Future Prospects of Positron Emission Tomography-Magnetic Resonance Imaging Hybrid Systems and Applications in Psychiatric Disorders.

A positron emission tomography (PET)-magnetic resonance imaging (MRI) hybrid system has been developed to improve the accuracy of molecular imaging with structural imaging. However, the mismatch in spatial resolution between the two systems hinders the use of the hybrid system. As the magnetic field of the MRI increased up to 7.0 tesla in the commercial system, the performance of the MRI system largely improved. Several technical attempts in terms of the detector and the software used with the PET were made to improve the performance. As a result, the high resolution of the PET-MRI fusion system enables quantitation of metabolism and molecular information in the small substructures of the brainstem, hippocampus, and thalamus. Many studies on psychiatric disorders, which are difficult to diagnose with medical imaging, have been accomplished using various radioligands, but only a few studies have been conducted using the PET-MRI fusion system. To increase the clinical usefulness of medical imaging in psychiatric disorders, a high-resolution PET-MRI fusion system can play a key role by providing important information on both molecular and structural aspects in the fine structures of the brain. The development of high-resolution PET-MR systems and their potential roles in clinical studies of psychiatric disorders were reviewed as prospective views in future diagnostics.

Topographic connectivity and cellular profiling reveal detailed input pathways and functionally distinct cell types in the subthalamic nucleus.

The subthalamic nucleus (STN) controls psychomotor activity and is an efficient therapeutic deep brain stimulation target in individuals with Parkinson's disease. Despite evidence indicating position-dependent therapeutic effects and distinct functions within the STN, the input circuit and cellular profile in the STN remain largely unclear. Using neuroanatomical techniques, we construct a comprehensive connectivity map of the indirect and hyperdirect pathways in the mouse STN. Our circuit- and cellular-level connectivities reveal a topographically graded organization with three types of indirect and hyperdirect pathways (external globus pallidus only, STN only, and collateral). We confirm consistent pathways into the human STN by 7 T MRI-based tractography. We identify two functional types of topographically distinct glutamatergic STN neurons (parvalbumin [PV+/-]) with synaptic connectivity from indirect and hyperdirect pathways. Glutamatergic PV+ STN neurons contribute to burst firing. These data suggest a complex interplay of information integration within the basal ganglia underlying coordinated movement control and therapeutic effects.

In vivo 3D Reconstruction of the Human Pallidothalamic and Nigrothalamic Pathways With Super-Resolution 7T MR Track Density Imaging and Fiber Tractography.

The output network of the basal ganglia plays an important role in motor, associative, and limbic processing and is generally characterized by the pallidothalamic and nigrothalamic pathways. However, these connections in the human brain remain difficult to elucidate because of the resolution limit of current neuroimaging techniques. The present study aimed to investigate the mesoscopic nature of these connections between the thalamus, substantia nigra pars reticulata, and globus pallidus internal segment using 7 Tesla (7T) magnetic resonance imaging (MRI). In this study, track-density imaging (TDI) of the whole human brain was employed to overcome the limitations of observing the pallidothalamic and nigrothalamic tracts. Owing to the super-resolution of the TD images, the substructures of the SN, as well as the associated tracts, were identified. This study demonstrates that 7T MRI and MR tractography can be used to visualize anatomical details, as well as 3D reconstruction, of the output projections of the basal ganglia.

Track-Density Ratio Mapping With Fiber Types in the Cerebral Cortex Using Diffusion-Weighted MRI.

