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The blood–brain barrier (BBB), which imposes significant water permeability restriction, effectively isolates the brain from the systemic circulation. Seemingly paradoxical, the abundance of aquaporin-4 (AQP-4) on the inside of the BBB strongly indicates the presence of unique water dynamics essential for brain function. On the basis of the highly specific localization of AQP-4, namely, astrocyte end feet at the glia limitans externa and pericapillary Virchow–Robin space, we hypothesized that the AQP-4 system serves as an interstitial fluid circulator, moving interstitial fluid from the glia limitans externa to pericapillary Virchow–Robin space to ensure proper glymphatic flow draining into the cerebrospinal fluid. The hypothesis was tested directly using the AQP-4 facilitator TGN-073 developed in our laboratory, and [17O]H2O JJ vicinal coupling proton exchange MRI, a method capable of tracing water molecules delivered into the blood circulation. The results unambiguously showed that facilitation of AQP-4 by TGN-073 increased turnover of interstitial fluid through the system, resulting in a significant reduction in [17O]H2O contents of cortex with normal flux into the cerebrospinal fluid. The study further suggested that in addition to providing the necessary water for proper glymphatic flow, the AQP-4 system produces a water gradient within the interstitial space promoting circulation of interstitial fluid within the BBB.

Synesthesia, an anomalous blending of senses in which stimulation of one sensory modality produces sensation in a different modality, provides a unique opportunity to study how multimodal information is represented in the human brain. We investigated how pitch classes (do, re, mi, etc.) are associated with the three dimensions of color (hue, saturation, and value/brightness) in 15 subjects who possessed “pitch class-color synesthesia”. Across-subject averaging of reported colors revealed that pitch classes have rainbow hues, beginning with do-red, re-yellow, and so forth, ending with si-violet, accompanied by a decrease in saturation. Enharmonic pitch classes that referred to the same pitch class with a different name produced color sensations according to the name of the base pitch class, e.g., a reddish color for do-sharp and a yellowish color for re-flat. Thus the main factor producing color sensations was the name, not the sound, of the note; behavioral experiments corroborated this interpretation. Pitch class-color synesthesia represents a newly described type of synesthesia that is distinct from the well-known crossmodal association between pitch height and value/brightness. Findings suggest that the two dimensions of musical pitch, pitch class and pitch height, are mapped to the hue-saturation plane and the value/brightness dimension of color, respectively.

Purpose To perform a systematic analysis of the intrinsic contrast parameters of the FLAIR hyperintense rim (FHR), a thin layer of high intensity covering the entire surface of the cerebral cortex detected on fluid-attenuated inversion recovery (FLAIR) sequence T2 weighted imaging performed on a 7T system, in an attempt to identify its anatomical correlate. Methods Fast spin echo inversion recovery (FSE-IR) and cardiac-gated fast spin echo (FSE) images were obtained with defined parameters in eight normal volunteers on a 7 T MRI system to determine T2 and proton density, T1 characteristics. K-means clustering analysis of parameter sets was performed using MATLAB version R2015b for the purpose of identifying the cluster reflecting FHR. The results were subsequently confirmed by independent component analysis (ICA) based on T1 behavior on FSE-IR using a MATLAB script of FastICA algorithm. Results The structure giving rise to FHR was found to have a unique combination of intrinsic contrast parameters of low proton density, long T2, and disproportionally short T1. The findings are in strong agreement with the functional and structural specifics of the glia limitans externa (GLE), a structure composed of snuggled endfeet of astrocytes containing abundant aquaporin-4 (AQP-4), the main water channel of the brain. Conclusion Intrinsic contrast parameters of FHR reflect structural and functional specifics of the GLE, and their values are highly dependent on the physiologic functionality of AQP-4. Microscopic imaging on a 7T system and analysis of GLE contrast parameters can be developed into a method for evaluating AQP-4 functionality.

BACKGROUND Aquaporin (AQP) water channels play a significant role in mesenchymal microvascular proliferation and infiltrative growth. AQPs are highly expressed in malignant astrocytomas, and a positive correlation is observed between their expression levels and histological tumor grade. OBJECTIVE To examine the utility of aquaporin positron emission tomography (PET) for differentiating between astrocytoma grade III and grade IV using the AQP radioligand [11C]TGN-020. METHODS Fifteen astrocytoma patients, grade III (n = 7) and grade IV (n = 8), and 10 healthy volunteers underwent [11C]TGN-020 aquaporin PET imaging. Surgical tissues of astrocytoma patients were examined for histopathological grading using the WHO classification standard and expression of AQP1 and AQP4 immunohistochemically. RESULTS Mean standardized uptake values of astrocytoma grade III and IV (0.51 ± 0.11 vs 1.50 ± 0.44, respectively) were higher than normal white matter (0.17 ± 0.02, P < .001) for both tumor grades. Importantly, mean standardized uptake values of astrocytoma grade IV were significantly higher than grade III (P < .01). CONCLUSION Our study demonstrated that [11C]TGN-020 aquaporin PET imaging differentiated between astrocytoma grades III and IV. We suggest its clinical application as a noninvasive diagnostic tool would lead to advancements in the management of these malignant brain tumors.

