[Federal Register Volume 74, Number 70 (Tuesday, April 14, 2009)]
[Notices]
[Pages 17199-17201]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-8475]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing: Methods 
for Improvements and Enhancements of Diffusion Tensor MRI

AGENCY: National Institutes of Health, HHS.

ACTION: Notice.

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SUMMARY: The inventions listed below are owned by an agency of the U.S. 
Government and are available for licensing in the U.S. in accordance 
with 35 U.S.C. 207 to achieve expeditious commercialization of results 
of Federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for companies and may also be available for licensing.

FOR FURTHER INFORMATION CONTACT: Licensing information and copies of 
the U.S. patent applications listed below may be obtained by contacting 
either Uri Reichman, PhD, MBA (Phone: 301-435-4616; Fax: 301-402-0220; 
E-mail: [email protected]) or John Stansberry, PhD (Phone: 301-435-5236; 
Fax: 301-402-0220; E-mail: [email protected]) at the Office of 
Technology Transfer, National Institutes of Health, 6011 Executive 
Boulevard, Suite 325, Rockville, Maryland 20852-3804. A signed 
Confidential Disclosure Agreement will be required to receive copies of 
the patent applications.

SUPPLEMENTARY INFORMATION: The technology offered for licensing is in 
the field of Diffusion Magnetic Resonance Imaging (MRI). Specifically, 
three new methods have been described and claimed that enhance the 
scope and applicability of Diffusion Tensor MRI (DTI or DT-MRI).
    The invention of DTI represented a breakthrough in MRI. It provides 
a method and system for measuring the effective diffusion tensor of 
spin-labeled molecules, and for generating images of key tensor-derived 
parameters that indicate features of tissue microstructure, 
organization and even physiological state. DTI data has improved the 
diagnosis of a large number of diseases, disorders, and conditions, and 
is also being used therapeutically, for instance, to aid neurosurgical 
planning.
    One of the pioneers in Diffusion MRI, Dr. Peter Basser, a Principal 
Investigator in NIH's Eunice Kennedy Shriver National Institute of 
Child Health and Human Development (NICHD), is the primary inventor of 
DTI. Dr. Basser's first contribution in this field is described in US 
Patent 5,539,310 (issued July 23, 1996), entitled ``Method and 
System for Measuring the Diffusion Tensor and for Diffusion Tensor 
Imaging.'' His new inventions (described below) extend the specificity 
and clinical value of diffusion MRI data, particularly in elucidating 
fine microstructural details and features that are not detectable using 
DTI.

Diffusion Tensor and q-Space MRI Specimen Characterization

Description of Technology

    Diffusion Tensor MRI (DTI or DT-MRI) provides information primarily 
about how water diffuses in the extracellular compartment of tissues, 
where water mobility is hindered (i.e., where water diffuses freely but 
encounters barriers from which it is reflected). However, DTI does not 
provide a complete characterization of diffusion in the intracellular 
compartment of some cells, particularly myelinated axons, where water 
mobility is restricted by impermeable membranes (i.e., where water is 
trapped but otherwise free to diffuse within the cell).
    The subject invention provides a new modeling framework that self-
consistently describes 3-D anisotropic diffusion within a hindered 
extracellular compartment and within a restricted intra-axonal 
compartment. It results in an improved characterization and measurement 
tissue and cell microstructure in neuronal tissue, which promises to 
advance diagnosis of neurological conditions (e.g., Stroke, MS, 
Alzheimer's disease), possibly cognitive and behavioral disorders 
(e.g., schizophrenia), as well as our ability to follow normal 
development and aging processes.
    More specifically, this new in vivo diffusion MRI method, 
especially suited for the characterization of brain white matter, 
marries q-space and DTI concepts: Diffusion within axons is modeled as 
hindered diffusion parallel to the axis of the axon, and restricted 
diffusion perpendicular to the axis. Diffusion exterior to axons is 
modeled as hindered diffusion with differing diffusivities parallel and 
perpendicular to the nerves' axis. To practice this method, diffusion 
weighted (DW) MRI data are acquired from specimens at different q-
values (with different diffusion gradient magnitudes and directions). 
Parameters associated with tissue microstructure, such as the intra and 
extra-axonal principal diffusivities and their corresponding principal 
directions, and the volume fractions of intra and extra-axonal space 
are then estimated from these data. Improved angular resolution of 
fiber tract orientation can be obtained for tractography studies and 
more microstructural information can be gleaned for both diagnostic and 
therapeutic purposes than from conventional DTI. This technology has 
been named CHARMED (Composite Hindered and Restricted Model of 
Diffusion).

