Inconsistency and uncertainty of the human visual area loci following surface-based registration: Probability and Entropy Maps.

Here we created two different multisubject maps (16 subjects) to characterize interindividual variability in the positions of human visual areas (V1, dorsal and ventral parts of V2/3, V3A, V3B, V7, LOc, MT+, and hV4 [or V4v and V8]), which were localized using fMRI and coregistered using a surface-based method. The first is a probability map representing the degree of alignment inconsistency for each area, in which each point in space is associated with the probability affiliated with a given area. The second, a novel map termed an entropy map in which each point is associated with Shannon entropy computed from the probabilities, represents the degree of uncertainty regarding the area that resides there, and is maximal when all areas are equally probable. The overall average probability and entropy values were about 0.27 and 1.15 bits, respectively, with dependencies on the visual areas. The probability and entropy maps generated here will benefit any application which requires predictions of areas that are most likely present at an anatomical point and know the uncertainty associated with such predictions.

In vivo assessment of peripheral nerve regeneration by diffusion tensor imaging.

PURPOSE: To evaluate the sensitivity of diffusion tensor imaging (DTI) in assessing peripheral nerve regeneration in vivo. We assessed the changes in the DTI parameters and histological analyses after nerve injury to examine degeneration and regeneration in the rat sciatic nerves. MATERIALS AND METHODS: For magnetic resonance imaging (MRI), 16 rats were randomly divided into two groups: group P (permanently crushed; n = 7) and group T (temporally crushed; n = 9). Serial MRI of the right leg was performed before the operation, and then performed at the timepoints of 1, 2, 3, and 4 weeks after the crush injury. The changes in fractional anisotropy (FA), axial diffusivity (λ(∥)), and radial diffusivity (λ(⟂)) were quantified. For histological analyses, the number of axons and the myelinated axon areas were quantified. RESULTS: Decreased FA and increased λ(⟂) were observed in the degenerative phase, and increased FA and decreased λ(⟂) were observed in the regenerative phase. The changes in FA and λ(⟂) were strongly correlated with histological changes, including axonal and myelin regeneration. CONCLUSION: DTI parameters, especially λ(⟂) , can be good indicators for peripheral nerve regeneration and can be applied as noninvasive diagnostic tools for a variety of neurological diseases.

In vivo visualization of reactive gliosis using manganese-enhanced magnetic resonance imaging.

Reactive astrogliosis occurs after diverse central nervous system (CNS) insults. While astrogliosis provides protection against inflammation, it is also obstructive in the progress of neuranagenesis after CNS insults. Thus, a method that enables in vivo visualization and tissue characterization for gliosis would be invaluable for studies of CNS insults and corresponding treatments. Manganese has proven to be a useful MRI contrast agent that enters cells via Ca(2+) channels and has been applied to manganese-enhanced MRI (MEMRI) for neuronal functional mapping. This study investigated whether MEMRI can detect astrogliosis after focal ischemia in vivo. Rats were divided into groups according to the number of days after either transient middle cerebral artery occlusion or a sham. Ring- or crescent-shaped enhancement of MEMRI corresponded to the GFAP-positive astroglia observed in the peripheral region of the ischemic core 11 days after middle cerebral artery occlusion. This indicates that MEMRI enhancement predominantly reflects reactive astrogliosis after stroke.

Neural correlates of color-selective metacontrast in human early retinotopic areas.

Metacontrast is a visual illusion in which the visibility of a target stimulus is virtually lost when immediately followed by a nonoverlapping mask stimulus. For a colored target, metacontrast is color-selective, with target visibility markedly reduced when the mask and target are the same color, but only slightly reduced when the colors differ. This study investigated neural correlates of color-selective metacontrast for cone-opponent red and green stimuli in the human V1, V2, and V3 using functional magnetic resonance imaging. Neural activity was suppressed when the target was rendered less visible by the same-colored mask, and the suppression was localized in the cortical region retinotopically representing the target, correlating with the perceptual topography of visibility/invisibility rather than the physical topography of the stimulus. Retinotopy-based group analysis found that activity suppression was statistically significant for V2 and V3 and that its localization to the target region was statistically significant for V2. These results suggest that retinotopic color representations in early visual areas, especially in V2, are closely linked to the visibility of color.

