A. Blood oxygenation-level dependent (BOLD) functional imaging techniques

B. Perfusion Imaging and Perfusion-based fMRI Techniques

C. Relative Oxygen Consumption Measurement from BOLD and CBF data

D. Arterial and Venous Blood Volume Measurements

E. Tissue Oxygen Tension Measurement

F. Synaptic Activity Based Functional Imaging Technique

A. Blood oxygenation-level dependent (BOLD) functional imaging techniques:
 
 

Seiji Ogawa at AT&T Bell Laboratories observed T2*-weighted imaging signal modulations induced by oxygenation level changes in rat brains at 1990. This observation is referred to as a "BOLD" contrast. During increased neural activity, an oxygen consumption (metabolism) rate does not increase to a level of cerebral blood flow (CBF) change, resulting in an increase in venous oxygenation level and an increase in T2/T2*-weighted MRI signal. Following his initial BOLD observation in rats, Dr. Ogawa collaborated with us for detecting neural activity-induced BOLD signal changes in humans. The first observation of BOLD-based functional MRI (referred to as "fMRI") in humans during visual stimulation was reported at journal PNAS at 1992. Since then, my laboratory involved many aspects of technical developments of BOLD-based functional MRI including high-resolution fMRI, spin-echo fMRI, and diffusion-weighted fMRI. True single-trial fMRI has been developed in my laboratory.

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Related (selected) references:

The original human fMRI paper:
Ogawa, S., Tank, D.W., Menon, R., Ellermann, J.M., Kim, S.-G., Merkle, H. and Ugurbil, K. "Intrinsic Signal Changes Accompanying Sensory Stimulation: Functional Brain Mapping with Magnetic Resonance Imaging", Proc. Natl. Acad. Sci. USA, 89: 5951-5955, 1992  Medline(PDF file).

Reproducibility and Test-Retest of BOLD functional images:
Tegeler C, Strother SC, Anderson JR, Kim SG.  "Reproducibility of BOLD based functional MRI obtained at 4 T", Human Brain Mapping, 7: 267-283, 1999. Medline(PDF file)

BOLD fMRI vs. PET functional maps in the same subject, same area, and same task:
 

We acquired fMRI images using BOLD and FAIR techniques at 4 Tesla, and water-based PET images in the same subjects during finger opposition.  We  co-registered PET and fMRI images using linear and non-linear transformation, and matched spatial resolution using spatial smoothing.  Activation maps (right figure) derived from matched fMRI and PET images are consistent even though large variations in the size of activation areas and its SNR across three modalities existed.  Three subject's functional images (three columns) during finger opposition using BOLD (top row), FAIR (2nd row), PET (3rd row), and noise-matched PET (bottom row) techniques.  The first three-rows images have the same spatial resolution.  Activation at the contralateral primary motor area (the left side of brain images) was observed in all subjects and all modalities.  Note that BOLD has the highest CNR, but is sensitive to draining veins.   Zaini, MR, Strother, SC, .Anderson, JR, Liow, JS, Kjems, U. Tegeler,  C and S.-G. Kim, "Comparison of matched BOLD and FAIR 4.0T-fMRI with [15O]water PET brain Volumes", Medical Physics, 26: 1559-1567, 1999. Medline


 

Technical  and Mechanistic Aspects (see also the Physiology section)

High-resolution functional MRI technique with Navigator Echo correction:
Kim SG, Hu X, Adriany G, Ugurbil K  "Fast Interleaved Echo-Planar Imaging with Navigator: High Resolution Anatomic and Functional Images at 4 Tesla", Magn. Reson. Med., 35: 895-902, 1996 Medline.

Navigator Echo Physiological Mation Correction:
Hu, X. and Kim, S.-G. "Reduction of Signal Fluctuation in Functional Imaging Using Navigator Echo", Magn. Reson. Med., 31: 495-503, 1994. Medline

Spin-echo BOLD fMRI technique at High Fields:
Lee SP, Silva AC, Ugurbil K, Kim SG  "Diffusion-weighted Spin-echo fMRI at 9.4T: Microvascular/tissue Contribution to BOLD Signal Changes", Magn. Reson. Med., 42: 919-928, 1999 Medline(PDF file).