Inventors

    Peter J. Basser (NICHD) et al.

Publications

    1. Y Assaf, RZ Freidlin, GK Rohde, PJ Basser. New modeling and 
experimental framework to characterize hindered and restricted water 
diffusion in brain white matter. Magn Reson Med. 2004 Nov;52(5):965-
978.
    2. Y Assaf and PJ Basser. Composite hindered and restricted model 
of diffusion (CHARMED) MR imaging of the human brain. Neuroimage 2005 
Aug 1;27(1):48-58.
    3. L Avram, E [Ouml]zarslan, Y Assaf, A Bar-Shir, Y Cohen, PJ 
Basser. Three-dimensional water diffusion in impermeable cylindrical 
tubes: theory versus experiments. NMR Biomed. 2008 Oct;21(8):888-898.
    4. A Bar-Shir, L Avram, Y Assaf, PJ Basser, Y Cohen. Experimental 
Parameters and Diffraction Patterns at High q Diffusion MR: Experiments 
and Theoretical Simulations. Proc Intl Soc Mag Reson Med. 2007;15:1530.

Patent Status

    U.S. Patent Application No. 10/888,917 filed 08 Jul 2004, claiming

[[Page 17200]]

priority to 08 Jul 2003 (HHS Reference No. E-079-2003/0-US-02).

Non-Invasive in vivo MRI Axon Diameter Measurement Methods

Description of Technology

    This invention describes an improvement and continuation of the 
CHARMED MRI framework described above, extending this technology to 
measure the axon diameter distribution (ADD) of nerve bundles 
(fascicles) in the central and peripheral nervous systems.
    The invention essentially consists of a non-obvious combination of 
CHARMED MRI and an improvement of an NMR method, originally developed 
for particle sizing in porous media applications, which was extended 
and enhanced to provide a direct measurement of the ADD within nerve 
fascicles in the brain, spine or other parts of the peripheral nervous 
system on a voxel-by-voxel basis. Additionally this approach can be 
extended to measure the fiber orientation distribution of axons within 
each voxel of an imaging volume and particularly the myelin content 
within each voxel.
    The significance of this invention is that it represents a way to 
provide a non-invasive, painless, in vivo measurement of 
microanatomical (histological) features of nerves (and possibly 
muscles) that are critically important in medicine and the 
neurosciences and previously were only available using invasive 
histological means requiring biopsy. The ADD is altered in abnormal 
development (possibly even in autism), in degenerative processes (e.g., 
aging, alcoholism, Alzheimer's disease) and diseases such as ALS (Lou 
Gehrig's disease). The ADD is a critically important parameter of a 
nerve bundle from a neuroscience perspective because axon diameter 
determines the conduction velocity of action potentials, and thus the 
arrival time and latency of nerve impulses traveling along them. The 
orientation or directional distribution of axons is important in 
Tractography applications to help determine how different cortical 
regions of the brain are connected to each other via white matter 
pathways. Myelin is dynamically regulated in vivo and affects the 
electrical insulating property of axons, and thus the conduction 
velocity of nerves. Myelin content is a critically important parameter 
in MS and a large number of dysmyelinating and demyelinating diseases 
as well as in normal and abnormal development.

Inventors

    Peter J. Basser (NICHD) et al.

