Publications

2007
Archip N, Tatli S, Morrison P, Jolesz FA, Warfield SK, Silverman S. Non-rigid registration of pre-procedural MR images with intra-procedural unenhanced CT images for improved targeting of tumors during liver radiofrequency ablations. Med Image Comput Comput Assist Interv. 2007;10 (Pt 2) :969-77.Abstract

In the United States, unenhanced CT is currently the most common imaging modality used to guide percutaneous biopsy and tumor ablation. The majority of liver tumors such as hepatocellular carcinomas are visible on contrast-enhanced CT or MRI obtained prior to the procedure. Yet, these tumors may not be visible or may have poor margin conspicuity on unenhanced CT images acquired during the procedure. Non-rigid registration has been used to align images accurately, even in the presence of organ motion. However, to date, it has not been used clinically for radiofrequency ablation (RFA), since it requires significant computational infrastructure and often these methods are not sufficient robust. We have already introduced a novel finite element based method (FEM) that is demonstrated to achieve good accuracy and robustness for the problem of brain shift in neurosurgery. In this current study, we adapt it to fuse pre-procedural MRI with intra-procedural CT of liver. We also compare its performance with conventional rigid registration and two non-rigid registration methods: b-spline and demons on 13 retrospective datasets from patients that underwent RFA at our institution. FEM non-rigid registration technique was significantly better than rigid (p < 10-5), non-rigid b-spline (p < 10-4) and demons (p < 10-4) registration techniques. The results of our study indicate that this novel technology may be used to optimize placement of RF applicator during CT-guided ablations.

Sierra R, DiMaio SP, Wada J, Hata N, Székely G, Kikinis R, Jolesz FA. Patient specific simulation and navigation of ventriculoscopic interventions. Stud Health Technol Inform. 2007;125 :433-5.Abstract

In this paper a comprehensive framework for pre-operative planning, procedural skill training, and intraoperative navigation is presented. The goal of this system is to integrate surgical simulation with surgical planning in order to improve the individual treatment of patients. Various surgical approaches and new, more complex procedures can be assessed using a safe and objective platform that will allow the physicians to explore and discuss possible risks and benefits prior to the intervention. A simulation environment extends the pre-operative planning in a natural way, as it allows for direct evaluation of the surgical approach envisioned for each case. In addition, by providing intraoperative navigation based on this simulation, surgeons can carry out the previously optimized plan with higher precision and greater confidence.

Larsen S, Kikinis R, Talos I-F, Weinstein D, Wells III WM, Golby AJ. Quantitative Comparison of Functional MRI and Direct Electrocortical Stimulation for Functional Mapping. Int J Med Robot. 2007;3 (3) :262-70.Abstract

BACKGROUND: Mapping functional areas of the brain is important for planning tumour resections. With the increased use of functional magnetic resonance imaging (fMRI) for presurgical planning, there is a need to validate that fMRI activation mapping is consistent with the mapping obtained during surgery using direct electrocortical stimulation (DECS). METHODS: A quantitative comparison of DECS and fMRI mapping techniques was performed, using a patient-specific conductivity model to find the current distribution resulting from each stimulation site. The resulting DECS stimulation map was compared to the fMRI activation map, using the maximal Dice similarity coefficient (MDSC). RESULTS: Our results show some agreement between these two mapping techniques--the stimulation site with the largest MOSC was the only site that demonstrated intra-operative effect. CONCLUSIONS: There is a substantial effort to improve the techniques used to map functional areas, particularly using fMRI. It seems likely that fMRI will eventually provide a valid non-invasive means for functional mapping.