BOLD mechanisms (see also Physiology section):
Kim, S.-G. et al. "Potential Pitfalls of Functional MRI using Conventional Gradient-Recalled Echo Techniques", NMR in Biomedicine, 7: 69-74, 1994. Medline

Lee, S.-P. et al. "Diffusion-weighted Spin-echo fMRI at 9.4T: Microvascular/tissue Contribution to BOLD Signal Changes", Magn. Reson. Med., 42: 919-928, 1999

Ogawa, S., Menon, R.S., Tank, D.W., Kim, S.-G., Merkle, H., Ellermann, J.M., and Ugurbil, K., "Functional Brain Mapping by blood oxygenation level-dependent contrast magnetic resonance imaging: A comparison of signal characteristics with a biophysical model", Biophys. J., 64: 803-812, 1993. Medline

S. Ogawa, R.S. Menon, S.-G. Kim, and K. Ugurbil, "On the characteristics of functional MRI of the brain", Annual Review of Biophysics and Biomolecular Biology, 27: 447-74, 1998.  (PDF file)  Medline
 
 

Single-Trial Event-related fMRI

Time-resolved Single-trial Event-related fMRI (see also Temporal section):
Kim, S.-G., Richter, W. and Ugurbil, K., "Limitations of Temporal Resolution in Functional MRI", Magn. Reson. Med., 37: 631-636, 1997. Medline

Richter, W., Andersen, P.M., Georgopoulos, A.P. and Kim, S.-G. "Sequential activity in human motor areas during a delayed cued finger movement task studied by time-resolved fMRI",  NeuroReport, 8: 1257-1261, 1997  Medline.
 
 

Review Articles
Kim, S.-G. and Ugurbil, K., "Functional Magnetic Resonance Imaging of the Human Brain", J. Neuroscience Methods, 74: 229-243, 1997  Medline.

Ugurbil K, Hu X, Chen W, Zhu XH, Kim SG, Georgopoulos A  "Functional mapping in the human brain using high magnetic fields", Phil. Trans. R. Soc. London B, 354: 1195-1213, 1999 Medline(PDF file).

K. Ugurbil, et al., "Magnetic Resonace Studies of Brain Function and Neurochemistry" Annu. Rev. Biomed. Eng. 2000. 02:633-60 (PDF file).

B. Perfusion Imaging and Perfusion-based fMRI Techniques:
 

Our laboratory is a forefront of perfusion NMR/MRI technical developments. PI as a graduate student at Joseph Ackerman's laboratory developed a deuterium NMR technique to measure tissue perfusion using deuterated water as a freely diffusible flow tracer. My lab developed a pulsed arterial spin tagging method, known as FAIR (flow-sensitive alternating inversion recovery) technique at 1995, using arterial blood water as an endogenous flow tracer. Two images are acquired; one with slice-selective inversion (with inflow), and the other with global inversion as a control. Difference of the two images is directly related to blood flow. This FAIR technique is widely used in human studies.  We validated this FAIR technique for quantitative CBF measurements.  The first approach was to compare quantitative CBF values in rats measured by using FAIR and iodoantipyrine autoradiographic techniques during normo- and hypercapnia in the same experimental conditions and in the same region (Tsekos et al., MRM, 1998).   We found that CBF values measured by the two methods agree extremely well.  The second approach was to compare relative CBF changes of the human motor cortex during finger movements measured by FAIR and PET in the same subject and same region (Zaini et al., 1999).  Relative CBF changes were consistent, suggesting the FAIR technique can provide accurate relative CBF changes. We also implemented continuous arterial spin tagging methods in animal NMR systems because of its superior sensitivity. To obtain dynamic blood flow changes due to perturbations, pseudo-continuous arterial spin tagging method was developed. Two images were obtained separately; one with continuous arterial spin tagging, and the other without spin tagging. Difference of the two images is related to CBF changes. We successfully achieved 100 msec temporal resolution. Arterial spin tagging methods (FAIR, continuous arterial spin tagging, and pseudo-continuous arterial spin tagging) can be applied to measure quantitative blood flow rate and relative blood flow changes induced by neural activity.	Click on image for viewing larger version Perfusion-based fMRI map during finger movements in human overlad on an original FAIR image. High background signal exists at gray matter area due to high CBF. Functional activation site is located at the contralateral precentral gyrus.
High Resolution Perfusion Imaging of Rat Brain: Coronal anatomic (top) and CBF (bottom) images of rat brain acquired with a single-shot EPI technique at 9.4T. Spatial resolution is 0.3 x 0.3 mm2. A gray scale bar indicates CBF levels in the unit of ml/g tissue/min. No signal averaging was performed.	Click on image for viewing larger version