Aquaporin-4 (AQP4) is a water conducting membrane integral protein channel which is widely expressed in the astrocyte system of the brain. During the development of the AQP4 positron emission tomography (PET) imaging agent [11C]TGN-020 (N-(1,3,4-thiadiazol-2-yl)pyridine-3-[11C]-carboxamide), significant radioligand uptake was observed in the skull, where there was no known distribution of any aquaporin family proteins. Herein we confirmed via a newly developed method for bone-tissue immunohistology, a hitherto unrecognized distribution of AQP4, and not AQP1, in the skull. Other bony structures, by contrast, showed virtually no uptake of [11C]TGN-020, and likewise, do not express either AQP4 or AQP1. Immunohistological analysis demonstrated that the AQP4 expression in the skull is restricted to the diploë. Consequently, we suspect AQP4 plays a pivotal role in the formation and maintenance of yellow marrow and the diploë. However, elucidating the exact nature of that role will require further studies., Anatomy; Pathology; Medical imaging; Nuclear medicine; Radiology; Tissue culture; Bone; Aquaporin 4 (AQP4); Skull; Positron emission tomography(PET); N-(1,3,4-thiadiazol-2-yl) pyridine-3-[11C]-carboxamide ([11C]TGN-020); Immunohistology.

Many of the focal neurological symptoms associated with Alzheimer’s disease (AD) are due to synaptic loss. Glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) is a candidate method to assess synaptic dysfunction. We assessed chronological changes in GluCEST in a 5xFAD mouse model of AD, comparing Glucest effects and regional cerebral blood flow (CBF). GluCEST effects and CBF in 5xFAD mice aged 1–15 months and their littermates (WT) were measured. Neurite orientation dispersion and density imaging (NODDI) MRI reflecting dendritic/axonal density was also measured and compared with GluCEST in 7-month-old mice. While regional CBF’s decrease began at 7 months, GluCEST-reduction effects preceded hypoperfusion of the temporal cortex and hippocampus. While longitudinal 5xFAD mouse measurements revealed a correlation between the regional GluCEST effects and CBF, a generalized linear mixed model revealed statistically different correlations in cortical and basal brain regions. Further, NODDI-derived neurite density correlated with GluCEST effects in the parietal cortex, but not in the hippocampus, thereby revealing regional differences in pathophysiological mechanisms. Finally, GluCEST’s effects correlated with regional synaptophysin. These results demonstrate that GluCEST can reflect subtle synaptic changes and may be a potential imaging method for AD diagnosis as well as serve as a biomarker of AD progression.

Matrix metalloproteinases (MMPs) damage the neurovascular unit, promote the blood-brain barrier (BBB) disruption following ischemic stroke, and play essential roles in hemorrhagic transformation (HT), which is one of the most severe side effects of thrombolytic therapy. However, no biomarkers have presently been identified that can be used to track changes in the distribution of MMPs in the brain. Here, we developed a new 19F-molecular ligand, TGF-019, for visualizing the distribution of MMPs in vivo using 19F-magnetic resonance spectroscopic imaging (19F-MRSI). We demonstrated TGF-019 has sufficient sensitivity for the specific MMPs suspected in evoking HT during ischemic stroke, i.e., MMP2, MMP9, and MMP3. We then utilized it to assess those MMPs at 22 to 24 hours after experimental focal cerebral ischemia on MMP2-null mice, as well as wild-type mice with and without the systemic administration of the recombinant tissue plasminogen activator (rt-PA). The 19F-MRSI of TGN-019-administered mice showed high signal intensity within ischemic lesions that correlated with total MMP2 and MMP9 activity, which was confirmed by zymographic analysis of ischemic tissues. Based on the results of this study, 19F-MRSI following TGN-019 administration can be used to assess potential therapeutic strategies for ischemic stroke.

During pre-clinical development, we tested the novel, internally developed AQP-4 facilitator TGN-073 for its effect in a rodent pain model. Therein, TGN-073 was found to exert a strong analgesic effect. Following a single 200 mg/kg (i.p.) administration of TGN-073, a virtually complete block in the acetic acid writhing test was observed. Subsequent in vitro tests demonstrated that TGN-073 had no binding affinity for the μ-opioid or NK-1 receptors. Accordingly, we suspect TGN-073 or other AQP-4 facilitators may be developed into potent non-opioid analgesic agents. Given the potential significance of this discovery, we feel it should be openly shared with the scientific community.

Matrix metalloproteinases (MMPs) damage the neurovascular unit, promote the blood-brain barrier (BBB) disruption following ischemic stroke, and play essential roles in hemorrhagic transformation (HT), which is one of the most severe side effects of thrombolytic therapy. However, no biomarkers have presently been identified that can be used to track changes in the distribution of MMPs in the brain. Here, we developed a new 19F-molecular ligand, TGF-019, for visualizing the distribution of MMPs in vivo using 19F-magnetic resonance spectroscopic imaging (19F-MRSI). We demonstrated TGF-019 has sufficient sensitivity for the specific MMPs suspected in evoking HT during ischemic stroke, i.e., MMP2, MMP9, and MMP3. We then utilized it to assess those MMPs at 22 to 24 hours after experimental focal cerebral ischemia on MMP2-null mice, as well as wild-type mice with and without the systemic administration of the recombinant tissue plasminogen activator (rt-PA). The 19F-MRSI of TGN-019-administered mice showed high signal intensity within ischemic lesions that correlated with total MMP2 and MMP9 activity, which was confirmed by zymographic analysis of ischemic tissues. Based on the results of this study, 19F-MRSI following TGN-019 administration can be used to assess potential therapeutic strategies for ischemic stroke.