The nerve fibers are divided into three categories: projection, commissural, and association fibers. This study demonstrated a novel cortical mapping method based on these three fiber categories using MR tractography data. The MR fiber-track data were extracted using the diffusion-weighted 3T-MRI data from 19 individuals' Human Connectome Project dataset. Anatomical MR images in each dataset were parcellated using FreeSurfer software and Brainnetome atlas. The 5 million extracted tracks per subject by MRtrix software were classified based on the basic cortical structure (cortical area in the left and right hemisphere, subcortical area), after the tracks validation procedure. The number of terminals for each categorized track per unit-sized cortical area (1 mm3) was defined as the track-density in that cortical area. Track-density ratio mapping with fiber types was achieved by mapping the density-dependent color intensity for each categorized tracks with a different primary color. The mapping results showed a highly localized, unique density ratio map determined by fiber types. Furthermore, the quantitative group data analysis based on the parcellation information revealed that the majority of nerve fibers in the brain are association fibers, particularly in temporal, inferior parietal, and occipital lobes, while the projection and commissural fibers were mainly located in the superior part of the brain. Hemispheric asymmetries in the fiber density were also observed, such as long association fiber in the Broca's and Wernicke's areas. We believe this new dimensional brain mapping information allows us to further understand brain anatomy, function.

Proposal for human visual pathway in the extrastriate cortex by fiber tracking method using diffusion-weighted MRI.

The extrastriate cortex in the human visual cortex is divided into two distinct clusters: the "what-information" processing area and the "where-information" processing area. It is widely accepted that the "what-information" cluster is processed through the ventral stream to the temporal cortex, and the "where-information" cluster through the dorsal stream to the parietal cortex. In human neuroanatomy, fiber bundles for the ventral stream (such as the inferior longitudinal fasciculus) are well defined, whereas fibers for the dorsal stream are poorly understood. In this study, we attempted to trace the dorsal stream fibers using a fiber tracking method using 7.0T diffusion-weighted MRI. We used data from a healthy male subject as well as from an unbiasedly selected nine-subject dataset in the Human Connectome Project. The surface of the visual area, including V1, V2, V3, V4, MT, was determined from the Brainnetome atlas (Fan et al., 2016), which is the connectivity-based parcellation framework of the human brain. The resulting visual pathway indicated that the putative pathway for the classical dorsal stream is unlikely to exist. Instead, we demonstrated that fiber connections exist between the angular gyrus with MT in the visual cortex, and between the angular gyrus and IT in the temporal cortex. Through that, we composed a two-pathway model for where-information processing that passes through the angular gyrus. Finally, we proposed a modified human visual pathway model based on our fiber tracking results in this report. The modified where-information pathway will provide a new aspect for the study of human visual processing.

Fiber-distance-based unsupervised clustering of MR tractography data.

BACKGROUND: MR tractography from diffusion tensor imaging provides a non-invasive way to explore white matter pathways in the human brain. However, a challenge to extracting reliable anatomical information from these data is the use of reliable and effective clustering methodologies. In this paper, we implemented a new version of a robust unsupervised clustering method from MR tractography data using the density-based spatial clustering of applications with noise (DBSCAN) algorithm. NEW METHOD: Conventional DBSCAN clustering methods for MR tractography data use each fiber's start and end point as well as the distance between start and end points. Instead, in this study, we extracted and used a fiber-distance matrix generated for all fiber combinations from the tractography dataset in DBSCAN clustering. The two DBSCAN parameters-minimum point number and maximum radius of the neighborhood-were selected according to the value generated with the cluster stability index (CSI). RESULTS: Performing the proposed CSI-optimized DBSCAN-based clustering method on MR tractography data of the superior longitudinal fasciculus generated 6 robust, non-overlapping, clusters that are neuroanatomically related. COMPARISON WITH EXISTING METHODS: Conventional DBSCAN-based clustering methods have intrinsic error potential in the clustering results due to deviations in fiber shape and fiber location. The proposed method did not exhibit clustering error caused by deviation in fiber trajectory or fiber location. CONCLUSIONS: We implemented a new, robust DBSCAN-based fiber clustering method for MR tractography data. The CSI-optimized DBSCAN-based unsupervised clustering is applicable to investigation of the neuroconnectome and the fiber structure of the brain.

Development of Positron Emission Tomography With Wobbling and Zooming for High Sensitivity and High-Resolution Molecular Imaging.

