Functional relevance of micromodules in the human association cortex delineated with high-resolution FMRI.

Recent advancement of resting-state functional connectivity magnetic resonance imaging (MRI) has provided a method for drawing boundaries of brain areas. However, it remains to be elucidated how the parcellated areas in the association cortex relate to the spatial extent of the brain activation which ought to reflect a functional unit in the neural network supporting that particular function. To address this issue, in the present study, we first mapped boundaries and 2 adjacent activations in the human inferior frontal cortex, and then examined the spatial relationship between the boundaries and the 2 activations. The boundaries mapped with high-resolution functional magnetic resonance imaging revealed a collection of micromodules, the size of which was approximately only 12 mm on average, much smaller than the Brodmann areas. Each of the 2 activations associated with 2 functions, response inhibition and feedback processing, was smaller in size than the micromodules. By comparing the spatial patterns between the boundaries and the 2 activations, it was revealed that the brain activations were less likely to be located on the boundaries. These results suggest the functional relevance of the areas in the association cortex delineated by the boundary mapping method based on resting-state functional connectivity MRI.

Investigation of the limiting factors of shoulder joint complex motion in college baseball players: motion analysis of the humeral head and rotator cuff using ultrasound.

Background: The relationship between lower mobility, as measured by the elbow forward translation motion (T-motion) test, a new indicator of shoulder joint complex movement that measures elbow position when both dorsal hands are placed on the iliac crest while in a sitting position, and the parameters calculated by ultrasonography is unknown. The purpose of this study was to investigate the limiting factors of T-motion through motion analysis of the humeral head and rotator cuff muscles using ultrasonography in college baseball players. Methods: Thirteen college baseball players participated in this cross-sectional study. The shortest distance from the posterior edge of the glenoid to the humeral head was measured in the static and T-motion positions, and the difference was calculated as the humeral head translation. The velocity of the infraspinatus was calculated during shoulder internal/external rotation using the particle image velocimetry method. These parameters were compared between the throwing and nonthrowing sides to examine the limiting factors of T-motion. Results: This study indicated moderate-to-good reliability for the parameters calculated by ultrasonography. The mean anterior translation distance was significantly greater on the throwing side than on the nonthrowing side (r = 0.56, P = .015). The mean velocity of infraspinatus during internal rotation was significantly lower on the throwing side than on the nonthrowing side (r = 0.51, P = .028). Conclusion: Increased anterior translation of the humeral head and decreased the velocity of infraspinatus are likely correlated with reduced T-motion mobility in college baseball players. These methods showed potential for physical therapy assessment and intervention to prevent shoulder dysfunction.

Functional dissociation between anterior and posterior temporal cortical regions during retrieval of remote memory.

Retrieval of remote memory is considered to differentially involve the anterior and posterior temporal neocortices. Previous neuropsychological studies suggest that the different posterior temporal cortical regions are involved in the retrieval of remote memory of different categories of stimuli, whereas the anterior region is involved more generally in remote memory retrieval. In the present study, using functional magnetic resonance imaging of human brains, we tested this dissociation by examining the more precise characteristics of the anterior and posterior temporal cortical regions. Two categories of stimuli, faces and scenes, were used for paired stimuli to be retrieved, and the brain activity during retrieval of paired stimuli that were learned immediately before the scanning was compared with that during retrieval of paired stimuli that were learned ∼8 weeks earlier. We found that the different posterior temporal cortical regions were activated during retrieval of different categories of remote memory in a category-specific manner, whereas the anterior temporal cortical region was activated during retrieval of remote memory in a category-general manner. Furthermore, by applying a multivariate pattern analysis to psychophysiological interactions during retrieval of remote memory relative to recent memory, we revealed the significant interaction from the category-specific posterior temporal cortical regions to the category-general anterior temporal region. These results suggest that the posterior temporal cortical regions are involved in representation and retrieval of category-specific remote memory, whereas the anterior cortical temporal region is involved in category-general retrieval process of remote memory.

Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1ß-treated hepatocytes.