The effects of a low dose of alcohol on car driving remain controversial. To address this issue, event-related potentials were recorded while subjects performed a simple car-following task in a driving simulator before and after consuming either "one drink" of beer (representing one standard alcoholic beverage containing 14g of alcohol) or mineral water (control condition). Subjects who had consumed the determined amount of alcohol demonstrated no detectable outward behavioral signs of intoxication while performing the driving task, an observation in agreement with previous findings. However, the parietal P3 elicited by the brake lights of the preceding car was significantly reduced in amplitude, approximately 50% that observed under the control condition, likely indicating alteration of the neural processing of visual information critical for safe driving. The finding suggests that alcohol begins to affect neural processes for driving even at quantities too low to modify behavior. Language: en

We performed detailed structural analysis of a case of a unilateral lesion of the inferior colliculus using magnetic resonance microscopy on a 7 T system. A 36-year-old right-handed man had an intracerebral hemorrhage circumscribed to the right inferior colliculus. Following recovery from the acute phase, he had only residual left ear tinnitus and left trochlear palsy and no hearing loss. Microscopic imaging analysis on a 7 T magnetic resonance imaging system demonstrated a chronic lesion confined primarily to the right central nucleus of the inferior colliculus. Sound localization was significantly impaired in the contralateral hemispace. The case confirms prior clinical reports of unilateral inferior colliculus dysfunction, the specific anatomic characterization of which was demonstrated in this case by magnetic resonance microscopy. It furthermore supports the notion that central nucleus of the inferior colliculus dysfunction can produce tinnitus and sound localization deficits, without hearing loss

The unique properties of brain capillary endothelium, critical in maintaining the blood-brain barrier (BBB) and restricting water permeability across the BBB, have important consequences on fluid hydrodynamics inside the BBB hereto inadequately recognized. Recent studies indicate that the mechanisms underlying brain water dynamics are distinct from systemic tissue water dynamics. Hydrostatic pressure created by the systolic force of the heart, essential for interstitial circulation and lymphatic flow in systemic circulation, is effectively impeded from propagating into the interstitial fluid inside the BBB by the tightly sealed endothelium of brain capillaries. Instead, fluid dynamics inside the BBB is realized by aquaporin-4 (AQP-4), the water channel that connects astrocyte cytoplasm and extracellular (interstitial) fluid. Brain interstitial fluid dynamics, and therefore AQP-4, are now recognized as essential for two unique functions, namely, neurovascular coupling and glymphatic flow, the brain equivalent of systemic lymphatics.

Recent studies on cerebrospinal fluid (CSF) homeostasis emphasize the importance of water influx into the peri-capillary (Virchow–Robin) space through aquaporin 4 (AQP-4). This water flow is believed to have the functionality equivalent to the systemic lymphatic system and plays a critical role in beta-amyloid clearance. Using a newly developed molecular imaging technique capable of tracing water molecules, in vivo, water influx into the CSF was quantitatively analyzed in senile plaque (SP) bearing transgenic Alzheimer’s disease (AD) model mice. The results unequivocally demonstrated that water influx into CSF is significantly impaired in SP-bearing transgenic mice, the degree of which being virtually identical to that previously observed in AQP-4 knockout mice. The study strongly indicates that disturbance in AQP-4-based water flow and, hence, impairment in beta-amyloid clearance play a significant role in SP formation.

BACKGROUND Development of molecular MR imaging (MRI) similar to PET imaging using contrast agents such as gadolinium as probe have been inherently hampered by incompatibility between potential probe (charged molecules) and membrane permeability. Nevertheless, considering the inherent spatial resolution limit for PET of 700μ, the superior microscopic resolution of MRI of 4 μ presents a strong incentive for research into ligand-based molecular MRI. METHODS 17O exhibits JJ vicinal coupling with a covalently bound proton in a hydroxyl group. This 17O coupled proton can be ionized in water solution and interexchange with other water protons. This property can be utilized as “probe” in T2-weighted imaging and developed into ligand-based molecular MRI. We examined β-amyloid distribution in human APP overexpressed transgenic mice in vivo following injection of 17O labeled Pittsburg compound B (17O-PiB). RESULTS JJVCPE imaging successfully imaged 17O-PiB, unequivocally establishing that 17O JJVCPE imaging can be developed into PET-like molecular MRI in clinical medicine. CONCLUSIONS The study represents the first successful ligand-based molecular MRI in vivo. This is also the first in vivo amyloid imaging using MRI. High-resolution molecular MRI with high specificity under clinical settings, such as in vivo microscopic imaging of senile plaque, is a foreseeable aim.

Recent studies on cerebrospinal fluid (CSF) homeostasis emphasize the importance of water flux through the pericapillary (Virchow–Robin) space for both CSF production and reabsorption (Oreskovic and Klarica hypothesis), and challenge the classic CSF circulation theory, which proposes that CSF is primarily produced by the choroid plexus and reabsorbed by the arachnoid villi. Active suppression of aquaporin-1 (AQP-1) expression within brain capillaries and preservation of AQP-1 within the choroid plexus together with pericapillary water regulation by AQP-4 provide a unique opportunity for testing this recent hypothesis. We investigated water flux into three representative regions of the brain, namely, the cortex, basal ganglia, and third ventricle using a newly developed water molecular MRI technique based on JJ vicinal coupling between 17O and adjacent protons and water molecule proton exchanges (JJVCPE imaging) in AQP-1 and AQP-4 knockout mice in vivo. The results clearly indicate that water influx into the CSF is regulated by AQP-4, and not by AQP-1, strongly supporting the Oreskovic and Klarica hypothesis.

