# Presentation: 740396

## The Biggest Unknowns in Functional MRI

- Peter A. Bandettini, Ph.D
- _[bandettini@nih.gov](mailto:bandettini@nih.gov)_
- Unit on Functional Imaging Methods
- &
- Functional MRI Facility
- Laboratory of Brain and Cognition
- National Institute of Mental Health

## Functional Neuroimaging Techniques

- Log Time (sec)

- Log Size (mm)

- Non-invasive

- Invasive

## Slide 3

## Uses

**Future Uses**

**Understanding normal brain organization and changes**
**	****-networks involved with specific tasks (low to high level processing)**
**	****-changes over time (seconds to years)**
**	****-correlates of behavior (response accuracy, performance changes...)**
**Clinical research**
**	****-correlates of specifically activated networks to clinical populations**
**	****-presurgical mapping**

- Complementary **use for clinical diagnosis**
**	****-utilization of clinical research results**
**	****-prediction of pathology**
**Clinical treatment and assessment**
**	****-drug, therapy, rehabilitation, biofeedback****	**
**	****-epileptic foci mapping**
**	****-drug effects**
**Non clinical uses**
**	****-complementary use with behavioral, anatomical, other modality results**
**	****-lie detection**
**	****-prediction of behavior tendencies **
**	****-brain/computer interface**

## Slide 5

## Type of fMRI research performed

**J. Illes, M. P. Kirschen, J. D. E. Gabrielli, Nature Neuroscience, 6 (3) p.205, 2001**

**Motor (black)**
**Primary Sensory (red)**
**Integrative Sensory (violet)**
**Basic Cognition (green)**
**High-Order Cognition (yellow)**
**Emotion (blue)**

**Type of fMRI research performed**

## Methodology

**Interpretation**

**Applications**

**Technology**

**Neuroscience**

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## 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**

## Flow modulation is not necessarily 

**Flow modulation is not necessarily **
**the same as BOLD modulation**

## Slide 12

## fMRI responses in human V1 are proportional 

- to average firing rates in monkey V1?

- 0.4 spikes/sec -> 1% BOLD

- Rees, G., Friston, K., and Koch, C. 2000. A direct quantitative relationship between the functional properties of human and macaque V5. *Nat. Neurosci. ***3: **716–723.

- Heeger, D. J., Huk, A. C., Geisler, W. S., and Albrecht, D. G. 2000.Spikes versus BOLD: What does neuroimaging tell us about neuronal activity? *Nat. Neurosci. ***3: **631–633.

- 9 spikes/sec -> 1% BOLD

**Notes:**
Towbin Zitat
Bogousslavski Zitat

## Magnitude

**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.**

**Magnitude**

## Magnitude

- 	Relationship between neuronal activity and BOLD.

## Location

- 	Relationship between neuronal activity and BOLD.

## 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***

## 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. **

## NeuroImage, 19: 132-144, (2003). 

*NeuroImage,* **19:** 132-144, (2003)*.*

## Slide 20

## Slide 21

## Relationship between neuronal activity and BOLD.

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## Sources of BOLD dynamic characteristics.

**Yacoub E, Le TH, Ugurbil K, Hu X (1999) Magn Res Med 41(3):436-41**

- Courtesy of Arno Villringer

**Notes:**
Towbin Zitat
Bogousslavski Zitat

## Sources of BOLD dynamic characteristics.

- Pre-undershoot

## Post-undershoot

## Sources of BOLD dynamic characteristics.

**Lu, et al (2004), ISMRM 271**

## 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 “OFF” 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

## 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.**

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## Sources of spatial and temporal variability.

- Latency and Magnitude
- From Subject to Voxel....

## Rapid event-related design with varying ISI

- 25% ON

- 50% ON

- 75% ON

-  8% ON

**R. Birn, et al (2001), OHBM 971**

## Estimated 

*Estimated *
*Impulse Response*

*Predicted Responses *
*to 20 s stimulation *

**R. Birn, et al (2001), OHBM 971**

## Sources of spatial and temporal variability.

- Spatial Variation

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## 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

**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**

## Signal / Thermal Noise

- Signal / Physiologic Noise

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

- Optimal for fMRI

- Signal to Noise Ratio

## Slide 48

## Slide 49

## 0.3 Hz

- Spontaneous Fluctuation Correlation

## What’s really in the noise?

- Correlation with External Measures

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## What is “resting” state?

- Decreases during activation

## Are decreases related 

- Are decreases related
- to resting correlations?

- What is “resting” state?

## Clinical applications?

- What is “resting” state?