Detection of necrotic neural response in super-acute cerebral ischemia using activity-induced manganese-enhanced (AIM) MRI.

Immediate and certain determination of the treatable area is important for choosing risky treatments such as thrombolysis for brain ischemia, especially in the super-acute phase. Although it has been suggested that the mismatch between regions displaying 'large abnormal perfusion' and 'small abnormal diffusion' indicates a treatable area on an MRI, it has also been reported that the mismatch region is an imperfect approximation of the treatable region named the 'penumbra'. Manganese accumulation reflecting calcium influx into cells was reported previously in a middle cerebral artery occlusion (MCAO) model using activity-induced manganese-enhanced (AIM) MRI. However, in the super-acute phase, there have been no reports about mismatches between areas showing changes to the apparent diffusion coefficient (ADC) and regions that are enhanced in AIM MRI. It is expected that the AIM signal can be enhanced immediately after cerebral ischemia in the necrotic core region due to calcium influx. In this study, a remote embolic rat model, created using titanium-oxide macrospheres, was used to observe necrotic neural responses in the super-acute phase after ischemia. In addition, images were evaluated by comparison between ADC, AIM MRI, and histology. The signal enhancement in AIM MRI was detected at 2 min after the cerebral infarction using a remote embolic method. The enhanced area on the AIM MRI was significantly smaller than that on the ADC map. The tissue degeneration highlighted by histological analysis corresponded more closely to the enhanced area on the AIM MRI than that on the ADC map. Thus, the manganese-enhanced region in brain ischemia might indicate 'necrotic' irreversible tissue that underwent calcium influx.

Toward a common circle: interhemispheric contextual modulation in human early visual areas.

Humans can readily and effortlessly perceive a rich, stable, and unified visual world from a complex visual scene. Yet our internal representation of a visual object appears to be sparse and fragmented. How and where in the brain are such fragmented representations organized into a whole percept? Recent studies have accumulated evidence that some global feature integration is mediated at the early stage of visual processing. However, the spatial operating range of the integration still remains unclear. The present human functional magnetic resonance imaging study provides support that the global integration process in early visual areas, including even the primary visual area V1, is mediated beyond the separated projection of visual hemifields from right and left sides of the fixation to the visual cortex of the contralateral cerebral hemisphere. Retinotopic neural responses corresponding to a visual target were significantly enhanced when another target was simultaneously presented at the point-symmetrical position in the nonassociated visual field quadrant. The result makes a convincing case that the contextual effects involve feedback from higher areas, because there are no direct callosal connections that allow such interhemispheric contextual modulation. This enhancement from the ipsilateral hemifield may help rapid position-and-size-invariant detection of a circular pattern, which may be special among visual structures because of its ubiquity in natural scenes. Early visual areas as well as higher ones may play a more essential role in perceiving the unity of the real world than previously thought.

Neuronal response to Shepard's tones: an auditory fMRI study using multifractal analysis.

Shepard's tones are a typical example for auditory illusion. They consist in a series of computer generated tones, which prohibit relative pitch discrimination. As a result, when repetitively played in sequence, the illusion of an ever-ascending scale is evoked. In order to investigate this aural phenomenon, fMRI time series were acquired during presentation of a conventional block-designed paradigm as well as during continuous presentation of Shepard's tones. With respect to the different setups of the two experiments, two fundamentally different methods were applied in order to conduct data analysis. Common Statistical Parameter Mapping served to evaluate the time series obtained with the block-designed paradigm. For the continuous experiment, a novel wavelet-based multifractal analysis was used, recently proposed as a classification tool for fMRI time series. This approach applies the wavelet transform to extract multifractal spectra from time-signals. For reasons of quantification, we introduced an ameliorated method for visual inspection of the multifractal properties. The results proved existence of characteristic neural responses to continuously presented Shepard's tones. Interestingly, the same was not restricted to the auditory cortex, but also involved areas of the visual cortex. Related impact on the imaged cognitive areas, primary motor cortex, and primary sensory cortex could not be observed. We further provide evidence that pitch misjudgment does not occur in temporal concurrence with the repetition of the whole scale, but according to whether the main perceived frequency is located in the sensitive range of auditory perception or not. We remark that this is the first time, continuously stimulated brain areas could be detected by means of fMRI.