BACKGROUND: Nobiletin is a polymethoxylated flavone that is abundant in the peels of citrus fruits, such as Citrus unshiu (Satsuma mandarin) and Citrus sinensis. The dried peels of C. unshiu (chinpi) have been included in several formulae of Japanese Kampo medicines. Nobiletin may suppress the induction of inducible nitric oxide synthase (iNOS), which synthesizes the inflammatory mediator nitric oxide (NO) in hepatocytes. METHODS: A C. unshiu peel (CUP) extract was prepared. Primary cultured rat hepatocytes were treated with the CUP extract or nobiletin in the presence of interleukin 1ß (IL-1ß), which induces iNOS expression. NO production and iNOS gene expression were analyzed. RESULTS: High-performance liquid chromatography analyses revealed that the nobiletin content in the CUP extract was 0.14%. Nobiletin dose-dependently reduced the NO levels and decreased iNOS expression at the protein, mRNA and antisense transcript levels. Flavone, which does not contain any methoxy groups, also suppressed iNOS induction. Nobiletin reduced the transcriptional activity of iNOS promoter-luciferase constructs and the DNA-binding activity of nuclear factor κB (NF-κB) in the nuclei. CONCLUSIONS: The suppression of iNOS induction by nobiletin suggests that nobiletin may be responsible for the anti-inflammatory effects of citrus peels and have a therapeutic potential for liver diseases.

Radiological features of IgG4-related disease in the head, neck, and brain.

INTRODUCTION: Immunoglobulin (Ig) G4-related disease is a recently designated benign clinical entity histopathologically characterized by sclerosing inflammation and infiltration of numerous IgG4+ plasma cells that affects multiple organs. The purpose of this study is to characterize the imaging findings of patients with histopathologically proven IgG4-related disease in the head, neck, and brain. METHODS: A total of 17 patients (15 males, 2 females; mean age, 66.1 ± 7.4 years) with histopathologically proven IgG4-related disease in the head, neck, and brain were identified in two hospitals between January 2004 and December 2010. Imaging findings were retrospectively reviewed, with particular attention to the location and number of lesions, internal architecture, enhancement patterns, presence of vascular occlusion or compression, and changes in adjacent bones. RESULTS: The lesions, presented as either enlarged gland(s), or focal, localized nodules/masses, were distributed in the lacrimal gland (n = 7), the parotid gland (n = 14), the submandibular gland (n = 10), the pituitary gland (n = 2), skull base dura mater (n = 2), and the pterygopalatine fossa (n = 3). All lesions were well-defined and iso- to hypointense on T2-weighted magnetic resonance images and showed homogeneous enhancement. No lesion showed vascular occlusion or compression. Bones adjacent to the lesions showed remodeling (erosion or sclerosis) without signs of destruction (n = 6). Four patients had lesions involving multiple areas which extended along the trigeminal nerve, accompanied by expansion of neural foramina along their courses, with no signs of bone destruction. CONCLUSION: Sites of predilection for IgG4-related disease in the head, neck, and brain include the lacrimal, salivary, and pituitary glands. Recognition of the typical radiological features of IgG4-related disease, such as well-defined lesion borders, T2 hypointensity, homogeneous and gradual enhancement pattern, absence of vascular occlusion or compression, and presence of bone remodeling without destruction, may be of help in the diagnosis of this benign clinical entity.

Prediction of subsequent recognition performance using brain activity in the medial temporal lobe.

Application of multivoxel pattern analysis (MVPA) to functional magnetic resonance imaging (fMRI) data enables reconstruction and classification of cognitive status from brain activity. However, previous studies using MVPA have extracted information about cognitive status that is experienced simultaneously with fMRI scanning, but not one that will be observed after the scanning. In this study, by focusing on activity in the medial temporal lobe (MTL), we demonstrate that MVPA on fMRI data is capable of predicting subsequent recognition performance. In this experiment, six runs of fMRI signals were acquired during encoding of phonogram stimuli. In the analysis, using data acquired in runs 1-3, we first conducted MVPA-based voxel-wise search for the clusters in the MTL whose signals contained the most information about subsequent recognition performance. Next, using the fMRI signals acquired in runs 1-3 from the selected clusters, we trained a classifier function in MVPA. Finally, the trained classifier function was applied to fMRI signals acquired in runs 4-6. Consequently, we succeeded in predicting the subsequent recognition performance for stimuli studied in runs 4-6 with significant accuracy. This accurate prediction suggests that MVPA can extract information that is associated not only with concurrent cognitive status, but also with behavior in the near future.

