Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
1999-10-29
2002-06-04
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S425000, C382S128000, C324S307000, C324S312000
Reexamination Certificate
active
06400978
ABSTRACT:
RELATED APPLICATIONS
Not applicable.
FIELD OF THE INVENTION
This invention relates to methods of measuring nuclear magnetic resonance characteristics of nuclei generally, and, in particular to a method of determining the spin-spin relaxation time (T
2
) of nuclei using spin echoes and for utilizing the T
2
relaxation time to aid in detection of mental disorders including but not limited to attention-deficit/hyperactivity disorder (ADHD).
BACKGROUND OF THE INVENTION
As is known in the art, magnetic resonance imaging (MRI) (aka nuclear magnetic resonance or NMR) is a form of medical imaging in which the data is displayed as images which are presented in the form of individual slices that represent planar sections of objects. The data in the images represents the density and bonding of protons (primarily in water) in the tissues of the body, based upon the ability of certain atomic nuclei in a magnetic field to absorb and re-emit electromagnetic radiation at certain frequencies.
As is also known, MRI is based on the magnetic properties of atomic nuclei with odd numbers of protons or neutrons, which exhibit magnetic properties because of their spin. The predominant source of magnetic resonance signals in the human body is hydrogen nuclei or protons. In the presence of an external magnetic field these hydrogen nuclei align along the axis of the external magnetic field and can precess or wobble around that field direction at a definite frequency known as the Larmor frequency.
The magnetic resonance effects occur when nuclei in a static magnetic field H are excited by a rotating magnetic field H
1
in the x, y plane resulting in a total vector M given by M=Hz+H
1
(x cos w0t+y sin w0t). Upon cessation of the excitation, the magnetic field decays back to its original alignment with the static field H, emitting electromagnetic radiation at the Larmor frequency which can be detected by the same coil which produced the excitation.
One method for imaging utilizes a transmit/receive coil to emit a magnetic field at frequency f
0
which is the Larmor frequency of plane P. Subsequently, magnetic gradients are applied in the y and x directions G
x
, G
y
for times t
x
, t
y
. A signal is detected in a data collection window over the period of time for which a magnetic gradient G
x
is applied.
The detected signal S(t
x
, t
y
) can be expressed as a two-dimensional Fourier transform of the magnetic resonance signal s(x,y) with u=&Ugr;G
x
t
x
/2&pgr;, v=&Ugr;G
y
t
y
/2&pgr;. The magnetic resonance signal s(x,y) depends on the precise sequence of pulses of magnetic energy used to perturb the nuclei.
For a typical sequence known as spin-echo the detected magnetic resonance signal can be expressed
s
(
x,y
)=&rgr;(1−
e
−tr
/T
1
)(
e
−tr
/T
2
)
where &rgr; is the proton density, and T
1
(the spin-lattice decay time) and T
2
(the spin-spin decay time) are constants of the material related to the interactions of water in cells. Typically T
1
ranges from 0.2 to 1.2 seconds, while T
2
ranges from 0.05 to 0.15 seconds.
By modification of the repetition and orientation of excitation pulses, an image can be made T
1
, T
2
, or proton density dominated. A proton density image shows static blood and fat as white and bone as black, while a T
1
weighted image shows fat as white, blood as gray, and cerebrospinal fluid as black and T
2
weighted images tend to highlight pathology since pathologic tissue tends to have longer T
2
than normal tissue.
To measure spin-spin decay or relaxation time (T
2
) a technique referred to as the spin echo technique was developed. The spin-echo technique includes the steps of applying an RF pulse sequence at the Larmor frequency of the nuclei, whose T
2
is being measured. The first RF pulse is sufficient duration to force the net magnetic moment of the nuclei to rotate 90°. This is followed by one or more RF pulses at the same Larmor frequency of sufficient duration to rotate the net magnetic field 180°. After each 180° pulse a signal referred to as a “spin-echo signal” is produced. The T
2
relaxation time of the nuclei is indicated by the curve drawn through the points of maximum amplitude of the echo signals received.
This technique would produce an accurate measurement of T
2
if the RF magnetic field was uniform at the same Larmor frequency because then only one spin-echo signal would be generated with each 180° pulse. Unfortunately, the RF magnetic field is not uniform. For example, some portions of the RF field may be at the Larmor frequency but other portions may be at a higher or lower frequency. It is believed that as a result of this, the inhomogeneities in the RF magnetic field produce so-called “stimulated echos” in addition to the primary echos.
In the present practice of the spin-echo technique for measuring T
2
, after the 90° pulse, the first 180° pulse occurs after a time period, usually called “tau.” Stimulated echos, however, can appear at these same times and when they do, they will be masked by and mingled with the primary echos. As a result, the degree of error in the measured T
2
is unknown. Because of the errors caused by inhomogeneities in the static and RF magnetic fields of NMR machines, it is thus not possible to directly measure the T
2
relaxation time (T
2
RT) with a reasonable degree of certainty or accuracy.
SUMMARY OF THE INVENTION
As is also known in the art, conventional Blood Oxygenation Level Dependent (BOLD) functional MRI (fMRI) is a technique which utilizes the paramagnetic properties of deoxyhemoglobin for observing dynamic brain activity changes between baseline and active conditions.
It has been recognized in accordance with the present invention that one problem with the BOLD technique is that the mismatch between blood flow and oxygen extraction that occurs as an acute reaction to enhanced neuronal activity in BOLD does not persist under steady state conditions. Instead, regional blood flow is regulated to appropriately match perfusion with ongoing metabolic demand and deoxyhemoglobin concentration becomes constant between regions in the steady-state.
It has also been recognized in accordance with the present invention that to delineate effects of chronic drug treatment on basal brain function and to detect other conditions, it is necessary to identify possible resting or steady-state differences in regional perfusion between groups of subjects. Thus, one problem with the BOLD technique is that it cannot be used to provide insight into possible resting or steady-state differences in regional perfusion between groups of subjects, or to delineate effects of chronic drug treatment on basal brain function.
Because regional blood flow is regulated to appropriately match perfusion with ongoing metabolic demand and deoxyhemoglobin concentration becomes constant between regions in the steady-state, this indicates that regions with greater continuous activity would be perfused at a greater rate, and these regions would receive, over time, a greater volume of blood and a greater number of deoxyhemoglobin molecules per volume of tissue. Thus, there should be an augmentation in the paramagnetic properties of the region which is not detectable using the BOLD technique. Such augmentation in the paramagnetic properties of the region should be detectable as a diminished T
2
relaxation time.
It has thus been further recognized in accordance with the present invention that it would be desirable to be able to identify possible resting or steady-state differences in regional perfusion between groups of subjects since such identification may provide an aid to diagnose or to directly diagnose different medical conditions.
For example, attention-deficit hyperactivity disorder (ADHD) is a highly heritable and prevalent neuropsychiatric disorder estimated to affect 6% of school-age children. Clinical hallmarks are inattention, hyperactivity and impulsivity, which often respond dramatically to treatment with methylphenidate or dextroamphetamine. Etiological theories postulate a deficit in co
Anderson Carl M.
Maas, III Luis C.
Renshaw Perry F.
Teicher Martin H.
Daly, Crowley & Mofford LLP
Lateef Marvin M.
Lin Jeoyuh
The McLean Hospital Corporation
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