Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2000-01-26
2002-10-08
Shaw, Shawna J (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S419000, C324S309000
Reexamination Certificate
active
06463315
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to the study of neurological disorders, and more particularly the invention relates to the use of magnetic resonance imaging techniques to study the microstructural integrity of cerebral white matter to ascertain the presence of a neurological disorder such as dyslexia or the likelihood of developing such a neurological disorder.
The use of diffusion tensor magnetic resonance imaging (DTI) for imaging anisotropic tissue such as brain white matter is known. See M. E. Moseley et al., “Diffusion-weighted MR Imaging of Anisotropic Water Diffusion in Cat Central Nervous System,” Radiology, 176, 439 (1990); P. J. Basser, J. Mattiello, and D. Le Bihan, “Estimation of the Effective Self-Diffusion Tensor from the NMR Spin Echo,” JMR B 103, 247-254 (1994); P. J. Basser, “Inferring Microstructural Features and the Physiological State of Tissues from Diffusion-Weighted Images,” NMR in Biomed 8, 333-344 (1995); P. J. Basser and C. Pierpaoli, “Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI,” J. Magn Reson B 111, 209-219 (1996); C. Pierpaoli, P. Jezzard, P. J. Basser, A. Barnett, and G. Di Chiro, “Diffusion Tensor MR Imaging of the Human Brain,” Radiology 201, 637-648 (1996); C. Pierpaoli and P. J. Basser, “Toward a Quantitative Assessment of Diffusion Anisotropy,” MRM 36, 893-906 (1996); C. Pierpaoli, A. Barnett, A. Virta, L. Penix, and R. Chen, “Diffusion MRI of Wallerian Degeneration. A New Tool to Investigate Neural Connectivity in vivo?” Proc. ISMRM 6th Meeting, Sydney (1998) 1247; and Lim et al., “Compromised White Matter Track Integrity in Schizophrenia Inferred From Diffusion Tensor Imaging,” Arch Gen Psychology/Vol. 56, April 1999. DTI provides a novel way to characterize tissues based on sensitivity to microscopic molecular motion of water. Clinical implementation requires strong, fast hardware and careful post processing of diffusion parameters. Diffusion weighted images and derivatives such as the three principal diffusivities of the diffusion tensor are quite specific in reflecting the physical properties of diffusion.
Diffusion weighted imaging (DI) consists of estimating the effective scalar diffusivity of water, D, in each voxel from a set of diffusion weighted images. During the time of a typical magnetic resonance data acquisition, water molecules diffuse on the order of a few microns, which is comparable to the dimensions of cellular structures, but significantly less than the dimensions of a voxel. Since D is sensitive to the physical properties, composition and spatial distribution of the tissue constituents, the measurement is sensitive to the tissue microstructure and physiological state.
Diffusion along a given axis is typically measured by placing a pair of diffusion sensitizing gradient pulses in the same axis in the magnetic resonance (MR) pulse sequence. The gradient pulses impose position-dependent phases on water protons that are equal in magnitude but opposite in sign and therefore cancel for stationary spins. However, for protons that move between the two gradient pulses, a finite net phase is accumulated. The sum of all phases from all protons results in attenuation of the MR signal due to interference effects. The magnitude of signal attenuation is dependent on the diffusivity of water, and the width, separation and amplitude of the gradient pulses. In a generalized case where the diffusivity may differ in different directions, a diffusion tensor matrix notation is used.
The present invention is directed to the use of DTI for the prognosis and diagnosis of a dyslexic neurologic disorder. Reading is a complex cognitive skill that requires multimodal processing of visual symbols, speech sounds (known as phonology), and linguistic entities such as words and sentences. Studies using neuroimaging have demonstrated that a widespread set of brain regions are engaged during reading tasks, highlighting the need for communication between these regions in skilled readers. About 5-10% of children, however, exhibit developmental dyslexia, an impairment in learning to read despite adequate instruction and normal intelligence. Dyslexia is associated with deficits in language processing beyond reading, particularly in the processing of phonology. In addition, dyslexic individuals exhibit deficits in nonlinguistic perceptual processing, particularly on tasks requiring the processing of rapidly transient auditory and visual signals.
A growing body of evidence suggests that dyslexia is a neurologically-based disorder perhaps with a genetic basis. Postmortem studies of dyslexic brains have discovered a consistent pattern of neuropathological changes (cortical Microlesions and glial scars) throughout the left perisylvian cortices, along with reduced left-right asymmetry of the planum temporale. Functional magnetic resonance imaging (fMRI) studies of dyslexia have found atypical activation patterns in temporo-parietal cortex during reading tasks, particularly those involving the recoding of written symbols in their phonological counterparts. Studies using neuromagnetic imaging have also found differences in the time course of cortical processing in dyslexic individuals compared to normal readers. Each of these findings is consistent with a neural basis for dyslexia, but the underlying cause of these differences in neural processing is not currently known.
Two studies have suggested that developmental dyslexia may represent a disconnection syndrome in which communication is impaired between temporo-parietal cortices and other brain regions such as frontal cortex. In particular, dyslexic individuals have exhibited decreased correlations of cortical activity between areas involved in reading, which may indicate that a communication between these areas is impaired. Another study has proposed such a disconnection on the basis of abnormal patterns of activation in the temporo-parietal, frontal, and insular cortices in dyslexic adults. This proposal is consistent with behavioral evidence that dyslexic individuals are impaired at the cross-modal mapping of visual and auditory information. The impaired communication could be the results of a structural disturbance or disruption. However, the nature and cause of a putative structure disruption is currently unknown.
A plausible locus for such a disruption in communication is the white matter tracts connecting tempora-parietal and frontal cortices, but to date there is no consistent evidence of white matter disturbance in dyslexia. Although a number of previous studies have examined the differences in neuroanatomical structure between dyslexic individuals and normal readers, these studies have focused primarily of hemispheric asymmetry of the planum temporale and differences in corpus callosum size, with mixed results in each of those areas. None of these studies has demonstrated specific differences in white matter morphology, but the imaging techniques used in these studies (such as T1-weighted structural MR imaging) can only image macrostructural features of white matter. A postmortem study of a single dyslexic individual revealed increased white matter volume in the left hemisphere and enlarged neurons in the cortex extending into the subcortical white matter. Subsequent postmortem studies, however, were focused on gray matter, and did not report white matter abnormalities in dyslexia.
SUMMARY OF THE INVENTION
In accordance with the invention, an objective and noninvasive measure of neural density and integrity in cerebral white matter is used to assess verbal and non-verbal mental skills and abilities. These measures, which reflect the organization of white matter structures in the central nervous system, can be used to predict verbal and non-verbal cognitive processing or capacity (such as word skill scores) in children as well as adults. This provides a quantitative indication of neuronal fiber density, integrity, myelination, and coherence. These measures, which reflect the organization of white matter structures
Gabrieli John D. E.
Hedehus Maj
Klingberg Torkel
Moseley Michael E.
Poldrack Russell A.
Shaw Shawna J
The Board of Trustees of the Leland Stanford Junior University
Townsend and Townsend / and Crew LLP
Woodward Henry K.
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