Methods for functional magnetic resonance imaging (FMRI). J. Neuroscience Methods 54, 171-187 (1994). 

**E. A. DeYoe, P. A. Bandettini, J. Nietz, D. Miller, P. Winas, Methods for functional magnetic resonance imaging (FMRI). *****J. Neuroscience Methods***** 54, 171-187 (1994). **

## Neuronal Activation Input Strategies

**Block Design**
**2. Parametric Design**
**3. Frequency Encoding**
**4. Phase Encoding**
**5. Event Related**
**6. Orthogonal Design**
**7. Free Behavior Design**

## P. A. Bandettini, A. Jesmanowicz, E. C. Wong, J. S. Hyde, Processing strategies for time-course data sets in functional MRI of the human brain. Magn. Reson. Med. 30, 161-173 (1993). 

**P. A. Bandettini, A. Jesmanowicz, E. C. Wong, J. S. Hyde, Processing strategies for time-course data sets in functional MRI of the human brain. *****Magn. Reson. Med.***** 30, 161-173 (1993). **

**0.08 Hz          0.05 Hz**

**spectral**
**density**

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

**P. A. Bandettini, A. Jesmanowicz, E. C. Wong, J. S. Hyde, Processing strategies for time-course data sets in functional MRI of the human brain. *****Magn. Reson. Med.***** 30, 161-173 (1993). **

## Neuronal Activation Input Strategies

**Block Design**
**2. Parametric Design**
**3. Frequency Encoding**
**4. Phase Encoding**
**5. Event Related**
**6. Orthogonal Design**
**7. Free Behavior Design**

## Slide 130

## Slide 131

## Neuronal Activation Input Strategies

**Block Design**
**2. Parametric Design**
**3. Frequency Encoding**
**4. Phase Encoding**
**5. Event Related**
**6. Orthogonal Design**
**7. Free Behavior Design**

## Word stem completion

## Slide 134

## Slide 135

## Slide 136

## Event Related Advantages

**Task Randomization**
**Post acquisition, Performance-based, data binning**
**Natural presentation**
**Reduction of habituation effects**
**Overt responses**
**Reduction of scanner noise effects**
**More precise estimation of hemodynamic response**

## Speaking - Blocked Trial

## fMRI during tasks that involve brief motion

- BOLD response

- motion

- task

- _Blocked Design_

- _Event-Related Design_

**R. M. Birn, P. A. Bandettini, R. W. Cox, R. Shaker, Event - related fMRI of tasks involving brief motion.***** Human Brain Mapping *****7: 106-114 (1999). **

## R. M. Birn, P. A. Bandettini, R. W. Cox, R. Shaker, Event - related fMRI of tasks involving brief motion. Human Brain Mapping 7: 106-114 (1999). 

**R. M. Birn, P. A. Bandettini, R. W. Cox, R. Shaker, Event - related fMRI of tasks involving brief motion.***** Human Brain Mapping *****7: 106-114 (1999). **

## Speaking - ER-fMRI

- Expected
- Response

**R. M. Birn, P. A. Bandettini, R. W. Cox, R. Shaker, Event - related fMRI of tasks involving brief motion.***** Human Brain Mapping *****7: 106-114 (1999). **

## Tongue Movement

- Jaw Clenching

## Motion

**Recognize?**
**Edge effects**
**Shorter signal change latencies**
**Unusually high signal changes**
**External measuring devices**
**Correct?**
**Image registration algorithms**
**Orthogonalize to motion-related function *****(cardiac, respiration, movement)***
**Navigator echo for k-space alignment ****	****	*****(for multishot techniques)***
**Re-do scan**
**Bypass?**
**Paradigm timing strategies..**
**Gating (with T1-correction)**
**Suppress?**
**Flatten image contrast**
**Physical restraint**
**Averaging, smoothing**

## 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**

## P. A. Bandettini, R. W. Cox. Functional contrast in constant interstimulus interval event - related fMRI: theory and experiment. Magn. Reson. Med. 43: 540-548 (2000). 