Magnetic Resonance Imaging Findings of Idiopathic Normal Pressure Hydrocephalus and Cognitive Function Before and After Ventriculoatrial Shunt.

BACKGROUND: The idiopathic normal pressure hydrocephalus (iNPH) is characterized by the triad of gait impairment, incontinence, and dementia. Cases that do not comply with the diagnostic criteria of ventriculomegaly have increased. It has led to the questions about the current criteria of guidelines. As the number of patients with dementia increases with aging, iNPH is importantly placed as a treatable dementia. The purpose of this study was to verify the validity of radiological diagnostic criteria of ventriculomegaly in iNPH. MATERIALS AND METHODS: A board-certified neuroradiologist retrospectively examined 80 patients with definite iNPH about magnetic resonance imaging (MRI) findings of Evans index (EI) and disproportionately enlarged subarachnoid space hydrocephalus (DESH). The score of mini-mental state examination (MMSE) was measured to represent the cognitive function. The presurgical score of MMSE (pre-MMSE) and postsurgical best score of MMSE (best-MMSE) were compared statistically between patients dichotomized by either EI >0.3 or DESH. RESULTS: The pre-MMSE was not different regardless of dichotomization by EI >0.3 or DESH. The MMSE score (median) increased significantly (P < 0.0001) by shunt from 20.0 to 26.0 in patients with EI >0.3 and from 21.5 to 25.5 with EI ≤0.3. No difference in the best-MMSE was observed between EI >0.3 and EI ≤0.3. The MMSE score increased significantly (P < 0.0001) by shunt from 21 to 27.5 with DESH and from 20 to 24.5 with non-DESH. Regardless of fulfilling or notfulfilling Japanese radiological diagnostic criteria (combination of EI >0.3 and DESH), cognitive function was significantly (P < 0.0001) improved to the same level. Only 24 cases (30%) fulfilled Japanese radiological diagnostic criteria. CONCLUSION: Cognitive function of iNPH patients was significantly improved by shunt regardless of MRI-findings. Radiological diagnostic criteria of iNPH may need careful reconsideration.

Reliability and Interobserver Variability of Evans' Index and Disproportionately Enlarged Subarachnoid Space Hydrocephalus as Diagnostic Criteria for Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: The image diagnosis of idiopathic normal-pressure hydrocephalus (iNPH) is based on the ventriculomegaly, whose criterion is an Evans' Index (EI) >0.3. Recently, disproportionately enlarged subarachnoid space hydrocephalus (DESH) has been proposed as a morphological characteristic to iNPH. Several studies cast doubt on the reliability of these criteria in the diagnosis of iNPH. Furthermore, interobserver differences of these criteria have not yet been investigated. The objective of this study was to assess the diagnostic reliability and interobserver variability of EI and DESH. MATERIALS AND METHODS: The preoperative magnetic resonance (MR) images of 84 definite iNPH patients were retrospectively evaluated by a neuroradiologist (NR) and physical therapist (PT). They independently assessed the EI and DESH. The MR images were evaluated preoperatively by a neurosurgeon (NS). The results were showed in mean (standard deviation). RESULTS: The mean age was 78.4 (6.3) years (male:female = 49:35). The mean EI was 0.33 (0.04), 0.32 (0.04), and 0.31 (0.03) for NS, NR, and PT, respectively (P < 0.0001). The rate of accurate diagnosis of iNPH with EI >0.3 was 74%, 66%, and 61% for NS, NR, and PT, respectively, and there was a moderate level of agreement. By contrast, there was a substantial lower level of accuracy in assessment with DESH for all three evaluators as 50%, 44%, and 27% for NS, NR, and PT, respectively, again with a moderate level of agreement. However, the rates of patients fulfilling both EI >0.3 and DESH were remarkably lower than either of the two parameters individually at a mere 37%, 30%, and 16% for NS, NR, and PT, respectively, with a low level of agreement between the rates. CONCLUSION: This study suggests that DESH cannot be a diagnostic criterion for iNPH. If EI >0.3 and DESH were both necessary to diagnose iNPH, then more than 70% of patients would have been misdiagnosed and would have been deprived of the chance of treatment and its benefits. These results request a paradigm shift in the concepts of iNPH.