Zhang JQ, Loughlin KR, Zou KH, Haker S, Tempany CM. Role of endorectal coil magnetic resonance imaging in treatment of patients with prostate cancer and in determining radical prostatectomy surgical margin status: report of a single surgeon's practice. Urology. 2007;69 (6) :1134-7.Abstract

OBJECTIVES: To evaluate the role of the combination of endorectal coil and external multicoil array magnetic resonance imaging (MRI) in the management of prostate cancer and predicting the surgical margin status in a single-surgeon practice. METHODS: We reviewed all patients referred by a single surgeon from January 1993 to May 2002 for staging prostate MRI before selecting treatment. All MRI examinations were performed using 1.5T (Signa, GE Medical Systems) with a combination of endorectal and pelvic multicoil array. The tumor size, stage, and total gland volume on MRI, prostate-specific antigen (PSA) level, and Gleason score were all compared with the pathologic stage and diagnosis of positive surgical margins (PSMs). RESULTS: A total of 232 patients were evaluated, of whom 110 underwent radical prostatectomy, all performed by one surgeon (group 1), and 122 did not (group 2). The results showed that MRI stage, PSA level, and age were all significantly different (P <0.001). In group 1, the results showed a high specificity (99%) and accuracy (91%) for MRI staging of T3 cancer. The postoperative follow-up (median 4.5 years) revealed that 90% of men had PSA levels of less than 0.1 ng/mL. The PSM rate was 16%. No significant difference was found on MRI between the PSM group and non-PSM group. A single tumor length greater than 1.8 cm was the cutpoint above which PSMs were found (P = 0.002). CONCLUSIONS: The results of our study have shown that the combined use of clinical data and endorectal MRI can help optimize patient treatment and selection for surgery and, in a single surgeon's practice, lead to successful outcomes.

McDannold N, Barnes AS, Rybicki FJ, Oshio K, Chen N-kuei, Hynynen K, Mulkern RV. Temperature mapping considerations in the breast with line scan echo planar spectroscopic imaging. Magn Reson Med. 2007;58 (6) :1117-23.Abstract

A line-scan echo planar spectroscopic imaging (LSEPSI) sequence was used to serially acquire spectra from 4,096 voxels every 6.4 s throughout the breasts of nine female subjects in vivo. Data from the serial acquisitions were analyzed to determine the potential of the technique to characterize temperature changes using either the water frequency alone or the water-methylene frequency difference. Fluctuations of the apparent temperature change under these conditions of no heating were smallest using the water-methylene frequency difference, most probably due to a substantial reduction of motion effects both within and without the imaged plane. The approach offers considerable advantages over other methods for temperature change monitoring in the breast with magnetic resonance but suffers from some limitations, including the unavailability of lipid and water resonances in some voxels as well as a surprisingly large distribution of water-methylene frequency differences, which may preclude absolute temperature measurement.

Blumenfeld P, Hata N, DiMaio S, Zou K, Haker S, Fichtinger G, Tempany CM. Transperineal Prostate Biopsy under Magnetic Resonance Image Guidance: A Needle Placement Accuracy Study. J Magn Reson Imaging. 2007;26 (3) :688-94.Abstract

PURPOSE: To quantify needle placement accuracy of magnetic resonance image (MRI)-guided core needle biopsy of the prostate. MATERIALS AND METHODS: A total of 10 biopsies were performed with 18-gauge (G) core biopsy needle via a percutaneous transperineal approach. Needle placement error was assessed by comparing the coordinates of preplanned targets with the needle tip measured from the intraprocedural coherent gradient echo images. The source of these errors was subsequently investigated by measuring displacement caused by needle deflection and needle susceptibility artifact shift in controlled phantom studies. Needle placement error due to misalignment of the needle template guide was also evaluated. RESULTS: The mean and standard deviation (SD) of errors in targeted biopsies was 6.5 +/- 3.5 mm. Phantom experiments showed significant placement error due to needle deflection with a needle with an asymmetrically beveled tip (3.2-8.7 mm depending on tissue type) but significantly smaller error with a symmetrical bevel (0.6-1.1 mm). Needle susceptibility artifacts observed a shift of 1.6 +/- 0.4 mm from the true needle axis. Misalignment of the needle template guide contributed an error of 1.5 +/- 0.3 mm. CONCLUSION: Needle placement error was clinically significant in MRI-guided biopsy for diagnosis of prostate cancer. Needle placement error due to needle deflection was the most significant cause of error, especially for needles with an asymmetrical bevel.