Related references:

Original FAIR paper:
Kim, S.-G. "Quantification of Relative Cerebral Blood Flow Change by Flow-sensitive Alternating Inversion Recovery (FAIR) Techniques: Application to Functional Mapping", Magn. Reson. Med., 34: 293-301, 1995. Medline

Full description of FAIR technique:
Kim, S.-G. and Tsekos, N., ``Perfusion Imaging by a Flow-sensitive Alternating Inversion Recovery (FAIR) Technique: Application to Functional Brain Imaging", Magn. Reson. Med., 37: 425-435, 1997. Medline

Multi-slice FAIR technique:
Kim et al. "Multi-slice Perfusion-based Functional MRI using the FAIR Technique: Comparison of CBF and BOLD effects", NMR in Biomedicine, 10: 191-196, 1997.   (PDF  file)  Medline

Validation of FAIR technique (absolute and relative blood flow):
Tsekos NV, Zhang F, Merkle H, Nagayama M, Iadecola C, Kim SG. "Quantitative Cerebral Blood Flow Measurement in Rats using the FAIR Technique: Correlation with Previous Iodoantipyrine Autoradiographic Studies", Magn. Reson. Med., 39: 564-573, 1998 Medline.

Zaini MR, Strother SC, Anderson JR, Liow JS, Kjems U, Tegeler C, Kim SG,  "Comparison of matched BOLD and FAIR 4.0T-fMRI with [¹⁵O]water PET brain Volumes", Medical Physics, 26: 1559-1567, 1999 Medline.

High temporal resolution method with 100 ms temporal resolution:
A.C. Silva and S.-G. Kim, "A pseudo-continuous arterial spin labeling technique for measuring CBF dynamics with high temporal resolution", Magn. Reson. Med., 42: 425-429, 1999. Medline(PDF file)

Dynamic Arterial Spin Tagging (DASL) with measurements of transit times, T₁ and CBF:
E.L. Barbier, A.C. Silva, S.-G. Kim, A.P. Koretsky, "Perfusion imaging using dynamic arterial spin labeling (DASL)", Magn. Reson. Med., 45: 1021-1029, 2001.  PDF file

Application to tumor flow measurements:
A.C. Silva, S.-G. Kim, M. Garwood, "Imaging blood flow in brain tumors using arterial spin labeling", Magn. Reson. Med., 44: 169-173, 2000. Medline(PDF file)

Deuterium NMR perfusion measurement methods:
Ackerman, J.J.H., Ewy, C.S., Kim, S.-G. and Shalwitz, R.A., "Deuterium Magnetic Resonance In Vivo: The Measurement of Blood Flow and Tissue Perfusion," Ann. N.Y. Acad. Sci., 508:89-98, 1987.  Medline

Kim, S.-G. and Ackerman, J.J.H., "Quantitative Determination of Tumor Blood Flow and Perfusion via Deuterium Nuclear Magnetic Resonance Spectroscopy in Mice", Cancer Res., 48:3449-3453, 1988.  Medline

Kim, S.-G. and Ackerman, J.J.H., "Multicompartment Analysis of Blood Flow and Tissue Perfusion Employing D2O as a Freely Diffusible Tracer: A Novel Deuterium NMR Technique Demonstrated via Application with Murine Tumor", Magn. Reson. Med., 8:410-426, 1988.  Medline