Diffusion-weighted line-scan echo-planar spectroscopic imaging technique to reduce motion artifacts in metabolite diffusion imaging.

Metabolite diffusion is expected to provide more specific microstructural and functional information than water diffusion. However, highly accurate measurement techniques have still not been developed, especially for reducing motion artifacts caused by cardiac pulsation and respiration. We developed a diffusion-weighted line-scan echo-planar spectroscopic imaging (DW-LSEPSI) technique to reduce such motion artifacts in measuring diffusion-weighted images (DWI) of metabolites. Our technique uses line-scan and echo-planar techniques to reduce phase errors induced by such motion during diffusion time. The phase errors are corrected using residual water signals in water suppression for each acquisition and at each spatial pixel specified by combining the line-scan and echo-planar techniques. We apply this technique to a moving phantom and a rat brain in vivo to demonstrate the reduction of motion artifacts in DWI and apparent diffusion coefficient (ADC) maps of metabolites. DW-LSEPSI will be useful for investigating a cellular diffusion environment using metabolites as probes.

Interindividual and interspecies variations of the extrastriate visual cortex.

Functional homology between human and macaque visual cortices has provided an important cue to functional subdivisions of the human visual cortex, but it is unclear beyond V1. We estimated the sizes and the visual field eccentricity functions of the extrastriate visual areas of human brains using MRI and fMRI measurements to analyze the interindividual and interspecies variations. We found distinctive features of the area fraction values relative to V1 and the visual field eccentricity functions beyond V2 between the human and the macaque visual cortices. This suggests that selection on color-form and stereoscopic vision, associated with processing and manipulating socio-visual stimuli, may generate variations of the architecture of the extrastriate visual cortex beyond V2.

Deconvolution analyses with tent functions reveal delayed and long-sustained increases of BOLD signals with acupuncture stimulation.

We used deconvolution analysis to examine temporal changes in brain activity after acupuncture stimulation and assess brain responses without expected reference functions. We also examined temporal changes in brain activity after sham acupuncture (noninsertive) and scrubbing stimulation. We divided 26 healthy right-handed adults into a group of 13 who received real acupuncture with manual manipulation and a group of 13 who received both tactical stimulations. Functional magnetic resonance imaging (fMRI) sequences consisted of four 15-s stimulation blocks (ON) interspersed between one 30-s and four 45-s rest blocks (OFF) for a total scanning time of 270 s. We analyzed data by using Statistical Parametric Mapping 8 (SPM8), MarsBaR, and Analysis of Functional NeuroImages (AFNI) software. For statistical analysis, we used 3dDeconvolve, part of the AFNI package, to extract the impulse response functions (IRFs) of the fMRI signals on a voxel-wise basis, and we tested the time courses of the extracted IRFs for the stimulations. We found stimulus-specific impulse responses of blood oxygen level-dependent (BOLD) signals in various brain regions. We observed significantly delayed and long-sustained increases of BOLD signals in several brain regions following real acupuncture compared to sham acupuncture and palm scrubbing, which we attribute to peripheral nocireceptors, flare responses, and processing of the central nervous system. Acupuncture stimulation induced continued activity that was stronger than activity after the other stimulations. We used tent function deconvolution to process fMRI data for acupuncture stimulation and found delayed increasing and delayed decreasing changes in BOLD signal in the somatosensory areas and areas related to pain perception. Deconvolution analyses with tent functions are expected to be useful in extracting complicated and associated brain activity that is delayed and sustained for a long period after various stimulations.

Preparation of polymer-based multimodal imaging agent to visualize the process of bone regeneration.