**P. A. Bandettini, R. W. Cox. Functional contrast in constant interstimulus interval event - related fMRI: theory and experiment. *****Magn. Reson. Med. *****43: 540-548 (2000). **

## Contrast to Noise Images

**( ISI, SD )**

**S1**

**S2**

**Contrast to Noise Images**

**P. A. Bandettini, R. W. Cox. Functional contrast in constant interstimulus interval event - related fMRI: theory and experiment. *****Magn. Reson. Med. *****43: 540-548 (2000). **

## 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).**

**Bandettini, et al., The functional dynamics of blood oxygenation level contrast in the motor cortex, 12'th Proc. Soc. Magn. Reson. Med., New York, p. 1382. (1993). **

## Slide 150

## M.A. Burock et al. NeuroReport, 9, 3735-9 (1998)

## Detectability – constant ISI

- Average ISI (s)

- Detectability

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- 40

- SD – stimulus duration

- ISI – inter-stimulus interval

## Detectability vs. Average ISI

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- 40

- average ISI (s)

- Detectability

- SD = 1000 ms.

- SD = 250 ms.

- SD = 4000 s.

**R. M. Birn, R. W. Cox, P. A. Bandettini, Detection versus estimation in Event-Related fMRI: choosing the optimal stimulus timing. *****NeuroImage***** 15: 262-264, (2002). **

## Estimation accuracy vs. average ISI

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- 40

- 0

- 5

- 10

- 15

- 20

- average ISI (sec)

- Estimation Accuracy

- SD = 4000 ms.

- SD = 1000 ms.

- SD = 250 ms.

**R. M. Birn, R. W. Cox, P. A. Bandettini, Detection versus estimation in Event-Related fMRI: choosing the optimal stimulus timing. *****NeuroImage***** 15: 262-264, (2002). **

## Slide 155

## Varying “ON” and “OFF” periods

*Rapid event-related design with varying ISI*

- 25% ON

- 50% ON

- 75% ON

-  8% ON

## Varying “ON” and “OFF” periods

*Estimated *
*Impulse Response*

*Predicted Responses *
*to 20 s stimulation *

## Neuronal Activation Input Strategies

**Block Design**
**2. Parametric Design**
**3. Frequency Encoding**
**4. Phase Encoding**
**5. Event Related**
**6. Orthogonal Design**
**7. Free Behavior Design**

## Example of a Set of Orthogonal Contrasts for Multiple Regression

**Courtney, S. M., L. G. Ungerleider, et al. (1997). “Transient and sustained activity in a distributed neural system for human working memory.” **_**Nature**_** 386(6625): 608-11.**

## Neuronal Activation Input Strategies

**Block Design**
**2. Parametric Design**
**3. Frequency Encoding**
**4. Phase Encoding**
**5. Event Related**
**6. Orthogonal Design**
**7.**** ****Free Behavior Design**

## Free Behavior Design

**Use a continuous measure as a reference function:**
**Task performance**
**Skin Conductance**
**Heart, respiration rate..**
**Eye position**
**EEG**

## The Skin Conductance Response (SCR)

- Sympathetic Nervous System

- _Ventromedial PFC_

- Hypothalamus

- Resistance change across
- two electrodes induced
- by changes in sweating.

- Sweat Gland

- Orbitofrontal Cortex

**Patterson et al. (submitted)**

## Brain activity correlated with SCR during “Rest”

**Patterson et al. (submitted)**

## OHBM 2002

**OHBM 2002**

## Resting Hemodynamic Autocorrelations

- low frequency autocorrelation map

- conventional BOLD map

- B. Biswal *et al*., MRM, 34:537 (1995)