2006
Chen N-kuei, Oshio K, Panych LP. Application of k-space energy spectrum analysis to susceptibility field mapping and distortion correction in gradient-echo EPI. Neuroimage. 2006;31 (2) :609-22.Abstract
Echo-planar imaging (EPI) is widely used in functional MRI studies. It is well known that EPI quality is usually degraded by geometric distortions, when there exist susceptibility field inhomogeneities. EPI distortions may be corrected if the field maps are available. It is possible to estimate the susceptibility field gradients from the phase reconstruction of a single-TE EPI image, after a successful phase-unwrapping procedure. However, in regions affected by pronounced field gradients, the phase-unwrapping of a single-TE image may fail, and therefore the estimated field maps may be incorrect. It has been reported that the field inhomogeneity may be calculated more reliably from T2*-weighted images corresponding to multiple TEs. However, the multi-TE MRI field mapping increases the scan time. Furthermore, the measured field maps may be invalid if the subject's position changes during dynamic scans. To overcome the limitations in conventional field mapping approaches, a novel k-space energy spectrum analysis algorithm is developed, which quantifies the spatially dependent echo-shifting effect and the susceptibility field gradients directly from the k-space data of single-TE gradient-echo EPI. Using the k-space energy spectrum analysis, susceptibility field gradients can be reliably measured without phase-unwrapping, and EPI distortions can be corrected without extra field mapping scans or pulse sequence modification. The reported technique can be used to retrospectively improve the image quality of the previously acquired EPI and functional MRI data, provided that the complex-domain k-space data are still available.
Madore B, Hoge SW, Kwong R. Extension of the UNFOLD method to include free breathing. Magn Reson Med. 2006;55 (2) :352-62.Abstract
Unaliasing by Fourier-encoding the overlaps using the temporal dimension (UNFOLD) is a method to reduce the data acquisition burden in dynamic MRI. The method works by forcing aliased signals to behave in specific ways through time, so that these unwanted signals can be detected and removed. Unexpected events in time, such as displacements caused by breathing, have the potential to disturb the temporal strategy and may affect UNFOLD's ability to suppress aliasing artifacts. This work presents an extension of the UNFOLD method to accommodate temporal encoding disruptions. While the main type of disruption considered here comes from respiratory motion, other types of disruption can be envisioned, such as departures from the usual UNFOLD k-space sampling scheme. This extended version of UNFOLD was incorporated into UNFOLD-sensitivity encoding (UNFOLD-SENSE), and should also be applicable to closely related methods such as temporal SENSE (TSENSE), k-t Broaduse Linear Acquisition Speed up Technique (k-t BLAST), and k-t SENSE. Five patients were imaged with a modified version of a myocardial-perfusion sequence, and UNFOLD was used either alone or in conjunction with SENSE to obtain an acceleration of 2.0 (in three patients) or 3.0 (in two patients). In both cases this extended version of UNFOLD was able to suppress artifacts caused by the presence of breathing motion.
DiMaio SP, Kacher DF, Ellis RE, Fichtinger G, Hata N, Zientara GP, Panych LP, Kikinis R, Jolesz FA. Needle artifact localization in 3T MR images. Stud Health Technol Inform. 2006;119 :120-5.Abstract
This work explores an image-based approach for localizing needles during MRI-guided interventions, for the purpose of tracking and navigation. Susceptibility artifacts for several needles of varying thickness were imaged, in phantoms, using a 3 tesla MRI system, under a variety of conditions. The relationship between the true needle positions and the locations of artifacts within the images, determined both by manual and automatic segmentation methods, have been quantified and are presented here.
DiMaio SP, Pieper S, Chinzei K, Hata N, Balogh E, Fichtinger G, Tempany CM, Kikinis R. Robot-assisted needle placement in open-MRI: system architecture, integration and validation. Stud Health Technol Inform. 2006;119 :126-31.Abstract
This work describes an integrated system for planning and performing percutaneous procedures-such as prostate biopsy-with robotic assistance under MRI-guidance. The physician interacts with a planning interface in order to specify the set of desired needle trajectories, based on anatomical structures and lesions observed in the patient's MR images. All image-space coordinates are automatically computed, and used to position a needle guide by means of an MRI-compatible robotic manipulator, thus avoiding the limitations of the traditional fixed needle template. Direct control of real-time imaging aids visualization of the needle as it is manually inserted through the guide. Results from in-scanner phantom experiments are provided.
Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. Biochem Biophys Res Commun. 2006;340 (4) :1085-90.Abstract
The blood-brain barrier (BBB) is a persistent obstacle for the local delivery of macromolecular therapeutic agents to the central nervous system (CNS). Many drugs that show potential for treating CNS diseases cannot cross the BBB and there is a need for a non-invasive targeted drug delivery method that allows local therapy of the CNS using larger molecules. We developed a non-invasive technique that allows the image-guided delivery of antibody across the BBB into the murine CNS. Here, we demonstrate that subsequent to MRI-targeted focused ultrasound induced disruption of BBB, intravenously administered dopamine D(4) receptor-targeting antibody crossed the BBB and recognized its antigens. Using MRI, we were able to monitor the extent of BBB disruption. This novel technology should be useful in delivering macromolecular therapeutic or diagnostic agents to the CNS for the treatment of various CNS disorders.
Zou KH, Bhagwat JG, Carrino JA. Statistical combination schemes of repeated diagnostic test data. Acad Radiol. 2006;13 (5) :566-72.Abstract
RATIONALE AND OBJECTIVES: When diagnostic tests are repeated and combined, a number of schemes may be adopted. Guidelines for their interpretations are required. MATERIALS AND METHODS: Three combination schemes, "and" (A), "or" (O), and "majority" (M), are considered. To evaluate these schemes, dependency by specifying kappa values quantifying repeated test agreement was structured. In a pilot study, the combined accuracies of magnetic resonance imaging using six different pulse sequences of medial collateral ligaments of the elbows of 28 cadavers, with eight having lesions artificially created surgically, were examined. Images were evaluated simultaneously by using a five-point ordinal scale. For each pulse sequence, individuals for whom the diagnosis varied from once to three repetitions were considered. RESULTS: Scheme M improves diagnostic accuracy when sensitivity and specificity of a single test exceed 0.5, with maximal improvement at 0.79. Under scheme A, sensitivity decreases to 0.38-0.59. Under scheme O, sensitivity increases to 0.53-0.79. Scheme M yields a small improvement, reaching 0.50-0.71. Under scheme A, specificity increases to 0.95-0.98. Under scheme O, specificity decreases to 0.91-0.98. Scheme M also yields a small improvement, reaching 0.94-0.98. CONCLUSION: Scheme A is recommended for ruling in diagnoses, scheme O is recommended for ruling out diagnoses, and scheme M is neutral. Consequently, different schemes may be used to optimize the target diagnostic accuracy.
Talos I-F, Zou KH, Ohno-Machado L, Bhagwat JG, Kikinis R, Black PM, Jolesz FA. Supratentorial low-grade glioma resectability: statistical predictive analysis based on anatomic MR features and tumor characteristics. Radiology. 2006;239 (2) :506-13.Abstract
PURPOSE: To retrospectively assess the main variables that affect the complete magnetic resonance (MR) imaging-guided resection of supratentorial low-grade gliomas. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective HIPAA-compliant study, with the requirement for informed consent waived. Data from 101 patients (61 men, 40 women; mean age, 39 years; age range, 18-72 years) who had nonenhancing supratentorial mass lesions that were histopathologically diagnosed as low-grade (World Health Organization grade II) gliomas and consecutively underwent surgery with intraoperative MR imaging guidance were analyzed. There were 21 low-grade astrocytomas, 64 oligodendrogliomas, and 16 mixed oligoastrocytomas. Initial and residual tumor volumes were measured on intraoperative T2-weighted MR images and three-dimensional spoiled gradient-echo MR images. The anatomic relationships between the tumor and eloquent cortical and/or subcortical regions and the influence of these relationships on the extent of resection were analyzed on the basis of preoperative MR imaging findings. Summary measures, univariate Fisher exact test and t test, and multivariate logistic regression analyses were performed. RESULTS: Tumor volume ranged from 2.7-231.0 mL. Univariate analyses revealed the following tumor characteristics to be significant predictive variables of incomplete tumor resection: diffuse tumor margin on T2-weighted MR images, oligodendroglioma or oligoastrocytoma histopathologic type, and large tumor volume (P < .05 for all). Tumor involvement of the following structures was associated with incomplete resection: corpus callosum, corticospinal tract, insular lobe, middle cerebral artery, motor cortex, optic radiation, visual cortex, and basal ganglia (P < .05 for all). Multivariate analyses revealed that incomplete tumor resection was due to tumor involvement of the corticospinal tract (P < .01), large tumor volume (P < .01), and oligodendroglioma histopathologic type (P = .02). CONCLUSION: The main variables associated with incomplete tumor resection in 101 patients were identified by using statistical predictive analyses.