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## Blood Volume

## Other sources of functional contrast?

## 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**

**R. Hoge et al.**

## Direct Neuronal Current Imaging

## Active condition: black line

**B: activity**
**C: scanner noise (cooling-pump)**

_**Active**_** condition: black line**
_**Inactive**_** condition: red line**

- Other sources of functional contrast?

- In Vitro Results

**Petridou, et al (2003), HBM**

## Temperature:

- Yablonskiy, D. A., J. J. H. Ackerman, et al. (2000). "Coupling between changes in human brain temperature and oxidative metabolism during prolonged visual stimulation." _Proceedings of the National Academy of Sciences of the United States of America_ **97**(13): 7603-7608.

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## 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).

## 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. **

## Ultimate temporal resolution?

**Magnitude**

- Voxel-wise hemodynamic variation

## Preliminary results: 

**Right Hemisphere**

**Left Hemisphere**

- Hemi-Field Experiment

**Preliminary results:**** **
***(with Savoy et al. ~ 1995)***** **

**Relative dynamics obtained by precise activation timing modulation**

## =

**+ 2.5 s**

**- 2.5 s**

**0 s**

**500 ms**

**500 ms**

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

**Left Hemifield**

**-**

## Ultimate temporal resolution?

- Task Timing Modulation

## Ultimate temporal resolution?

- In an ideal world...no hemodynamic variation over space.

## Neuronal Communication Timing

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## Magnitude

**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.**

**Magnitude**

## Ocular Dominance Column Mapping using fMRI

**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 77

## Parallel acquisition  (16 radio frequency channels)

- Custom-built Radio-frequency (RF) coil

*Nova Medical, Inc.*

## Parallel acquisition  (16 radio frequency channels)

*Parallel acquisition  (16 radio frequency channels)*

- Receiver Hardware

## Individual coil images

- Single combined image

## Parallel acquisition  (16 radio frequency channels)

- Large improvement in signal-to-noise ratio (SNR)

-   Increased resolution
-   Increased imaging speed
-   Increased sensitivity

## Single Shot EPI

**T2* decay**

**EPI Readout Window**

**≈ ****20 to 40 ms**

## Multishot Imaging

**T2* decay**

**EPI Window 2**

## Partial k-space imaging

## ≈ 5 to 30 ms

**≈ ****5 to 30 ms**

**Pruessmann, et al. **

**SENSE Imaging**

## Ultimate spatial resolution?

- Resolving columns with single shot EPI is a goal..

- ...using SENSE, 32 channels, 7T,
- and perhaps partial k-space we might get to 0.5 mm3

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## Ultimate clinical utility?

- Needs:
- 	Real time feedback
- 	Characterization of confounding effects
- 	Robust yet incisive set of probe tasks
- 	Baseline information?

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## Best processing and display methods?

- Classification methods?
- Multivariate methods?
- Connectivity (across time and space scales?)

- Signal and noise models...
- Model free, open ended, methods?

- fMRI data, and noise is time and space varying in predictable and unpredictable ways over several temporal and spatial scales...

- Processing

## Surface

- Glass brain
- ROI
- Time courses
- Example slices
- Connectivity maps?
- “Quality” index?

- To convey:
- -collapsed multidimensional data
- -sense of data quality

- Best processing and display methods?

- Display

## The Biggest Unknowns in Functional MRI

- Relationship between neuronal activity and fMRI.
- Sources of fMRI dynamic characteristics.
- Sources of spatial and temporal variability.
- What’s really in the noise?
- What’s “resting” state?
- Other sources of functional contrast?
- Ultimate temporal resolution?
- Ultimate spatial resolution?
- Ultimate clinical utility?
- Best processing and display methods?
- Optimal field strength?

## Difficulty: 

- Utility vs. Difficulty

- Difficulty:
- Shimming (generally lower T2 and T2*)
- RF penetration effects
- Stability
- Utility:
- Higher SNR
- Better susceptibility contrast
- Better ASL perfusion contrast (longer T1)

## Functional MRI Facility	

**Sean Marrett**
**Jerzy Bodurka**
**Frank Ye**
**Wen-Ming Luh**
**Rasmus Birn**

**Functional Imaging Methods Unit**
**&**
**Functional MRI Facility**

**Program Assistant:**
**Kay Kuhns**

**Computer Specialist:**
**Adam Thomas**

**Post Docs:**
**Hauke Heekeren**
**David Knight**
**Anthony Boemio**
**Niko Kriegeskorte**

**Graduate Student:**
**Natalia Petridou**

**Scanning Technologists:**
**Karen Bove-Bettis**
**Paula Rowser**
**Alda Ottley**
**Ellen Condon**

## Unit on Functional Imaging & FMRI Core Facility

- _[http://sodium.nimh.nih.gov/upload](http://sodium.nimh.nih.gov/upload)_
- T165.ppt