Kim, S.-G. and Ackerman, J.J.H. "Quantification of Regional Blood Flow by Monitoring of Exogenous Tracer via Nuclear Magnetic Resonance Spectroscopy", Magn. Reson. Med., 14:266-282, 1990.  Medline
 

C. Relative Oxygen Consumption Measurement from BOLD and CBF data:

Relationship between CBF and oxygen consumption (CMRO₂) changes induced by neural activity is controversial. Thus, it is very important to develop a simple, reliable method to measure oxygen consumption changes. Since BOLD signal is related to a mismatch between CBF and oxygen consumption changes during increased neural activity, oxygen consumption changes can be derived from simultaneously acquired BOLD and CBF data. Our laboratory originally proposed this idea, and demonstrated the feasibility of this method. We used FAIR technique to acquire BOLD and CBF simultaneously.

Reference:
Kim, S.-G. and Ugurbil, K., ``Comparison of Blood Oxygenation and Cerebral Blood Flow Effects in fMRI: Estimation of Relative Oxygen Consumption Change'', Magn. Reson. Med., 38: 59-65, 1997 Medline.

Kim SG, Rostrup E, Larsson HB, Ogawa S, Paulson OB "Determination of Relative CMRO₂ from CBF and BOLD changes: Significant oxygen consumption rate during visual stimulation", Magn. Reson. Med., 41: 1152-1161, 1999. Medline(PDF file).

D. Arterial and Venous Blood Volume Measurements:

Although regional arterial and venous volume fractions are important for basic and clinical physiology, these can not be measured in vivo. Thus, we developed an NMR method to separate arterial and venous blood volumes by employing intravascular perfluorocarbons using the linear dependence of the perfluorocarbon ¹⁹F 1/T₁ on the dissolved paramagnetic oxygen concentration. Also, these can be resolved based on pseudo-diffusion coefficients in diffusion-weighted NMR since arterial blood has higher flow velocity than venous blood.

Reference:
T.Q. Duong and S.-G. Kim, "In vivo MR measurements of regional arterial and venous blood volume fractions in intact rat brain", Magn. Reson. Med., 43: 393-402, 2000. Medline(PDF file)

E. Tissue Oxygen Tension Measurement:

Since T₁ of ¹⁹F in perfluorocarbons in tissue is dependent on dissolved oxygen tension, oxygen tension can be measured by determining T₁ of ¹⁹F in conjunction with a calibration curve. This technique involved administrating an oxygen-sensitive perfluorocarbon directly into the cerebral interstitial space.

Reference:
T.Q. Duong, C. Iadecola, S.-G. Kim, "Effect of hyperoxia, hypercapnia and hypoxia on cerebral interstitial oxygen tension and cerebral blood flow", Magn. Reson. Med., 45: 61-70, 2001. Medline, PDF file

F. Synaptic Activity Based Functional Imaging Technique:

Calcium-dependent synaptic activity can be mapped by using the manganese ion (Mn⁺²) as a calcium analog and a contrast agent. When Mn⁺² accumulates selectively into neuronally active areas, T₁ of water in the region is shortened, leading to MRI signal changes. We have demonstrated that quantitative manganese accumulation can be detected by using MRI.
 

Calcium-Activity Fucntional Study during Somatosensory Stimulation: The synaptic activity map of rat brain (right) was expanded within a green ROI from the left-side image. A red arrow indicates the primary somatosensory cortex. Selective accumulation of Mn+2 (shown as color in the right panel) during forepaw stimulation in the rat somatosensory cortex. To visualize better, cartoons of layer information were overlaid on the synaptic activity map. The largest Calcium influx is located at the layer 4, which is the middle of the cortex.

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Reference:
Duong TQ, Silva AC, Lee SP, Kim SG "Functional Imaging of Calcium-Dependent Synaptic Activity: Cross Correlation with CBF and BOLD measurements",Magn. Reson. Med., 43: 383-392, 2000  Medline(PDF file)

         Reference:
         Ronen I, Kim S-G  "Measurement of Intravascular Na⁺ during increased CBF using ²³Na NMR with a shift agent",  NMR in Biomedicine,
         14: 448-452, 2001.  PDF file .