Reduction in the motor unit number estimate (MUNE) after cerebral infarction.

We examined the relationship between the degree to which motor unit number estimates (MUNEs) decrease in association with the clinical features of patients with the infarction. Using a multiple-point stimulation technique, we obtained the MUNE of the hypothenar muscle group in 13 age-matched control subjects and 30 patients with cerebral infarction. In all patients, we obtained the Japan Stroke Scale (JSS) and head MR images. In 8 patients with acute cerebral infarction, admitted within 24 h after onset, we also obtained head MR angiograms and single-photon emission CT. There was a decrease in the MUNE of the hypothenar muscle group on the affected side of 24 patients with cerebral infarction and hand weakness. The decrease in the MUNE started from 4 to 30 h after the infarction, when T1-weighted MR images of the brain involved were normal. The degree to which the MUNE decreased correlated with the part of the JSS showing the upper extremity weakness. A decrease in the MUNE of the hypothenar muscle group within 30 h after cerebral infarction may be due to transsynaptic inhibition of the spinal alpha motor neurons innervating this muscle.

Reduction in the motor unit number estimate (MUNE) after cerebral infarction.

BACKGROUND: The mechanism of the decrease in motor unit number estimates (MUNEs) after cerebral infarction has not been studied systematically. We examined the relationship between the degree to which MUNEs decreased and the other clinical features of patients with the infarction. METHODS: Using a multiple point stimulation technique, we obtained the MUNE of the hypothenar muscle group in 13 age-matched control subjects and 30 patients with cerebral infarction. In all patients, we obtained the Japan Stroke Scale (JSS) and head MR images. In eight patients with acute cerebral infarction, admitted within 24 h after onset, we also obtained head MR angiograms and single-photon emission CT. FINDINGS: There was a decrease in the MUNE of the hypothenar muscle group on the affected side of 24 patients with cerebral infarction and hand weakness. The decrease in the MUNE started from 4 to 30 h after the infarction, when T1-weighted MR images of the brain involved were normal. The degree to which the MUNE decreased correlated with the part of the JSS showing the upper extremity weakness. INTERPRETATIONS: A decrease in the MUNE of the hypothenar muscle group within 30 h after cerebral infarction may be due to trans-synaptic inhibition of the spinal alpha motor neurons innervating this muscle.

Lateral-Medial Dissociation in Orbitofrontal Cortex-Hypothalamus Connectivity.

The orbitofrontal cortex (OFC) is involved in cognitive functions, and is also closely related to autonomic functions. The OFC is densely connected with the hypothalamus, a heterogeneous structure controlling autonomic functions that can be divided into two major parts: the lateral and the medial. Resting-state functional connectivity has allowed us to parcellate the cerebral cortex into putative functional areas based on the changes in the spatial pattern of connectivity in the cerebral cortex when a seed point is moved from one voxel to another. In the present high spatial-resolution fMRI study, we investigate the connectivity-based organization of the OFC with reference to the hypothalamus. The OFC was parcellated using resting-state functional connectivity in an individual subject approach, and then the functional connectivity was examined between the parcellated areas in the OFC and the lateral/medial hypothalamus. We found a functional double dissociation in the OFC: the lateral OFC (the lateral orbital gyrus) was more likely connected with the lateral hypothalamus, whereas the medial OFC (the medial orbital and rectal gyri) was more likely connected with the medial hypothalamus. These results demonstrate the fundamental heterogeneity of the OFC, and suggest a potential neural basis of the OFC-hypothalamic functional interaction.

