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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.

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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.

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Localized versions of two-dimensional (2D) magnetic resonance spectroscopic (MRS) sequences, namely JPRESS and L-COSY, have been implemented on a whole-body 3T MRI/MRS scanner. Volume selection was achieved using three slice-selective radio-frequency (RF) pulses: 90 degrees-180 degrees-180 degrees in JPRESS and 90 degrees-180 degrees-90 degrees in L-COSY with a CHESS sequence prior to voxel localization for global water suppression. The last 180 degrees RF pulse was used for resolving the J-coupled cross peaks in JPRESS, whereas the last 90 degrees RF pulse was used for coherence transfer between J-coupled metabolites in L-COSY. A head MRI coil for 'transmission' and a 4 inch receive surface coil for 'reception' or a head coil transmit/receive were used. A total of 16 healthy volunteers were investigated using these 2D MRS sequences. Voxel sizes of 18 and 27 ml were localized in the occipito-parietal gray and white matter regions and the total duration for each 2D signal acquisition was typically 35 min. Compared with 2D L-COSY, reduced spectral width along the second spectral dimension and shorter 2D spectral acquisition were the major advantages of 2D JPRESS. In contrast, increased spectral width along the new spectral dimension in L-COSY resulted in an improved spectral dispersion enabling the detection of several brain metabolites at low concentrations that have not been resolved using the conventional one-dimensional (1D) MRS techniques. Due to increased sampling rate, severe loss of metabolite signals due to T2 during t1 was a major drawback of 2D JPRESS in vivo.

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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.

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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.

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