## Calibration methods for

**Temporal Resolution and **
**Interpretation...**

##  Neuronal Activity

- Number of Neurons

- Spiking Rate

- Local Field Potential

- Metabolism

- Hemodynamics

- Blood
- Volume

- Flow Velocity

- Aerobic Metabolism

- Anaerobic Metabolism

- BOLD Contrast

**-**

**-**

- Spiking Coherence

- Deoxy-Hb

- Oxygenated
- Blood

- Deoxygenated
- Blood

**+**

- MRI Pulse
- Sequence

- Perfusion

- Perfusion Contrast

- Inflow Contrast

## Slide 168

## Latency

**Latency**

**Magnitude**

**+ 2 sec**

**- 2 sec**

**P. A. Bandettini, The temporal resolution of Functional MRI *****in*****  "Functional MRI" (C. Moonen, and P. Bandettini., Eds.), p. 205-220, Springer - Verlag,. 1999. **

## Venograms (3T)

**Venograms (3T)**

## Slide 171

## Hemi-Field Experiment

**Right Hemisphere**

**Left Hemisphere**

## =

**+ 2.5 s**

**- 2.5 s**

**0 s**

**500 ms**

**500 ms**

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

**Left Hemifield**

**-**

**Calibration Techniques.....**

**P. A. Bandettini, The temporal resolution of Functional MRI *****in*****  "Functional MRI" (C. Moonen, and P. Bandettini., Eds.), p. 205-220, Springer - Verlag,. 1999. **

## 0

- 5

- 10

- 15

- 20

- 25

- 30

- 100

- 200

- 300

- 400

- 500

- Number of runs

- 8 sec on/off

- 16 sec on/off

- Smallest latency
- Variation Detectable
- (ms) (p < 0.001)

- t

- 1 run:

- -1000

- -500

- 500

- 1000

- Number

- delay estimate (ms)

- delay = 107ms

**11**

- 1% Noise
- 4% BOLD
- 256 time pts /run
- 1 second TR

## Hemodynamic Response Modulation

**Bottleneck**
**In Processing**
**(upstream)**

**Delayed**
**Processing**
**(downstream)**

**Hemodynamic Response Modulation**

## Use of Task Timing Modulation to Extract Processing Streams  

- Use of Task Timing Modulation to Extract Processing Streams

- Stimuli – Six-letter English words and pronounceable non-words.
- 	   Each word or non-word was rotated either 0, 60,or 120 degrees
- Task – Lexical Decision (word / non-word).
- Dependent Measures – Percent Correct and Reaction Time.

- Hypotheses :
- 	**1) Stimulus rotation of 120 degrees will result in:**
- 		a) Longer Reaction Times
- 		b) Stimulus rotation demands a change in perceptual
- 		perspective prior to linguistic processing. This will
- 		result in a delayed IRF onset in areas involved in
- 		Lexical and Pre-Lexical processing.
- 	 2**) Lexical discrimination will result in :**
- 		a) Longer Reaction Times for non-words due to
- 		increased Pre-Lexical processing demands.
- 		b) Wider IRF in Inferior Frontal cortex for non-words
- 		c) Delayed IRF onset in Left Middle Frontal Cortex

## Lexical Delay

- smudge

- slouch

- dierts

- cuhlos

- gedmus

**Lexical Delay**

- Words

- Non-Words

**Rotational Delay**

- 00

- 600

- 1200

- Mean
- Reaction Time

- 823 ms

- 891 ms

- 1446 ms

- 986 ms

- 1219 ms

- Mean
- Reaction Time

## Slide 178

## Graphs depicting the estimated Impulse Response Functions.

**Inferior Frontal Gyrus**

**Middle Temporal Gyrus**

**Pre-Central Gyrus**

**Magnitude**

**Delay**

**Width**

- Warm colors are areas where Words > Non-words.  Cool colors (blues) are areas
- Where Non-words > words. The Left hemisphere is toward the left margin.
- The green arrows highlight the inferior frontal gyrus.