Publications

    1. Y Assaf, T Blumenfeld-Katzir, Y Yovel, PJ Basser. AxCaliber: a 
method for measuring axon diameter distribution from diffusion MRI. 
Magn Reson Med. 2008 Jun;59(6):1347-1354.
    2. D Barazany, PJ Basser, Y Assaf. In vivo measurement of axon 
diameter distribution in the corpus callosum of rat brain. Brain 2009; 
p 1-11.
    3. D Barazany, PJ Basser, Y Assaf. In-vivo measurement of the axon 
diameter distribution in the rat's corpus callosum. In Proc Intl Soc 
Mag Reson Med. 2008;16:567.
    4. D Barazany, P Basser, Y Assaf. AxCaliber--in-vivo measurement of 
axon diameter distribution with MRI. In 16th Annual Meeting of The 
Israel Society for Neuroscience, Eilat, Israel; November 25-27, 2007; 
p. 8-9.
    5. PJ Basser, T Blumenfeld, G Levin, Y Yovel, Y Assaf. AxCaliber: 
an MRI method to measure the diameter distribution and density of axons 
in neuronal tissue. In Magn Reson Imaging 2007;25:550.
    6. Y Assaf and PJ Basser. Non parametric approach for axon diameter 
distribution estimation from diffusion measurements. In Proc Intl Soc 
Mag Reson Med. 2007;15:1536.
    7. PJ Basser, T Blumenfeld, G Levin, Y Yovel, Y Assaf. AxCaliber: 
an MRI method to measure the diameter distribution and density of axons 
in neuronal tissue. In 8th International Bologna Conference on Magnetic 
Resonance in Porous Media 2006; p. 37.
    8. Y Assaf, T Blumenfeld, G Levin, Y Yovel, PJ Basser. AxCaliber--a 
method to measure the axon diameter distribution and density in 
neuronal tissues. In Proc Intl Soc Mag Reson Med. 2006;14:637.

Patent Status

    U.S. Patent Application No. 12/114,713 filed 02 May 2008 (HHS 
Reference No. E-079-2003/1-US-01), which is a CIP of the above U.S. 
Patent Application No. 10/888,917.

Magnetic Resonance Specimen Evaluation Using Multiple Pulse Field 
Gradient Sequences

Description of Technology

    A further enhancement to the diffusion MRI technologies described 
above is offered in this further extension. The invention proposes and 
claims an MRI-method that is based on the measurement and acquisition 
of multiple pulsed field gradient (m-PFG) rather than the previously 
used single-pulsed field gradient (s-PFG) MRI sequences. In particular, 
double PFG (d-PFG) sequences offer higher sensitivity and greater 
robustness, as it is more sensitive to the effect of ``restriction'', 
i.e., to water trapped within the axon's intracellular space, and thus 
to the diameter of the axons. It renders the MR sequence more sensitive 
to ``pore size'' and ``pore shape'' and thus makes the measurement of 
the ADD more sensitive and accurate. Moreover, measurements using the 
multiple-PFG sequence can be performed readily at ``low b'' or ``low 
q'', making it biologically relevant and clinically feasible.

Inventors

    Peter J. Basser and Evren [Ouml]zarslan (NICHD).