Japanese and Chinese share virtually identical morphographic characters invented in ancient China. Whereas modern Chinese retained the original morphographic functionality of these characters (hanzi), modern Japanese utilizes these characters (kanji) as complex syllabograms. This divergence provides a unique opportunity to systematically investigate brain strategies for sentence reading in Japanese-Chinese bi-literates. Accordingly, we investigated brain activation associated with Japanese and Chinese reading in 14 native Japanese speakers literate in Mandarin and 14 native Mandarin speakers literate in Japanese using functional magnetic resonance imaging performed on a 3T system. The activation pattern exhibited clearly distinct features specific for each language. Regardless of the subject's native language literacy, Chinese reading activated an area significantly larger than Japanese reading, suggesting that brain processes involved in Chinese reading were much more complex than Japanese reading. Significant recruitment of corresponding cortical areas in the right hemisphere with Chinese reading was also apparent. The activation patterns associated with Japanese reading by native Japanese literates was highly consistent with previous reports, and included the left inferior frontal gyrus (IFG), left posterior temporal lobe (PTL), and left ventral premotor cortex (PMv). The activation pattern associated with Chinese reading by native Chinese literates was also highly consistent with previous reports, namely the left IFG, left PTL, left PMv, left anterior temporal lobe (ATL), and bilateral parieto occipital lobes (LPOL). The activation pattern associated with Chinese reading by native Japanese literates was virtually identical to that by native Chinese literates, whereas the activation pattern associated with Japanese reading by native Chinese literates was signified by additional activation of LPOL compared to that by native Japanese literate. The study indicated that IFG and PTL are universal language areas, while PMv is the area for decoding complex syllabograms. LPOL is the "Chinese language area," while ATL is essential for languages with analytic morphosyntax.

The precise movement of human fingers requires continuous and reciprocal interaction between motor and sensory systems. Similar to other primates, there is double representation of the digits and wrists within the human primary motor cortex (M1), which are generally referred to as area 4 anterior (M1-4a) and area 4 posterior (M1-4p). In this high-field (3.0 T) functional magnetic resonance imaging (fMRI) study, we hypothesized that M1-4p is more important for initiation of motion, whereas M1-4a is important for execution of a given motion involving more complex sensoriomotor interaction. We investigated M1-4a and M1-4p activation associated with two representative motor tasks, namely, finger tapping (voluntary motion, VM) and passive finger movement accomplished by continuous pressure (passive motor, PM), and two representative sensory stimulations, namely, simple stimulation of flutter vibration (simple sensory, SS), and complex stimulation by a row of pins moving either vertically or horizontally (complex sensory, CS). Both M1-4a and M1-4p were activated in both motor tasks, VM and PM. M1-4p was not activated by either of the two sensory tasks, whereas M1-4a was activated by CS but not by SS. Analysis of the center of gravities (COG) of the activated areas showed that VM and PM moved COG towards M1-4p and 3a. SS moved COG towards somatosensory cortex Brodmann areas 1, 2, and 3b, whereas CS towards M1-4a. The result clearly showed that M1-4a represents the area of secondary motor execution, which actively participates in CS processing.

BACKGROUND Microscopic application of magnetic resonance imaging (MRI) has entered the era of clinical application. One of the most important targets is the visualization of pathological findings such as senile plaques (SP), in vivo, in patients with Alzheimer's disease (AD). Such an application provides not only the most accurate diagnostic tool for clinicians but also a solid basis for scientists for developing effective treatment and preventive strategies for AD. METHODS Focused microscopic studies were performed on parietal association cortex at the level of the centrum semiovale identified on conventional axial slices using a system constructed based on General Electric Signa LX (Waukesha, WI) equipped with a 900-mm clear bore superconducting magnet operating at 7.0 T in 10 patients (67-83-year old, five males, five females) who fulfilled the NINCD and the SADRDA criteria for probable AD, 10 age-matched controls (71-85-year old, five males, five females), and 20 young adults (22-35-year old, 10 males, 10 females) using a susceptibility weighted imaging (SWI) algorithm. RESULTS SWI microscopy consistently provided images with SP-like pathology extending within the entire parietal cortex in all cases of AD and 2 out of 10 age-matched volunteers. CONCLUSIONS Although the precise mechanisms leading to the higher susceptibility rendering SP-like pathology observable within the cortical mantle are not totally understood, the study unambiguously demonstrated that MR microscopy is capable of directly visualizing cortical pathology in AD patients in vivo.

Placement of detachable coil(s) for intracranial aneurysms has become one of the standard methods of management. Although detailed analysis of post-procedure changes in aneurysmal lumen is essential, technical difficulties often limit such evaluation. Development of higher magnetic field systems is steadily widening clinical usage of magnetic resonance imaging (MRI) primarily due to its significantly higher signal to noise ratio.In this study, we evaluated a multi-planar reconstruction (MPR) technique of magnetic resonance angiography (MRA) on a 3.0T system in an attempt to develop a routine method of post-procedure evaluation following detachable coil placement.Eleven patients with an intracranial aneurysm following placement of a Guglielmi detachable coil (GDC) participated in the study. Time of flight (TOF) magnetic resonance angiography (MRA) was obtained immediately after, and up to two years after coil embolisation utilising a GE 3.0T system. Data was analysed using standard maximum intensity projection (MIP) as well as the MPR technique and the results were compared to conventional catheter angiography.The study demonstrated that, compared to MIP, MPR can provide further information of alteration in aneurysm lumen, especially in analysis of: 1) jet of blood flow, 2) thrombus formation, 3) neck remnant or re-filling of blood, 4) location and shape of coils including compaction, and 5) coil protrusion into the parent artery.Combined MPR/MIP analysis of high-field MRA appears to be a powerful non-invasive method for evaluating GDC-treatment that can potentially replace conventional catheter angiography in many clinical situations.