## Laminar Specificity of fMRI Onset Times During Somatosensory Stimulation in Rat

**Afonso C. Silva and Alan P. Koretsky**
***Laboratory of Functional and Molecular Imaging***
**National Institute of Neurological Disorders and Stroke**
**Bethesda, Maryland, USA**

## Can fMRI be used to distinguish neuronal signaling within laminar sub-regions of the brain?

## fMRI Methods

- 11.7T/31cm magnet (Magnex Scientific, Ltd.)
- AVANCE electronics (Bruker-Biospin, Inc.)
- Conventional gradient-echo images
- FOV = 1.28 x 1.28 x 0.2 cm3
- TE = 10 ms, TR = 40 ms, tip-angle ≈ 11°
- Matrix size:
- 64 x 64 (200 x 200 x 2000 m3), 2.5 s/frame
- 128 x 128 (100 x 100 x 2000 m3, 5.0 s/frame
- 256 x 256 (50 x 50 x 2000 m3), 10 s/frame
- CBV: 20 mg/kg of AMI-227 (Advanced Magnetics, MA)

## Somatosensory Stimulation 

- Electrical stimulation of the forepaw:
- Two needle electrodes inserted subcutaneously
- Stimulation parameters: 2.0 mA; 3 Hz; 0.3 ms
- Paradigm:
- Single stimulation **off – on – off** epoch
- 	               24        12      24   images
- 	               60        30      60   seconds,   200 x 200 m2
-                    240      120    240   seconds,     50 x   50 m2
-   Multiple stimuli block design
- 	                     325     100    325   images     200 x 200 m2
- 		               13         4      13   seconds,   repeated 64 times

## MRI of Functional Hemodynamics

- Gradient-Echo Sequence
- Resolution = 100x100x2000 m3

- Iron Oxide Contrast Agent
- Resolution = 100x100x2000 m3

- BOLD

- rCBV

## Mapping Onset Times of fMRI Response

- Hemodynamic response is stable if duty-cycle of repeated stimuli is low enough
_*Strategy*_: to acquire multiple high-resolution images using conventional GRE-MRI, swapping phase-encode loop with image repetition loop to obtain one k-space line for all images per stimulus epoch
- Spatial in-plane resolution: 200 x 200 m2
- Temporal resolution: 40 ms

## Averaged BOLD Time-Courses

## Onset Time Detail

## 5% CO2

**5% CO2**

**12% O2**

## N=12

**CBF**

**BOLD**

**Simultaneous Perfusion and BOLD imaging during **
**graded ****visual activation**** and ****hypercapnia**

**Notes:**
here we see the resultant perfusion and BOLD responses;
on the left, we see that the perfusion increases evoked by the two stimulus types are well matched...
while on the right we see that the BOLD signals are significantly different.
what is happening here is that increased dHb production associated with accelerated aerobic metabolism during brain activation is attenuating the visually evoked BOLD signal.

## Computed CMRO2 Changes

- Computed CMRO2 Changes

**Subject 1**

**Subject 2**

**%**

**%**

**40**

**0**

**10**

**20**

**30**

**-10**

**-20**

**-30**

**-40**

## CBF

**CBF**

**OEF**

**CMRO****2**

## 11026–11031  PNAS  September 26, 2000 vol. 97  no. 20

## Future....

**Acoustic Noise**
**Multishot Techniques**
**Increased Gradient Performance**
**Higher Field Strengths**
**Surface Coil Arrays**
**Calibration / Quantification**
**Embedded Functional Contrast**
**Noise / Fluctuations**
**Direct Neuronal Current Imaging**
**Clinical Populations**
**Neuronal,Vascular, and Metabolic Information**