Demands for in-vivo human molecular imaging with high resolution and high sensitivity in positron emission tomography (PET) require several new design formulae. A classical problem of the PET design, however, was the trade-off between sensitivity and resolution. To satisfy both requirements, the brain-body convertible PET with wobbling and zooming is proposed. The features of this new proposed system are wobble sampling for high-resolution imaging and zooming mode for high sensitivity, especially for the brain dedicated imaging. For the high resolution, wobbling with a linear interpolation and line spread function (LSF) deconvolution reconstruction algorithm was introduced. The result of the proposed system provided resolution up to 1.56 mm full width at half maximum (FWHM) in the brain mode and resulting in the detector-to-resolution ratio (DRR) was 2.47. For both brain phantom and in-vivo rat brain imaging, the proposed system demonstrated superior image quality compared with the commercial PET systems. The newly designed PET with wobbling and zooming also demonstrated the possibility of developing practically usable high-resolution human brain PET-MRI fusion system, especially for the neuroscience research.

Papez Circuit Observed by in vivo Human Brain With 7.0T MRI Super-Resolution Track Density Imaging and Track Tracing.

The Papez circuit has been considered as an important anatomical substrate involved in emotional experience. However, the circuit remains difficult to elucidate in the human brain due to the resolution limit of current neuroimaging modalities. In this article, for the first time, we report the direct visualization of the Papez circuit with 7-Tesla super-resolution magnetic resonance tractography. Two healthy, young male subjects (aged 30 and 35 years) were recruited as volunteers following the guidelines of the institutional review board (IRB). Track density imaging (TDI) generation with track tracing was performed using MRtrix software package. With these tools, we were able to visualize the entire Papez circuit. We believe this is the first study to visualize the complete loop of the Papez circuit, including the perforant path (PP), thalamocortical fibers of the anterior nucleus (AN), and mammillothalamic tract (MTT), which were hitherto difficult to visualize by conventional imaging techniques.

Newly observed anterior thalamocortical fiber of the thalamus using 7.0T super-resolution magnetic resonance tractography and its implications for the classical Papez circuit.

Here, we have employed recently developed super-resolution tractography using 7.0T-MRI to analyze the fine structures involved in thalamocortical connections, something that has proved difficult using conventional techniques. We detail a newly observed thalamocortical pathway connecting the anterior nucleus of the thalamus and the cingulate cortex not via the internal capsule but via the septal area. The observed pathway is believed to be a classical pathway of the Papez circuit but had not been previously identified.

Advances in MR angiography with 7T MRI: From microvascular imaging to functional angiography.

Over the past few decades, vascular flow-dependent imaging techniques have proven to be effective for the visualization of large vessel diseases. However, these approaches are unlikely to be efficacious for small vessels because the affected small vessels cannot always be visualized directly, owing to a lack of detection sensitivity. Recently, many researchers have introduced state-of-the-art imaging techniques to visualize cerebral microvessels using ultra-high-field (UHF) magnetic resonance angiography (MRA). They have demonstrated the superiority of UHF MRA, especially for visualization of the microvasculature compared with clinical MRA images using 1.5T or 3T magnetic resonance imaging (MRI). Thus, UHF MRA may become an important investigative tool for research, facilitating examinations of vascular mechanisms for small vessel diseases and contributing to the early detection of cerebrovascular diseases in clinics. Furthermore, new imaging methods for visualizing vascular dynamics or flow effects may help investigate brain functions, especially in conjunction with blood oxygenation level-dependent contrast functional MRI modalities, as well as situations in which small vessel abnormalities are clinically important. The present article reviews recent technological advances in UHF MRA, especially 7T MRA, and discusses the potential benefits and future directions of UHF MRA.

Progressive Minimal Path Method for Segmentation of 2D and 3D Line Structures.

We propose a novel minimal path method for the segmentation of 2D and 3D line structures. Minimal path methods perform propagation of a wavefront emanating from a start point at a speed derived from image features, followed by path extraction using backtracing. Usually, the computation of the speed and the propagation of the wave are two separate steps, and point features are used to compute a static speed. We introduce a new continuous minimal path method which steers the wave propagation progressively using dynamic speed based on path features. We present three instances of our method, using an appearance feature of the path, a geometric feature based on the curvature of the path, and a joint appearance and geometric feature based on the tangent of the wavefront. These features have not been used in previous continuous minimal path methods. We compute the features dynamically during the wave propagation, and also efficiently using a fast numerical scheme and a low-dimensional parameter space. Our method does not suffer from discretization or metrication errors. We performed qualitative and quantitative evaluations using 2D and 3D images from different application areas.