OBJECTIVE. The purpose of this work was to detect brain developmental abnormalities in Prader-Willi syndrome by using diffusion tensor imaging based on a high-field MRI system.METHODS. Eight patients with Prader-Willi syndrome and 8 age- and gender-matched normal control subjects were examined using a high-field (3.0 T) MRI system. Trace value and fractional anisotropy were assessed simultaneously in multiple representative brain regions: the deep gray matter (putamen, caudate head, and dorsomedial thalamus) and the white matter structures (frontal and parietal white matter, posterior limb of internal capsule, and corpus callosum).RESULTS. In Prader-Willi syndrome patients, trace value was found to be significantly higher in the left frontal white matter and the left dorsomedial thalamus, whereas fractional anisotropy was significantly reduced in the posterior limb of the internal capsule bilaterally, the right frontal white matter, and the splenium of the corpus callosum. The observed diffusivity characteristics indicate developmental abnormalities in these areas, which are highly consistent with the clinical features of Prader-Willi syndrome.CONCLUSIONS. The study provides the first objective evidence that Prader-Willi syndrome patients indeed have developmental abnormalities in specific areas of the brain, providing a new window toward understanding the pathophysiology of Prader-Willi syndrome.

A new method for analyzing diffusion tensor imaging (DTI) of the brain, based on a recently introduced algorithm, lambda chart analysis (LCA), is presented. Pre-treatment of a given DTI data set with LCA, which effectively segregates isotropic and anisotropic components, allows for total removal of the anisotropic component from the DTI data set. The remaining pure isotropic component can therefore be subjected to further analysis similar to that applied in the trace histogram method. Deconvolution of the trace function yielded 3 Gaussian elements. Remapping of these 3 deconvoluted isotropic elements back onto the 2-dimensional image plane provided anatomical correlates of each element. The algorithm, referred to here as isotropic component trace analysis, can be used as a pictorial analytic tool, as well as a numerical analytical tool, for the noninvasive assessment of isotropic parenchymal components. The presented method provides quantitative indices of certain parenchymal parameters with better clarity than currently available methods. A ready-to-use program, EZ-LCA, for this powerful method is provided (available at http://coe.bri.niigata-u.ac.jp).

To investigate the fine structural integrity of the hippocampus in patients with transient global amnesia (TGA) using high-resolution T2 reversed (T2R) MRI.The authors performed detailed structural analysis of the hippocampus in 15 patients who had recovered from an episode of TGA and 150 randomly recruited normal volunteers across the adult age spectrum using high-resolution T2R MRI obtained on a 3.0-T system. An additional 100 subjects, with stroke or tumor, were similarly studied and served as disease controls.The overall incidence of hippocampal cavities detected in normal volunteers increased with age but never exceeded 40%, whereas the incidence in disease control group was 31%. They were always unilateral. In contrast, cavities were found in all 15 patients with TGA (100%), an incidence higher than in normal or disease controls (p0.05; Ryan's multiple comparison test), and were bilateral in eight patients (53%). The cavities in all but one of the normal volunteers (99%) and all disease controls (100%) were crescent shaped andor =2 mm in width. The cavities in 14 of 15 patients with TGA (93%) were considerably larger (3 mm in width), and five of the patients had giant cavities (5 mm in width). Most of the cavities in patients with TGA had a rounded shape and resembled pathologic cavities described in specimens of hypoxia-related CA1 necrosis.The data indicate that transient global amnesia may not be a benign entity. Delayed neuronal loss within CA1 area of Lorente de No may represent its important sequel.

The objective of this study was to delineate further the nature of diffusion anisotropy abnormalities in frontal white matter previously observed in schizophrenic patients using a high-field magnetic resonance imaging (MRI) system. Six schizophrenia patients and six healthy control subjects were examined using a highfield MRI (3.0T) system. In order to confirm previously reported abnormalities in anisotropy, data were first analyzed to determine fractional anisotropy (FA), a frequently utilized general index of anisotropy. Subsequently, the identical data set was subjected to lambda chart analysis (LCA), a newly developed algorithm for diffusion tensor analysis (DTA) that more effectively provides eigenvalue information. Frontal white matter FA was found to be significantly reduced in schizophrenic patients compared to control subjects, confirming previously reported findings. LCA revealed that the decline in FA was due to a disproportionate increase in small eigenvalue components, and not due to a decline in principal eigenvalue components.

While activity of MT+/V5 neurons is believed to be necessary for the conscious perception of visual motion, whether neural activity in MT+/V5 is a sufficient condition for the conscious perception of motion in vision still remains unanswered. A high-field (3.0 Tesla) functional magnetic resonance imaging (fMRI) study was designed and performed to answer this specific question. Eleven healthy subjects viewed a checkerboard pattern stimulus reversed in contrast at 0.2, 12, 30, and 60 Hz while being probed for activation in MT+/V5. At 0.2 Hz, all viewers perceived pattern-reversal which was stationary in position. However, at 12, 30, and 60 Hz, many subjects perceived apparent motion (e.g., vertical and horizontal flows) in the square pattern. At 12 and 30 Hz reversals, MT+/V5 was activated in all subjects (11/11). Nevertheless, three out of eleven (3/11) subjects denied motion perception in these conditions. At 60 Hz reversal, as many as seven out of eleven (7/11) subjects failed to see motion but activation in MT+/V5 was found in the majority (5/7) of the subjects. The results demonstrated that significant MT+/V5 activation occurs without accompanying subjective awareness of seeing motion in an apparent-motion stimulus, indicating that neural activity in MT+/V5 does not represent a sufficient condition for conscious perception of motion in vision.

Object. The authors investigated brain strategies associated with hand use in an attempt to clarify genetic and nongenetic factors influencing handedness by using high-field functional magnetic resonance imaging. Methods. Three groups of patients were studied. The first two groups comprised individuals in whom handedness developed spontaneously (right-handed and left-handed groups). The third group comprised individuals who were coercively trained to use the right hand and developed mixed handedness, referred to here as trained ambidexterity. All trained ambidextrous volunteers were certain that they were innately left-handed, but due to social pressure had modified their preferred hand use for certain tasks common to the right hand. Although right-handed and left-handed volunteers displayed virtually identical cortical activation, involving homologous cortex primarily located contralateral to the hand motion, trained ambidextrous volunteers exhibited a clearly unique activation pattern. During right-handed motion, motor areas in both hemispheres were activated in these volunteers. During left-handed motion, the right supplemental motor area and the right intermediate zone of the anterior cerebellar lobe were activated significantly more frequently than observed in naturally right-handed or left-handed volunteers. Conclusions. The results provide strong evidence that cortical organization of spontaneously developed right- and left-handedness involves homologous cortex primarily located contralateral to the hand motion, and this organization is likely to be prenatally determined. By contrast, coerced training of the nondominant hand during the early stages of an individual's development results in mixed handedness (trained ambidexterity), indicating cortical reorganization.