Publications

    1. E [Ouml]zarslan and PJ Basser. Microscopic anisotropy revealed 
by NMR double pulsed field gradient experiments with arbitrary timing 
parameters. J Chem Phys 2008 Apr 21;128(15):154511.
    2. ME Komlosh, MJ Lizak, F Horkay, RZ Freidlin, PJ Basser. 
Observation of microscopic diffusion anisotropy in the spinal cord 
using double-pulsed gradient spin echo MRI. Magn Reson in Med. 2008 
Apr;59(4):803-809.
    3. E [Ouml]zarslan and PJ Basser. MR diffusion -``diffraction'' 
phenomenon in multi-pulse-field-gradient experiments. J Magn Reson. 
2007 Oct;188(2):285-294.
    4. ME Komlosh, F Horkay, RZ Freidlin, U Nevo, Y Assaf, PJ Basser. 
Detection of microscopic anisotropy in gray matter and in a novel 
tissue phantom using double Pulsed Gradient Spin Echo MR. J Magn Reson. 
2007 Nov;189(1):38-45.
    5. ME Komlosh, RZ Freidlin, F Horkay, Y Assaf, PJ Basser. Detection 
of microscopic anisotropy in gray matter using d-PGSE. In Proc Intl Soc 
Mag Reson Med. 2005;13:843.
    6. ME Komlosh, MJ Lizak, F Horkay, RZ Friedlin, PJ Basser. (2006) 
Detection of local anisotropy using double-PGSE filtered imaging. In 
47th Experimental Nuclear Magnetic Resonance Conference, 2006.
    7. E [Ouml]zarslan and PJ Basser. Diffusion-Diffraction Phenomenon 
in multi-PFG experiments. In Science Networking Development Scheme 
Meeting. Ein-Boqeq, Israel, 2007.
    8. M E Komlosh, MJ Lizak, F Horkay, RZ Freidlin, PJ Basser. 
Observation of microscopic diffusion anisotropy in the spinal cord 
using double-pulsed gradient spin echo MRI. In Proc Intl Soc Mag Reson 
Med. 2008;16:763.
    9. E [Ouml]zarslan and PJ Basser. Microscopic anisotropy revealed 
by double-PFG NMR. In 9th International Bologna Conference on Magnetic 
Resonance in Porous Media 2008; p. 26.

[[Page 17201]]

    10. E [Ouml]zarslan, CG Koay, PJ Basser. Double-PFG diffusion-
diffraction in ellipsoidal pores. In 9th International Bologna 
Conference on Magnetic Resonance in Porous Media 2008; p. 115.

Patent Status

    U.S. Provisional Application No. 61/087,968 filed 11 Aug 2008 (HHS 
Reference No. E-276-2008/0-US-01).

Advantages

    The three inventions described above and collectively offered for 
licensing offer a non-invasive, painless means for measurement 
quantities such as the axon diameter distribution (ADD) and significant 
improvements in sensitivity and robustness to existing MRI methods, in 
particular for imaging of the Central Nervous System, and for in vivo 
measurement of microanatomical (histological) features of nerves (and 
possibly muscles) that are critically important in medicine and in 
particular in neuroscience. Furthermore, ADD is altered in abnormal 
development (possibly even in autism), in degenerative process (e.g., 
aging, alcoholism, Alzheimer's disease) and diseases such as ALS (Lou 
Gehrig's disease) and thus the improved sensitivities offered by the 
subject inventions is of utmost significance for public health.

Development Status

    These inventions are fully developed.

Market

    The market for MRI in human diagnostics is huge and rapidly 
growing. The race to improve the sensitivities of MRI measurement and 
to enhance the capabilities of measuring and examining fine structures 
in general, and in neuroscience in particular is of significant 
magnitude. The three inventions described above may collectively offer 
significant commercial opportunity to MRI companies.
    The market for medical imaging equipment industry is approximately 
$9.0 billion dollars now and has been growing by approximately 7.6% 
annually. MRI instrumentation constitutes a significant portion of this 
market.

Related Technology

    U.S. Patent No. 5,539,310 issued 23 Jul 1996--``Method and System 
for Measuring the Diffusion Tensor and for Diffusion Tensor Imaging'' 
(HHS Reference No. E-203-1993/0).

Licensing Status

    Available for licensing.

Licensing Contacts

    Uri Reichman, PhD, MBA; 301-435-4616; [email protected]; John 
Stansberry, PhD; 301-435-5236; [email protected].

Collaborative Research Opportunity

    The Eunice Kennedy Shriver National Institute of Child Health and 
Human Development, Section on Tissue Biophysics and Biomimetics, is 
seeking statements of capability or interest from parties interested in 
collaborative research to further develop, evaluate, or commercialize 
novel MRI methods to probe tissue structure and organization, 
particularly for neuroimaging applications. Please contact Alan Hubbs, 
PhD at 301-594-4263 or [email protected] for more information.

    Dated: April 7, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E9-8475 Filed 4-13-09; 8:45 am]
BILLING CODE 4140-01-P