Structural and Functional Alterations at Pre-Epileptic Stage Are Closely Associated with Epileptogenesis in Pilocarpine-induced Epilepsy Model.

Pilocarpine-induced rat epilepsy model is an established animal model that mimics medial temporal lobe epilepsy in humans. The purpose of this study was to investigate neuroimaging abnormalities in various stages of epileptogenesis and to correlate them with seizure severity in pilocarpine-induced rat epilepsy model. Fifty male Sprague-Dawley rats were subject to continuous video and electroencephalographic monitoring after inducing status epilepticus (SE) and seizure severity was estimated by frequency and total durations of class 3 to 5 spontaneous recurrent seizures (SRS) by modified Racine's classification. The 7.0 Tesla magnetic resonance imaging (MRI) with high resolution flurodeoxyglucose positron emission tomography (FDG-PET) was performed at 3 hours, 1, 3, 7 days and 4 weeks after the initial insult. The initial SRS was observed 9.7±1.3 days after the pilocarpine injection. MRI revealed an abnormal T2 signal change with swelling in both hippocampi and amygdala in acute (day 1 after injection) and latent phases (days 3 and 7), in association with PET hypometabolism in these areas. Interestingly, the mean frequency of class 3 to 5 SRS was positively correlated with abnormal T2 signals in hippocampal area at 3 days. SRS duration became longer with more decreased glucose metabolism in both hippocampi and amygdala at 7 days after pilocarpine injection. This study indicates that development and severity of SRS at chronic phase could be closely related with structural and functional changes in hippocampus during the latent period, a pre-epileptic stage.

SCA2 family presenting as typical Parkinson's disease: 34 year follow up.

OBJECTIVE: We describe a Korean family in SCA2 with long-duration levodopa-responsive parkinsonism without cerebellar ataxia. METHODS: Clinical evaluation, genetic testing, and extensive imaging studies were done. RESULTS: All family members showed a typical Parkinson's disease phenotype without cerebellar ataxia for a long disease duration (up to 34 years). Genetic testing showed 40 CAG repeats and 4 CAA interruptions which is the longest repeat number among the families or patients manifesting with a parkinsonian phenotype without ataxia. Structural imaging (7T MRI and brain CT) showed a normal cerebellum and functional images showed nigrostriatal dopaminergic degeneration and normal D2 receptor binding activity, in agreement with the clinical phenotype. CONCLUSION: SCA2 should be considered as a cause of typical Parkinson's disease phenotype even in the absence of cerebellar ataxia.

An Actively Decoupled Dual Transceiver Coil System for Continuous ASL at 7 T.

7 T arterial spin labeling (ASL) faces major challenges including the increased specific absorption rate (SAR) and increased B0 and B1 inhomogeneity. This work describes the design and implementation of a dual-coil system that allows for continuous ASL (CASL) at 7 T. This system consisted of an actively detunable eight-channel transceiver head coil, and a three-channel transceiver labeling coil. Four experiments were performed in 5 healthy subjects: (i) to demonstrate that active detuning during ASL labeling reduces magnetization transfer; (ii) to measure the B1 profile at the labeling plane; (iii) to quantify B0 off-resonance at the labeling plane; and (iv) to collect in vivo CASL data. The magnetization transfer ratio in the head coil was reduced to 0.0 ± 0.2% by active detuning during labeling. The measured B1 profiles in all 5 subjects were sufficient to satisfy the flow-driven adiabatic inversion necessary for CASL, however the actual labeling efficiency was significantly impacted by B0 off-resonance at the labeling plane. The measured CASL percent signal change in gray matter (0.94% ± 0.10%) corresponds with the low labeling efficiency predicted by the B0 off-resonance. This work demonstrates progress in the technical implementation of 7 T CASL, and reinforces the need for improved B0 homogeneity at the labeling plane.