Relatedness-dependent rapid development of brain activity in anterior temporal cortex during pair-association retrieval.

Functional MRI studies have revealed that the brain activity in the anterior temporal cortex during memory retrieval increases over months after memory encoding. Behavioral evidence has demonstrated that long-term memory can sometimes be consolidated more rapidly in one or two days. In the present functional MRI study, we manipulated the relatedness between paired faces to be retrieved in a pair-association task. The brain activity in the anterior temporal cortex during retrieval of paired associates increased rapidly in one day, as shown in previous studies. We found that the speed of the brain activity development was dependent on the level of semantic relatedness of paired faces. The results suggest that the semantic relatedness enhances the speed of formation of memory representation in the anterior temporal cortex.

Data for behavioral results and brain regions showing a time effect during pair-association retrieval.

The current data article provides behavioral and neuroimaging data for the research article "Relatedness-dependent rapid development of brain activity in anterior temporal cortex during pair-association retrieval" (Jimura et al., 2016) [1]. Behavioral performance is provided in a table. Fig. 2 of the article is based on this table. Brain regions showing time effect are provided in a table. A statistical activation map for the time effect is shown in Fig. 3C of the article.

Neural correlates of recency judgment.

The prefrontal cortex plays a critical role in recollecting the temporal context of past events. The present study used event-related functional magnetic resonance imaging (fMRI) and explored the neural correlates of temporal-order retrieval during a recency judgment paradigm. In this paradigm, after study of a list of words presented sequentially, subjects were presented with two of the studied words simultaneously and were asked which of the two words was studied more recently. Two types of such retrieval trials with varied (high and low) levels of demand for temporal-order retrieval were intermixed and compared using event-related fMRI. The intraparadigm comparison of high versus low demand trials revealed brain regions with activation that was modulated on the basis of demand for temporal-order retrieval. Multiple lateral prefrontal regions including the middle and inferior lateral prefrontal cortex were prominently activated. Activation was also observed in the anterior prefrontal cortex and the medial temporal cortex, regions well documented to be related to memory retrieval in general. The modulation of brain activity in these regions suggests a detailed pathway that is engaged during recency judgment.

[Study of elliptical centric view ordering technique with spectrally selected inversion recovery pulse (spec-IR pulse)].

Among several techniques for contrast-enhanced MRA, the elliptical centric view ordering method, originally developed at the Mayo Clinic, is a promising one. It has been difficult to apply a fat-suppression prepulse, mainly because the conventional fat suppression method requires a longer acquisition time during sampling of the low-frequency domain in k-space, and it causes severe image distortion due to the great change in longitudinal magnetization derived from fat tissue. We developed a novel method to append fat saturation to the elliptical centric view ordering technique, and assessed the feasibility of its use. Our method is to apply fat-saturation pulses only at selected sampling points when any gradient is applied in the slice-encoding direction. In this way, we achieved efficient suppression of fat-derived signal within a relatively short time, comparable to that of the conventional fat-saturation method, and succeeded in minimizing artifacts.

The anti-inflammatory effects of flavanol-rich lychee fruit extract in rat hepatocytes.