To clarify regional difference in 1H magnetic resonance spectral changes in the acute stage of focal cerebral ischemia, and to assess whether any correlation exists between spectral changes in acute stage and pathological outcome in the chronic stage, we measured the non-volume selected 1H-MRSI serially in the acute stage of focal ischemia in rat brain and correlated histopathological findings. The focal ischemia was induced by intraluminal MCA thread occlusion. After induction of focal ischemia, 1H-MR Spectroscopic Images (MRSI) were taken serially up to 10 h after the occlusion. NAA in the peri-ischemic area was maintained. On the other hand, the decline of NAA in the ischemic lesion was linear and drastic during the first 10 h after MCA occlusion, and the rates of decline of NAA concentrations up to 10 h after induction of ischemia, calculated with linear regression, were 0.44 m mol/kg/h in the ischemic core and 0.29 m mol/kg/h in the ischemic rim (p

Brain activation associated with reading was investigated in ten normal Japanese volunteers (five highly literate in both Japanese and English) and ten American native English speakers (five highly literate in both English and Japanese) in order to determine the neuroanatomic substrates employed in reading the first language (L1), and to determine the effect of L1 on the neurosubstrates involved in reading the second language (L2). The study was performed using blood oxygenation level dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) on a high-field (3.0T) system specifically optimized for fMRI. The activation patterns in Japanese subjects reading Japanese (L1) were substantially different from the patterns obtained in American subjects reading English text (L1). The activation patterns reading L2 were virtually identical to the patterns seen when reading L1 in both Japanese and English natives highly literate in both language systems. The results demonstrated that the neuroanatomical substrates underlying the cognitive processing of reading are differentially determined based on the language system. The study further indicates that the cognitive processes for reading in the second language involve the same cortical structures employed for the first language, supporting the hypothesis that the second language represents the cognitive extension of the first language.

A new technique for functional magnetic resonance imaging (fMRI) time series analysis is presented. The technique referred to here as independent component-cross correlation-sequential epoch (ICS) analysis is a hybrid technique of two standard methodologies of biological signal analysis, namely, data driven methods, represented by independent component analysis, and hypothesis driven methods, represented by a general linear model. The technique successfully identified four functionally discrete areas within the primary sensorimotor cortex (SMI) in normal human subjects based on blood oxygenation level dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) time series performed on a high field (3.0 T) system. Each of the four areas identified corresponded to the four physiological subdivisions of SMI, recognized in primates to be essential for voluntary hand motion, namely, 4 anterior (MI-4a) and 4 posterior (MI-4p) of the primary motor cortex, and 3a and the ‘classical’ (Brodmann areas 1, 2, and 3b) primary sensory cortex, respectively. ICS analysis appears to be a highly reliable and versatile technique for fMRI time series analysis.

✓ The utility of three-dimensional anisotropy contrast (3DAC) magnetic resonance (MR) axonography, a method sensitive to neuronal fibers and their directionality, was investigated in the clinical setting using a 3-tesla MR imaging system based on a General Electric Signa platform. The study focused on healthy volunteers and patients with common structural central nervous system disorders, namely chronic infarction, brainstem cavernous hemangioma, supratentorial meningioma, and astrocytoma. Three orthogonal anisotropic diffusion-weighted images were first obtained. Three primary colors were each assigned to a diffusion-weighted image, respectively, and the images were subsequently combined into a single-color image in full-color spectrum (3DAC MR axonography image). Fiber-tract definition in the cerebral peduncle of the midbrain of healthy volunteers showed intersubject variation, with two general patterns recognized: dispersed (60% of cases) and compact (40% of cases). Pathological alterations in the fiber tracts were readily identified in cases involving wallerian degeneration of the pyramidal tract, as illustrated in the cases of chronic infarction. Displacement of major tracts, such as the medial lemniscus or corticospinal tract, as well as fiber directionality, was also easily recognized in cases of mass lesions. As an imaging method uniquely capable of providing information regarding axonal connectivity, 3DAC MR axonography appears to have promising potential for routine clinical application.

BACKGROUND Development of molecular MR imaging (MRI) similar to PET imaging using contrast agents such as gadolinium as probe have been inherently hampered by incompatibility between potential probe (charged molecules) and membrane permeability. Nevertheless, considering the inherent spatial resolution limit for PET of 700μ, the superior microscopic resolution of MRI of 4 μ presents a strong incentive for research into ligand-based molecular MRI. METHODS 17O exhibits JJ vicinal coupling with a covalently bound proton in a hydroxyl group. This 17O coupled proton can be ionized in water solution and interexchange with other water protons. This property can be utilized as “probe” in T2-weighted imaging and developed into ligand-based molecular MRI. We examined β-amyloid distribution in human APP overexpressed transgenic mice in vivo following injection of 17O labeled Pittsburg compound B (17O-PiB). RESULTS JJVCPE imaging successfully imaged 17O-PiB, unequivocally establishing that 17O JJVCPE imaging can be developed into PET-like molecular MRI in clinical medicine. CONCLUSIONS The study represents the first successful ligand-based molecular MRI in vivo. This is also the first in vivo amyloid imaging using MRI. High-resolution molecular MRI with high specificity under clinical settings, such as in vivo microscopic imaging of senile plaque, is a foreseeable aim.