Experience with 7.0 T MRI in Patients with Supratentorial Meningiomas.

Meningiomas are typically diagnosed by their characteristic appearance on conventional magnetic resonance imaging (MRI). However, detailed image findings regarding peri- and intra-tumoral anatomical structures, tumor consistency and vascularity are very important in pre-surgical planning and surgical outcomes. At the 7.0 T MRI achieving ultra-high resolution, it could be possible to obtain more useful information in surgical strategy. Four patients who were radiologically diagnosed with intracranial meningioma in 1.5 T MRI underwent a 7.0 T MRI. Three of them underwent surgery afterwards, and one received gamma knife radiosurgery. In our study, the advantages of 7.0 T MRI over 1.5 T MRI were a more detailed depiction of the peri- and intra-tumoral vasculature and a clear delineation of tumor-brain interface. In the safety issues, all patients received 7.0 T MRI without any adverse event. One disadvantage of 7.0 T MRI was the reduced image quality of skull base lesions. 7.0 T MRI in patients with meningiomas could provide useful information in surgical strategy, such as the peri-tumoral vasculature and the tumor-brain interface.

Loss of substantia nigra hyperintensity on 7 Tesla MRI of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.

BACKGROUND: Seven Tesla (7T) MRI can visualize anatomical alterations occurring in a hyperintense structure of the substantia nigra in Parkinson's disease (PD). OBJECTIVE: We investigated whether 7T MRI can detect the loss of substantia nigra hyperintensity in patients with PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). METHODS: Using 7T MRI, we evaluated 26 healthy subjects, 30 patients with PD, 7 patients with MSA, and 3 patients with PSP. Two blinded readers independently assessed the images. We carried out a comparative analysis of five patients with hemiparkinsonism via (123)I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ((123)I-FP-CIT) SPECT. RESULTS: 7T MRI revealed a definitive shape of nigral hyperintensity in healthy subjects, nearly identical to neuropathological characterization of nigrosome 1, and enabled instantaneous determination of its presence or absence in all subjects. Nigral hyperintensity was lost in all patients with PD, MSA with predominant parkinsonism, and PSP. One of five patients with MSA with predominant cerebellar ataxia showed an intact nigral hyperintensity. The side effects were mild and tolerable, and imaging was successful in patients with dyskinesia. Motion artifact incidence was higher in elderly subjects. In hemiparkinsonism cases, we observed partial loss of nigral hyperintensity on the side of less reduced (123)I-FP-CIT binding, suggesting an ongoing iron deposition on the unaffected side in hemiparkinsonism. CONCLUSIONS: The present findings suggest that 7T MRI represents an excellent tool for evaluating nigral hyperintensity in PD, MSA, and PSP, with tolerable side effects and limited motion artifacts. Thus, imaging of parkinsonism may benefit from using 7T MRI.

Basal Forebrain Cholinergic Deficits Reduce Glucose Metabolism and Function of Cholinergic and GABAergic Systems in the Cingulate Cortex.

PURPOSE: Reduced brain glucose metabolism and basal forebrain cholinergic neuron degeneration are common features of Alzheimer's disease and have been correlated with memory function. Although regions representing glucose hypometabolism in patients with Alzheimer's disease are targets of cholinergic basal forebrain neurons, the interaction between cholinergic denervation and glucose hypometabolism is still unclear. The aim of the present study was to evaluate glucose metabolism changes caused by cholinergic deficits. MATERIALS AND METHODS: We lesioned basal forebrain cholinergic neurons in rats using 192 immunoglobulin G-saporin. After 3 weeks, lesioned animals underwent water maze testing or were analyzed by ¹8F-2-fluoro-2-deoxyglucose positron emission tomography. RESULTS: During water maze probe testing, performance of the lesioned group decreased with respect to time spent in the target quadrant and platform zone. Cingulate cortex glucose metabolism in the lesioned group decreased, compared with the normal group. Additionally, acetylcholinesterase activity and glutamate decarboxylase 65/67 expression declined in the cingulate cortex. CONCLUSION: Our results reveal that spatial memory impairment in animals with selective basal forebrain cholinergic neuron damage is associated with a functional decline in the GABAergic and cholinergic system associated with cingulate cortex glucose hypometabolism.