Flavanol (flavan-3-ol)-rich lychee fruit extract (FRLFE) is a mixture of oligomerized polyphenols primarily derived from lychee fruit and is rich in flavanol monomers, dimers, and trimers. Supplementation with this functional food has been shown to suppress inflammation and tissue damage caused by high-intensity exercise training. However, it is unclear whether FRLFE has in vitro anti-inflammatory effects, such as suppressing the production of the proinflammatory cytokine tumor necrosis factor α (TNF-α) and the proinflammatory mediator nitric oxide (NO), which is synthesized by inducible nitric oxide synthase (iNOS). Here, we analyzed the effects of FRLFE and its constituents on the expression of inflammatory genes in interleukin 1ß (IL-1ß)-treated rat hepatocytes. FRLFE decreased the mRNA and protein expression of the iNOS gene, leading to the suppression of IL-1ß-induced NO production. FRLFE also decreased the levels of the iNOS antisense transcript, which stabilizes iNOS mRNA. By contrast, unprocessed lychee fruit extract, which is rich in flavanol polymers, and flavanol monomers had little effect on NO production. When a construct harboring the iNOS promoter fused to the firefly luciferase gene was used, FRLFE decreased the luciferase activity in the presence of IL-1ß, suggesting that FRLFE suppresses the promoter activity of the iNOS gene at the transcriptional level. Electrophoretic mobility shift assays indicated that FRLFE reduced the nuclear transport of a key regulator, nuclear factor κB (NF-κB). Furthermore, FRLFE inhibited the phosphorylation of NF-κB inhibitor α (IκB-α). FRLFE also reduced the mRNA levels of NF-κB target genes encoding cytokines and chemokines, such as TNF-α. Therefore, FRLFE inhibited NF-κB activation and nuclear translocation to suppress the expression of these inflammatory genes. Our results suggest that flavanols may be responsible for the anti-inflammatory and hepatoprotective effects of FRLFE and may be used to treat inflammatory diseases.

Energy landscapes of resting-state brain networks.

During rest, the human brain performs essential functions such as memory maintenance, which are associated with resting-state brain networks (RSNs) including the default-mode network (DMN) and frontoparietal network (FPN). Previous studies based on spiking-neuron network models and their reduced models, as well as those based on imaging data, suggest that resting-state network activity can be captured as attractor dynamics, i.e., dynamics of the brain state toward an attractive state and transitions between different attractors. Here, we analyze the energy landscapes of the RSNs by applying the maximum entropy model, or equivalently the Ising spin model, to human RSN data. We use the previously estimated parameter values to define the energy landscape, and the disconnectivity graph method to estimate the number of local energy minima (equivalent to attractors in attractor dynamics), the basin size, and hierarchical relationships among the different local minima. In both of the DMN and FPN, low-energy local minima tended to have large basins. A majority of the network states belonged to a basin of one of a few local minima. Therefore, a small number of local minima constituted the backbone of each RSN. In the DMN, the energy landscape consisted of two groups of low-energy local minima that are separated by a relatively high energy barrier. Within each group, the activity patterns of the local minima were similar, and different minima were connected by relatively low energy barriers. In the FPN, all dominant local minima were separated by relatively low energy barriers such that they formed a single coarse-grained global minimum. Our results indicate that multistable attractor dynamics may underlie the DMN, but not the FPN, and assist memory maintenance with different memory states.

Development of a new compact intraoperative magnetic resonance imaging system: concept and initial experience.

BACKGROUND: Magnetic resonance imaging (MRI) during surgery has been shown to improve surgical outcomes, but the current intraoperative MRI systems are too large to install in standard operating suites. Although 1 compact system is available, its imaging quality is not ideal. OBJECTIVE: We developed a new compact intraoperative MRI system and evaluated its use for safety and efficacy. METHODS: This new system has a magnetic gantry: a permanent magnet of 0.23 T and an interpolar distance of 32 cm. The gantry system weighs 2.8 tons and the 5-G line is within the circle of 2.6 m. We created a new field-of-view head coil and a canopy-style radiofrequency shield for this system. A clinical trial was initiated, and the system has been used in 44 patients. RESULTS: This system is significantly smaller than previous intraoperative MRI systems. High-quality T2 images could discriminate tumor from normal brain tissue and identify anatomic landmarks for accurate surgery. The average imaging time was 45.5 minutes, and no clinical complications or MRI system failures occurred. Floating organisms or particles were minimal (1/200 L maximum). CONCLUSION: This intraoperative, compact, low-magnetic-field MRI system can be installed in standard operating suites to provide relatively high-quality images without sacrificing safety. We believe that such a system facilitates the introduction of the intraoperative MRI.

A pairwise maximum entropy model accurately describes resting-state human brain networks.