Wang LI, Greenspan M, Ellis R. Validation of bone segmentation and improved 3-D registration using contour coherency in CT data. IEEE Trans Med Imaging. 2006;25 (3) :324-34.Abstract
A method is presented to validate the segmentation of computed tomography (CT) image sequences, and improve the accuracy and efficiency of the subsequent registration of the three-dimensional surfaces that are reconstructed from the segmented slices. The method compares the shapes of contours extracted from neighborhoods of slices in CT stacks of tibias. The bone is first segmented by an automatic segmentation technique, and the bone contour for each slice is parameterized as a one-dimensional function of normalized arc length versus inscribed angle. These functions are represented as vectors within a K-dimensional space comprising the first K amplitude coefficients of their Fourier Descriptors. The similarity or coherency of neighboring contours is measured by comparing statistical properties of their vector representations within this space. Experimentation has demonstrated this technique to be very effective at identifying low-coherency segmentations. Compared with experienced human operators, in a set of 23 CT stacks (1,633 slices), the method correctly detected 87.5% and 80% of the low-coherency and 97.7% and 95.5% of the high coherency segmentations, respectively from two different automatic segmentation techniques. Removal of the automatically detected low-coherency segmentations also significantly improved the accuracy and time efficiency of the registration of 3-D bone surface models. The registration error was reduced by over 500% (i.e., a factor of 5) and 280%, and the computational performance was improved by 540% and 791% for the two respective segmentation methods.
Archip N, Rohling R, Dessenne V, Erard P-J, Nolte LP. Anatomical structure modeling from medical images. Comput Methods Programs Biomed. 2006;82 (3) :203-15.Abstract
Some clinical applications, such as surgical planning, require volumetric models of anatomical structures represented as a set of tetrahedra. A practical method of constructing anatomical models from medical images is presented. The method starts with a set of contours segmented from the medical images by a clinician and produces a model that has high fidelity with the contours. Unlike most modeling methods, the contours are not restricted to lie on parallel planes. The main steps are a 3D Delaunay tetrahedralization, culling of non-object tetrahedra, and refinement of the tetrahedral mesh. The result is a high-quality set of tetrahedra whose surface points are guaranteed to match the original contours. The key is to use the distance map and bit volume structures that were created along with the contours. The method is demonstrated on computed tomography, MRI and 3D ultrasound data. Models of 170,000 tetrahedra are constructed on a standard workstation in approximately 10s. A comparison with related methods is also provided.
Yoo S-S, O'Leary HM, Fairneny T, Chen N-kuei, Panych LP, Park HW, Jolesz FA. Increasing cortical activity in auditory areas through neurofeedback functional magnetic resonance imaging. Neuroreport. 2006;17 (12) :1273-8.Abstract
We report a functional magnetic resonance imaging method to deliver task-specific brain activities as biofeedback signals to guide individuals to increase cortical activity in auditory areas during sound stimulation. A total of 11 study participants underwent multiple functional magnetic resonance imaging scan sessions, while the changes in the activated cortical volume within the primary and secondary auditory areas were fed back to them between scan sessions. On the basis of the feedback information, participants attempted to increase the number of significant voxels during the subsequent trial sessions by adjusting their level of attention to the auditory stimuli. Results showed that the group of individuals who received the feedback were able to increase the activation volume and blood oxygenation level-dependent signal to a greater degree than the control group.