The objective of this study is to design a new multimodal imaging system for the evaluation of bone regeneration process. Pamidronate (PA) of bisphosphonates with a high affinity for hydroxyapatite, was introduced to pullulan with different molecular weights (PA-pullulan). Then, two probes for fluorescence and magnetic resonance (MR) imagings were introduced into the PA-pullulan to prepare the PA-pullulan conjugates containing both the imaging probes (PA-pullulan-F/M). The PA-pullulan-F/M conjugates had an affinity for hydroxyapatite. A gelatin hydrogel incorporating bone morphogentic protein (BMP)-2 was prepared and implanted subcutaneously into mice to obtain an animal model of bone regeneration. When intravenously injected into mice with the bone tissue ectopically formed by the BMP-2-incorporated hydrogel to fluorescently evaluate their body distribution, the PA-pullulan-F/M conjugates were accumulated in the bone tissue regenerated. The time profile of fluorescent intensity well corresponded with that of calcium amount in the bone tissue newly formed. In addition, the PA-pullulan-F/M conjugates showed an MR ability similar to Gd-DTPA (gadopentetate dimeglumine) of a MR imaging agent clinically used. The MR signal around the bone tissue newly formed was enhanced for mice injected with PA-pullulan-F/M prepared from pullulan with the molecular weight of 6000. It is concluded that the PA-pullulan-F/M conjugate is a useful multimodal agent of polymeric delivery system to evaluate the process of bone regeneration.

Cell labeling for magnetic resonance imaging with the T1 agent manganese chloride.

There is growing interest in using MRI to track cellular migration. To date, most work in this area has been performed using ultra-small particles of iron oxide. Immune cells are difficult to label with iron oxide particles. The ability of adoptively infused tumor specific T cells and N cells to traffic to the tumor microenvironment may be a critical determinant of their therapeutic efficacy. We tested the hypothesis that lymphocytes and B cells would label with MnCl2 to a level that would allow their detection by T1-weighted MRI. Significant signal enhancement was observed in human lymphocytes after a 1 h incubation with 0.05-1.0 mM MnCl2. A flow cytometry-based evaluation using propidium iodide and Annexin V staining showed that lymphocytes did not undergo apoptosis or necrosis immediately after and 24 h following a 1 h incubation with up to 1.0 mM MnCl2. Importantly, NK cells and cytotoxic T cells maintained their in vitro killing capacity after being incubated with up to 0.5 mM MnCl2. This is the first report to describe the use of MnCl2 to label lymphocytes. Our data suggests MnCl2 might be an alternative to iron oxide cell labeling for MRI-based cell migration studies.

Manganese-enhanced magnetic resonance imaging (MEMRI) of brain activity and applications to early detection of brain ischemia.

Divalent manganese ion (Mn2+) has been reported to be a useful contrast agent for functional MRI, through a technique named activity-induced manganese-dependent MRI (AIM). In AIM, signal enhancement is related to functional increases in calcium influx, and therefore AIM is, thus far, the only MRI method able to map brain activation in vivo independently of the surrogate hemodynamic changes used in functional MRI. Because of its high signal-to-noise ratio (SNR) and high sensitivity, AIM allows the use of multi-slice or three-dimensional MRI techniques to map functional activity at high spatial resolution. In the present review, we define AIM as a functional MRI tool based on the administration of divalent ionized manganese through an open or disrupted blood-brain barrier (BBB). The adequacy and efficacy of AIM in detecting neural activation is described in light of supporting experiments on inhibition of calcium channels, FOS expression, and on direct comparison to BOLD- and perfusion-based functional MRI. Two main applications of AIM, mapping brain activation in rat somatosensory cortex, as well stroke research based on the well-established middle cerebral artery occlusion model, are described in detail. Methodological problems associated with a strong dependence on anesthetic conditions, potential corruption due to disruption of the BBB, and unspecific increase of the baseline signal due to acoustical noise are discussed. Finally, recommended preparation methods and experimental protocols for AIM are introduced.

Functional analysis of human parotid gland in vivo using the (1)H MRS MT effect.