**Future....**

## Pulse

- Sequence

- Stimulus

- Response

- Image
- Reconstruction

- Image Registration/
- Motion Detection

- Time Series
- Analyses

- Compute & Display
- Neuropsychological
- Stuff

**Investigator**

**Processing Stream with Real Time fMRI**

## The

**The**
**End**

**< 1 s to render**

**Blocked trials:**
**  ****20 s on/20 s off**
**  ****8 blocks**

**Color shows**
**  ****through brain**

**Correlation > 0.45**

**Blocks**: _1_

- _2_

- _3_

- _4_

- _5_

- _6_

- _7_

- _8_

## 2 G/cm, 350 T/m/s

- 4 G/cm, 150 T/m/s

- Diffusion imaging
- Faster imaging
- Higher resolution

## Neuronal

**Neuronal**
**Current**
**Imaging**

**J. Bodurka, P. A. Bandettini. Toward direct mapping of neuronal activity: MRI detection of ultra weak transient magnetic field changes,***** Magn. Reson. Med***** 47: 1052-1058, (2002)***** ***

## Methodology

- 02

- 01

- 00

- 99

- 98

- 97

- 96

- 95

- 94

- 93

- 92

- 91

- 90

- 89

- 88

- 82

**Methodology**

- Hemoglobin

- Blood T2

- IVIM

- Baseline Volume

**Interpretation**

**Applications**

- Volume-V1

- BOLD

- Correlation Analysis

- Linear Regression

- Event-related

- BOLD -V1, M1, A1

- TE dep

- Veins

- IV vs EV

- BOLD models

- ASL

- Deconvolution

- Phase Mapping

- V1, V2..mapping

- Language

- Memory

- Presurgical

- Attention

- PSF of BOLD

- Pre-undershoot

- Ocular Dominance

- Mental Chronometry

- Electrophys. correlation

- 1.5T,3T, 4T

- 7T

- SE vs. GE

- Performance prediction

- Emotion

- Real time fMRI

- Balloon Model

- Post-undershoot

- Inflow

- PET correlation

- CO2 effect

-  CO2 Calibration

- Drug effects

- Optical Im. Correlation

- Imagery

- Clinical Populations

- Plasticity

- Complex motor

- Motor learning

- Venography

- Face recognition

- Children

- Simultaneous ASL and BOLD

- Surface Mapping

- Linearity

- Mg+

- Dynamic IV volume

- Bo dep.

- Diff. tensor

- Volume - Stroke

- Z-shim

- Free-behavior Designs

- Extended Stim.

- Local Human Head Gradient Coils

- NIRS Correlation

- SENSE

- Baseline Susceptibility

- Metab. Correlation

- Fluctuations

- Priming/Learning

- Resolution Dep.

- Tumor vasc.

**Technology**

- EPI on Clin. Syst.

- EPI

- Quant. ASL

- Multi-shot fMRI

- Parametric Design

- Current Imaging?

- Multi-Modal Mapping

- Nav. pulses

- Motion Correction

- MRI

- Spiral EPI

- ASL vs. BOLD

- >8 channels

- Multi-variate Mapping

- ICA

- Fuzzy Clustering

## FIM Unit & FMRI Core Facility 	

**Peter Bandettini**
**Staff Scientists:**
**Sean Marrett**
**Jerzy Bodurka**
**Frank Ye**
**Wen-Ming Luh**
**Computer Specialist:**
**Adam Thomas**
**Post Docs:**
**Rasmus Birn**
**Hauke Heekeren**
**David Knight**
**Patrick Bellgowan**
**Ziad Saad**

**FIM Unit & FMRI Core Facility **

**Graduate Student:**
**Natalia Petridou**
**Post-Back. IRTA Students:**
**Elisa Kapler**
**August Tuan**
**Dan Kelley**
**Visiting Fellows:**
**Sergio Casciaro**
**Marta Maieron**
**Guosheng Ding**
**Clinical Fellow:**
**James Patterson**
**Psychologist:**
**Julie Frost**

**Summer Students:**
**Hannah Chang**
**Courtney Kemps**
**Douglass Ruff**
**Carla Wettig**
**Kang-Xing Jin**** **
**Program Assistant:**
**Kay Kuhns**
**Scanning Technologists:**
**Karen Bove-Bettis**
**Paula Rowser**