✓ The recent development of magnetic resonance (MR) axonography, which uses three-dimensional anisotropy contrast (3DAC), a new algorithm for the treatment of an apparent diffusion tensor, has provided an unprecedented opportunity for visualizing the anatomical details of the spinal cord in live animals. In this study, the authors investigated the sensitivity of the 3DAC method in detecting pathological conditions by obtaining chronological MR axonography of the rat spinal cord immediately after induction of cardiac arrest. The results clearly demonstrated that 3DAC is highly sensitive to any perturbation of physiological conditions. Trichromatic coefficient analyses indicated postmortem changes observed pictorially are indeed due to loss of anisotropy. The study further indicated the presence of at least two independent factors responsible for observed physiological anisotropy. Considering its rather simple implementational process and high anatomical resolution as well as its sensitivity to pathological alteration, MR axonography based on the 3DAC method appears to be the ideal noninvasive imaging technique for assessment of the spinal cord in biomedicine.

The effects of musical training on the early auditory cortical response to pitch transitions in music were investigated by use of the change-N1 component of auditory event-related potentials. Musicians and non-musicians were presented with music stimuli comprising a melody and a harmony under various listening conditions. First, when the subjects played a video game and were instructed to ignore the auditory stimuli, the onset of stimuli elicited a typical, fronto-central onset-N1, whereas melodic and harmonic pitch transitions within the stimuli elicited so-called change-N1s that were more posterior in scalp distribution. The pitch transition change-N1s, but not onset-N1, were enhanced in musicians. Second, when the listeners attended to the same stimuli as above to detect infrequently occurring target stimuli, the change-N1 elicited by pitch changes (in non-target stimuli) was augmented, in non-musicians only when the target was easily detectable, and in both musicians and non-musicians when it was difficult to detect. Thus, the early, obligatory cortical response to pitch transitions during passive listening was chronically enhanced by training in musicians, and, reflecting this training-induced enhancement, the task-related modulation of this response was also different between musicians and non-musicians. These results are the first to demonstrate the long-term effects of training, short-term effects of task and the effects of their interaction on the early (~100-ms) cortical processing of pitch transitions in music. The scalp distributions of these enhancement effects were generally right dominant at temporal electrode sites, suggesting contributions from the radially oriented subcomponent of change-N1, namely, the Tb (N1c) wave of the T-complex.

In spite of dramatic advancement in biomedical imaging technologies, non-invasive visualization of anatomic detail of the spinal cord has remained a major challenge. Here, a novel color-coded contrast method for magnetic resonance imaging (MRI) which provides superb resolution of the spinal cord in live animals, comparable to that of histological preparations, is described. The method, referred to here as three dimensional anisotropy (3DAC) contrast MRI, displays cross-sectional images in the full visible color spectrum, encoding directional information regarding intravoxel anisotropic water motion in space. Since neuronal fibers, especially axons, possess significantly higher intravoxel anisotropic water motion compared with other elements in the nervous system, 3DAC is highly sensitive to axonal direction and density. Axonography of the spinal cord of rats obtained using this technique showed anatomic detail at a resolution hitherto unobtainable in live animals.

Maturational changes in intracellular brain phosphocreatine (PCr) transport were investigated using 31P-nuclear magnetic resonance diffusion spectroscopy. The diffusivities of PCr showed significant maturational facilitation in rat brain in vivo. Physicochemical analysis of the cytosol microenvironment as a multicomponent solution, where one of the components is a dilute polymer, indicated that the observed developmental facilitation of PCr diffusivity is likely to be due to a decline in the concentration of the free amino acid taurine. Changes in the concentrations of biopolymers (i.e., proteins or lipids) have only little effect, if any, on PCr diffusivity. PCr diffusivity values of rat brain measured in vivo showed excellent quantitative agreement with the predicted values estimated using a model for multicomponent diffusion. The study confirmed that the taurine/N-acetylaspartate exchange observed during postnatal development of rat brain plays a major, it not unique, role in maturational facilitation of intracellular high-energy phosphate transport.

Object The authors assessed the role of 3D anisotropy contrast (3DAC) in evaluating specific ascending tract degeneration in patients with cervical spondylotic myelopathy (CSM). Methods The authors studied 10 patients (2 women, 8 men; mean age 59.8 ± 14.6 years) with CSM and spinal cord compression below the C2–3 disc level, as well as 10 healthy control individuals (3 women, 7 men; mean age 42.0 ± 24.1 years). Images of the cervical cord at the C2–3 level were obtained using a 3.0-T MR imaging system. Results Three-dimensional anisotropy contrast imaging clearly made possible tract-by-tract analysis of the fasciculus cuneatus, fasciculus gracilis, and spinocerebellar tract. Tract degeneration identified using 3DAC showed good correlation with a decline in fractional anisotropy. Degeneration of the fasciculus gracilis detected by “vector contrast” demonstrated a good correlation with Nurick grades. Conclusions The study unambiguously demonstrated that 3DAC imaging is capable of assessing ascending tract degeneration in patients with CSM. Degeneration of an individual tract can be easily identified as a vector contrast change on the 3DAC image, a reflection of quantitative changes in anisotropism, similar to fractional anisotropy. Excellent correlation between Nurick grades and fasciculus gracilis degeneration suggests potential application of 3DAC imaging for tract-by-tract clinical correlation.