Magnetization transfer (MT) was measured in the parotid gland in vivo by (1)H MR spectroscopy in 10 adult volunteers. A comparison was made of stimulated (excess saliva) and resting parotid gland (SPG and RPG, respectively). Following irradiation at an MT pulse of 150 Hz downfield from the water proton signal, signal reductions in SPG and RPG were 83.8 +/- 4.7 and 91.4 +/- 5.7%, respectively. The larger reduction for SPG indicates that an increase in the amount of water in gland cells for the production of more parotid saliva may lead to greater affinity between the protons adjacent to macromolecules and free water which contributes to the MT effect. Activity in the parotid gland correlates with the effect. This method is useful for diagnosing disorders of parotid gland secretion.

Neuroprotective effects of an immunosuppressant agent on diffusion/perfusion mismatch in transient focal ischemia.

The immunosuppressant FK506 (tacrolimus) exerts potent neuroprotection following focal ischemia in animals; however, the separate effects of FK506 on the ischemic core and penumbra have not been reported. The ischemic penumbra is clinically defined as the difference between a large abnormal area on perfusion-weighted imaging (PWI) and a smaller lesion on diffusion-weighted imaging (DWI). The goal of this study was to determine the effect of FK506 on DWI/PWI match and mismatch areas in transient focal ischemia in rats. Twelve rats were subjected to 1 hr of transient middle cerebral artery (MCA) occlusion, and given an intravenous injection of a placebo (N = 6) or 1 mg/kg FK506 (N = 6) immediately before reperfusion. Magnetic resonance imaging (MRI) was performed during MCA occlusion, and 0.5, 1, and 24 hr after reperfusion. FK506 significantly protected the ischemic brain only in the mismatch cortex where the initial apparent diffusion coefficient (ADC) was normal and there was a mild reduction of cerebral blood flow (CBF). This is the first report to describe the protective effects of FK506 on ischemic penumbra, as measured by DWI/PWI mismatch. The findings provide direct evidence for the utility of DWI/PWI mismatch as a guideline for therapeutic intervention with FK506.

Dynamic activity-induced manganese-dependent contrast magnetic resonance imaging (DAIM MRI).

Activity-induced manganese-dependent contrast (AIM) MRI is a hemodynamic-independent functional MRI method that used manganese ion as an MR-detectable contrast agent. In AIM, MnCl(2) is infused intra-arterially after the blood-brain barrier (BBB) is opened with a hyperosmolar agent. Upon functional stimulation of the brain, Mn(2+) accumulates in the active region(s) by entering active cells through voltage-gated Ca(2+) channels, causing local signal increases in T(1)-weighted images. The contrast of AIM MRI depends strongly on the depth of anesthesia, and the low levels used in somatosensory stimulation studies can lead to significant nonspecific accumulation of manganese ion throughout the brain. The purpose of this study was to produce an AIM functional map of somatosensory stimulation, which separates the stimulation-specific signal increase from the nonspecific activation due to light anesthesia. A dynamic AIM (DAIM) paradigm was developed, which used sequential MR scans during MnCl(2) infusion, prior to and following functional stimulation of the brain. Stimulation-specific functional maps were produced using time-course analysis. The new method was tested during glutamate administration and electric stimulation of the rat forepaw. It was shown that DAIM maps are better confined to the specific region of brain activated by somatosensory stimulation as compared to AIM MRI.

Detection of the anoxic depolarization of focal ischemia using manganese-enhanced MRI.

Mismatch between diffusion- and perfusion-weighted MRI was used to indicate a treatable area following focal ischemia, called the penumbra. Activity-induced manganese contrast MRI has been reported as a new visualization method for neural activation using manganese ions as a depolarization-dependent contrast agent. It is well known that energy failure induced by cerebral ischemia produces anoxic depolarization. The purpose of this study was to detect manganese accumulation caused by permanent middle cerebral artery occlusion (MCAO) of rat brain and to compare regional differences between manganese accumulation and decreased apparent diffusion coefficient (ADC). The ratios of signal intensity of manganese-enhanced MRI in the ipsilateral cortex to that in the contralateral cortex were 171.0 +/- 17.5% in MCAO group and 108.4 +/- 13.2% in the sham group. In addition, the enhanced region was much smaller than the area which was detected as having a reduced ADC.