Kettenbach J, Kacher DF, Kanan AR, Rostenberg B, Fairhurst J, Stadler A, Kienreich K, Jolesz FA. Intraoperative and interventional MRI: recommendations for a safe environment. Minim Invasive Ther Allied Technol. 2006;15 (2) :53-64.Abstract
In this paper we report on current experience and review magnetic resonance safety protocols and literature in order to define practices surrounding MRI-guided interventional and surgical procedures. Direct experience, the American College of Radiology White paper on MR Safety, and various other sources are summarized. Additional recommendations for interventional and surgical MRI-guided procedures cover suite location/layout, accessibility, safety policy, personnel training, and MRI compatibility issues. Further information is freely available for sites to establish practices to minimize risk and ensure safety. Interventional and intraoperative MRI is emerging from its infancy, with twelve years since the advent of the field and well over 10,000 cases collectively performed. Thus, users of interventional and intraoperative MRI should adapt guidelines utilizing universal standards and terminology and establish a site-specific policy. With policy enforcement and proper training, the interventional and intraoperative MR imaging suite can be a safe and effective environment.
White PJ, Clement GT, Hynynen K. Longitudinal and shear mode ultrasound propagation in human skull bone. Ultrasound Med Biol. 2006;32 (7) :1085-96.Abstract
Recent studies have attempted to dispel the idea of the longitudinal mode being the only significant mode of ultrasound energy transport through the skull bone. The inclusion of shear waves in propagation models has been largely ignored because of an assumption that shear mode conversions from the skull interfaces to the surrounding media rendered the resulting acoustic field insignificant in amplitude and overly distorted. Experimental investigations with isotropic phantom materials and ex vivo human skulls demonstrated that, in certain cases, a shear mode propagation scenario not only can be less distorted, but at times allowed for a substantial (as much as 36% of the longitudinal pressure amplitude) transmission of energy. The phase speed of 1.0-MHz shear mode propagation through ex vivo human skull specimens has been measured to be nearly half of that of the longitudinal mode (shear sound speed = 1500 +/- 140 m/s, longitudinal sound speed = 2820 +/- 40 m/s), demonstrating that a closer match in impedance can be achieved between the skull and surrounding soft tissues with shear mode transmission. By comparing propagation model results with measurements of transcranial ultrasound transmission obtained by a radiation force method, the attenuation coefficient for the longitudinal mode of propagation was determined to between 14 Np/m and 70 Np/m for the frequency range studied, while the same for shear waves was found to be between 94 Np/m and 213 Np/m. This study was performed within the frequency range of 0.2 to 0.9 MHz.
Madore B, Farnebäck G, Westin C-F, Durán-Mendicuti A. A new strategy for respiration compensation, applied toward 3D free-breathing cardiac MRI. Magn Reson Imaging. 2006;24 (6) :727-37.Abstract
In thorax and abdomen imaging, image quality may be affected by breathing motion. Cardiac MR images are typically obtained while the patient holds his or her breath, to avoid respiration-related artifacts. Although useful, breath-holding imposes constraints on scan duration, which in turn limits the achievable resolution and SNR. Longer scan times would be required to improve image quality, and effective strategies are needed to compensate for respiratory motion. A novel approach at respiratory compensation, targeted toward 3D free-breathing cardiac MRI, is presented here. The method aims at suppressing the negative effects of respiratory-induced cardiac motion while capturing the heart's beating motion. The method is designed so that the acquired data can be reconstructed in two different ways: First, a time series of images is reconstructed to quantify and correct for respiratory motion. Then, the corrected data are reconstructed a final time into a cardiac-phase series of images to capture the heart's beating motion. The method was implemented, and initial results are presented. A cardiac-phase series of 3D images, covering the entire heart, was obtained for two free-breathing volunteers. The present method may prove especially useful in situations where breath-holding is not an option, for example, for very sick, mentally impaired or infant patients.
Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci U S A. 2006;103 (31) :11719-23.Abstract
Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system.

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