The resting-state human brain networks underlie fundamental cognitive functions and consist of complex interactions among brain regions. However, the level of complexity of the resting-state networks has not been quantified, which has prevented comprehensive descriptions of the brain activity as an integrative system. Here, we address this issue by demonstrating that a pairwise maximum entropy model, which takes into account region-specific activity rates and pairwise interactions, can be robustly and accurately fitted to resting-state human brain activities obtained by functional magnetic resonance imaging. Furthermore, to validate the approximation of the resting-state networks by the pairwise maximum entropy model, we show that the functional interactions estimated by the pairwise maximum entropy model reflect anatomical connexions more accurately than the conventional functional connectivity method. These findings indicate that a relatively simple statistical model not only captures the structure of the resting-state networks but also provides a possible method to derive physiological information about various large-scale brain networks.

Magnetic resonance evaluation of brain metastases from systemic malignances with two doses of gadobutrol 1.0 m compared with gadoteridol: a multicenter, phase ii/iii study in patients with known or suspected brain metastases.

OBJECTIVES: To determine the efficacy and safety of 2 doses of gadobutrol 1.0 M (0.1 and 0.2 mmol/kg body weight [BW]), compared with gadoteridol 0.5 M (0.2 mmol/kg BW), in contrast-enhanced magnetic resonance imaging (CE-MRI) of brain metastases in patients with known or suspected brain metastases from systemic malignancies. The study also compared the usefulness of gadobutrol in treatment planning for stereotactic radiosurgery (SRS). MATERIALS AND METHODS: This was a Phase II/III, multicenter, single-blind, randomized, controlled, crossover, intraindividual comparison study. Each patient underwent one MRI study examination with gadobutrol and the other with gadoteridol, each at a dose of 0.1 mmol/kg BW, administered twice, for a total dose of 0.2 mmol/kg BW. Image acquisition was carried out after the first and second doses of gadobutrol, but only after the second dose of gadoteridol. Contrast agents were assigned in a randomized order and their administration separated by an interval of 1 to 14 days. Images were evaluated through blinded readings by 3 independent experienced radiologists. Treatment planning for SRS was assessed in a blinded manner, as a consensus between a diagnostic neuroradiologist and a radiation oncologist, in addition to the clinical investigator's assessment. The safety and tolerability of gadobutrol and gadoteridol were evaluated in all patients who received the study drugs. The primary efficacy variable was the number of lesions detected in CE-MRI images; the secondary efficacy variables were the degree of contrast enhancement and border delineation of lesions, and experts' confidence in treatment planning for SRS. RESULTS: A total of 175 patients were enrolled and randomized, with 164 (93.7%) included in the safety analysis set, and 151 (86.2%) evaluable in the efficacy analysis. The mean number of detected lesions per patient using the average of the 3 blinded readers was 6.28, 6.92, and 6.87 for gadobutrol 0.1 and 0.2 mmol/kg BW, and gadoteridol 0.2 mmol/kg BW, respectively. Noninferiority of gadobutrol (both doses) to gadoteridol 0.2 mmol/kg BW was demonstrated. The degree of contrast enhancement and the border delineation of each lesion were categorized as "good" or "excellent" for most lesions for both agents. Almost all enhanced images were rated as "confident" in treatment planning for SRS. Sixty-five (43%) and 62 (41%) patients in the gadobutrol 0.1 and 0.2 mmol/kg BW groups, respectively, were selected as eligible for SRS treatment. The percentage of images assessed as "gadobutrol was better than gadoteridol" was higher than that assessed as "gadoteridol was better than gadobutrol" for both doses of gadobutrol. Eight adverse events were reported as being related to the study drug in 7 patients (4.3%) in each group. CONCLUSION: In this study, a single dose of gadobutrol was shown to be noninferior to a double dose of gadoteridol at detecting brain metastases, and could be effectively used for treatment planning in patients eligible for SRS. A dose of gadobutrol 0.1 mmol/kg BW is recommended as the clinical dose for the detection of brain metastases.