Extended Monopole antenna Array with individual Shield (EMAS) coil: An improved monopole antenna design for brain imaging at 7 tesla MRI.

PURPOSE: To propose a new Extended Monopole antenna Array with individual Shields (EMAS) coil that improves the B1 field coverage and uniformity along the z-direction. METHODS: To increase the spatial coverage of Monopole antenna Array (MA) coil, each monopole antenna was shielded and extended in length. Performance of this new coil, which is referred to as EMAS coil, was compared with the original MA coil and an Extended Monopole antenna Array coil with no shield (EMA). For comparison, flip angle, signal-to-noise ratio (SNR), and receive sensitivity maps were measured at multiple regions of interest (ROIs) in the brain. RESULTS: The EMAS coil demonstrated substantially larger flip angle and receive sensitivity than the MA and EMA coils in the inferior aspect of the brain. In the brainstem ROI, for example, the flip angle in the EMAS coil was increased by 45.5% (or 60.0%) and the receive sensitivity was increased by 26.9% (or 14.9%), resulting in an SNR gain of 84.8% (or 76.3%) when compared with the MA coil (or EMA). CONCLUSION: The EMAS coil provided 25.7% (or 24.4%) more uniform B1+ field distribution compared with the MA (or EMA) coil in sagittal. The EMAS coil successfully extended the imaging volume in lower part of the brain. Magn Reson Med 75:2566-2572, 2016. © 2015 Wiley Periodicals, Inc.

Velocity measurement of microvessels using phase-contrast magnetic resonance angiography at 7 Tesla MRI.

PURPOSE: The purpose of this study was to measure the velocity and direction of blood flow in microvessels, such as lenticulostriate arteries (LSAs), using PC MRA. METHODS: Eleven healthy subjects were scanned with 7 Tesla (T) MRI. Three velocity encoding (VENC) values of 15, 50, and 100 cm/s were tested for detecting the flow velocity in LSAs. The flow directions in Circle of Willis (CoW) were also examined with images obtained by the proposed method. Three subjects were also scanned with 3T MRI to determine the possibility of velocity measurement in LSAs. Difference between 3T and 7T was quantitatively analyzed in terms of signal-to-noise ratio and velocities in vessels and static tissues. RESULTS: In 7T MRI, use of VENC = 15 cm/s provided great visualization and velocity measurements in small and slow flowing vessels, such as the LSAs. The mean of peak velocities in LSAs was 9.61 ± 1.78 cm/s. The results obtained with low VENC also clearly depicted the directions of flow in CoW, especially in posterior communicating arteries. However, 3T MRI could not detect the velocity of blood flow in LSAs. CONCLUSION: This study demonstrated the potential for measuring the velocity and direction of blood flow in the targeted microvessels using an appropriate VENC and 7T MRI.

A Newly Identified Frontal Path from Fornix in Septum Pellucidum with 7.0T MRI Track Density Imaging (TDI) - The Septum Pellucidum Tract (SPT).

The high anatomical contrast achieved with the newly emerging MRI tractographic technique of super-resolution track density imaging (TDI) encouraged us to search for a new fiber tract in the septum pellucidum. Although this septum pellucidum tract (SPT) has been observed previously, its connections were unclear due to ambiguity and limited resolution of conventional MRI images. It is now possible to identify detailed parts of SPT with the increased resolution of TDI, which involves diffusion MRI imaging, whole-brain tractography, and voxel subdivision using the track-count information. Four healthy male subjects were included in the study. The experiment was performed with 7.0T MRI, following the guidelines of the institute's institutional review board. Data were processed with the super-resolution TDI technique to generate a tractographic map with 0.18 mm isotropic resolution. The SPT was identified in all subjects. Based on additional seed tracking method with inter-axis correlation search, we have succeeded in identifying a new frontal lobe pathway in the SPT. We hypothesize that the tract is connected as a superior dorsal branch of the fornix that leads to the prefrontal cortex.