BACKGROUND Susceptibility-weighted imaging (SWI) microscopy on a 7.0T system demonstrated the corticomedullary junction (CMJ) to be a high-susceptibility region (HSR) in young normal subjects, suggesting that functional alteration of cortical microcirculation could be assessed with this imaging method. METHODS Focused microscopic studies were performed on the parietal association cortex in 74 normal volunteers (ages 20-79 years; 35 female, 39 male) using a SWI algorithm on a system constructed based on General Electric Signa LX (Waukesha, WI, USA), equipped with a 900-mm clear bore superconducting magnet operating at 7.0T. RESULTS There was a clear-cut reduction in the thickness of the normal-appearing cortex (cortex, R2= .5290, P < .001) and expansion of CMJ-HSR (R2= .6919, P < .001). The sum of cortex thickness and CMJ-HSR thickness was essentially constant, suggesting that the observed expansion of CMR-HSR with aging likely occurred within the cortical mantle. CONCLUSION CMJ-HSR expands significantly as a function of aging. Since CMJ-HSR represents a functionally distinct area with relatively slow venous flow, the observed expansion is believed to reflect alteration in cerebral microcirculation with increased age, providing another clue for pathogenesis of Alzheimer's disease.

Hemispheric differences in the temporal processing of musical sounds within the primary auditory cortex were investigated using functional magnetic resonance imaging (fMRI) time series analysis on a 3.0 T system in right-handed individuals who had no formal training in music. The two hemispheres exhibited a clear-cut asymmetry in the time pattern of fMRI signals. A large transient signal component was observed in the left primary auditory cortex immediately after the onset of musical sounds, while only sustained activation, without an initial transient component, was seen in the right primary auditory cortex. The observed difference was believed to reflect differential segmentation in primary auditory cortical sound processing. Although the left primary auditory cortex processed the entire 30-s musical sound stimulus as a single event, the right primary auditory cortex had low-level processing of sounds with multiple segmentations of shorter time scales. The study indicated that musical sounds are processed as 'sounds with contents', similar to how language is processed in the left primary auditory cortex.

The differential effects of systemic anoxia on the immature rat brain in two postnatal developmental age groups, group I (1–2 days postnatal) and group II (9—10 days postnatal), were studied utilizing phosphorus-31 nuclear magnetic resonance spectroscopy. While all pups in group I survived the 15-min anoxic period, only half of the pups in group II survived. Brain adenosine triphosphate and intracellular pH of pups in group I remained essentially unchanged throughout the anoxic period, while phosphocreatine and inorganic phosphate were sensitive indicators of anoxia. These parameters were all more drastically affected in group II pups than in group I pups. Group II pups also exhibited a significant increase in phosphomonoester, indicating developmental differences in phospholipid metabolism. © 1992 Academic Press, Inc.

Maturational changes in intracellular high energy phosphate (HEP) transport in brain were investigated in rats in vivo using 31P nuclear magnetic resonance (NMR) diffusion spectroscopy and saturation transfer experiments. The diffusivities of phosphocreatine (PCr) and adenosine triphosphate (ATP) in adult brain were significantly higher than in newborn pup brain. The estimated diffusion lengths of PCr and ATP were similar in adult and newborn pup brain. The findings indicate firstly that the faster diffusivities of HEP effectively compensates for the higher energy demands in adult brain and secondly that ATP diffusion appears sufficient for brain HEP transport without need for a PCr shuttle mechanism.

Unsaturation indices of cerebral cortex membrane phospholipids in Alzheimer's disease were determined utilizing high resolution proton nuclear magnetic resonance (NMR) spectroscopy of lipid extracts. The unsaturation index of Alzheimer's brain was found to be significantly higher (P < 0.01) than that of age-matched controls. The study provides further support for the hypothesis that alteration in phospholipid metabolism, especially an elevation in unsaturated fatty acids, may play a role in the pathogenesis of Alzheimer's disease. © 1991 Academic Press, Inc.

Taurine, a sulfur amino acid abundant in brain of the fetus and early day neonate, has been postulated to play a major role in mediating the immature brain's unusually high buffering ability for lactic acidosis reported previously. In this study, we directly investigated this 'taurine effect' using a 10-day-old rat pup model and multinuclear (31P and 1H) nuclear magnetic resonance (NMR) in-vivo spectroscopy. Brain of taurine-supplemented pups exhibited significantly higher acid buffering ability against lactic acidosis than age-matched control pups. The study supports the hypothesis that high levels of free cytosolic taurine increase the brain's ability to buffer against lactic acidosis.

Intracellular pH levels of infarcted brain determined by phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy disclosed a notable phenomenon. The acidotic brain pH seen in the acute stage of infarction was observed to rebound into the alkalotic range in the subacute phase before returning to the normal range in the chronic phase. This "rebound alkalosis" which was usually observed between the 24th and the 48th hour after experimental induction of infarction in rats was accompanied by significant lactate levels as detected by proton NMR spectroscopy. Analysis of the satellite methyl resonance of 13C-lactate using high-resolution proton NMR spectroscopy after 13C-glucose infusion indicated that no lactate was produced in the subacute phase of infarction and that the lactate detected during this phase must have been generated prior to this phase of infarction.

We investigated the role of aquaporin-4 (AQP4), a water channel expressed in glial cells, in neural activity mediated morphological changes observed in brain slice preparation. Changes in flavoprotein fluorescence (FF) and infrared light scattering (LS) signals were measured before and after repetitive stimulation of layer VI in rostral somatosensory cortical slices taken from AQP4 knockout (KO) and wild-type (WT) mice. Changes in FF, which reflect neural aerobic activities, were comparable for the two groups in all cortical layers. However, changes in LS signals, which are indicative of cell swelling, were significantly decreased in layer I of AQP4 KO mice compared to that of WT mice. We conclude that AQP4 likely plays a significant role in neural activity-dependent glial swelling.