Risto A. Kauppinen

Proliferating resident microglia after focal cerebral ischaemia in mice.

Cerebral ischaemia usually results in the rapid death of neurons within the immediate territory of the affected artery. Neuronal loss is accompanied by a sequence of events, including brain oedema, blood-brain barrier (BBB) breakdown, and neuroinflammation, all of which contribute to further neuronal death. Although the role of macrophages and mononuclear phagocytes in the expansion of ischaemic injury has been widely studied, the relative contribution of these cells, either of exogenous or intrinsic central nervous system (CNS) origin is still not entirely clear. The purpose of this study, therefore, was to use different durations of transient middle cerebral artery occlusion (tMCAo) in the mouse to investigate fully post-occlusion BBB permeability and cellular changes in the brain during the 72 h post-MCAo period. This was achieved using in vivo magnetic resonance imaging (MRI) and cell labelling techniques. Our results show that BBB breakdown and formation of the primary ischaemic damage after tMCAo is not associated with significant infiltration of neutrophils, although more are observed with longer periods of MCAo. In addition, we observe very few infiltrating exogenous macrophages over a 72 h period after 30 or 60 mins of occlusion, instead a profound increase in proliferating resident microglia cells was observed. Interestingly, the more severe injury associated with 60 mins of MCAo leads to a markedly reduced proliferation of resident microglial cells, suggesting that these cells may play a protective function, possibly through phagocytosis of infiltrating neutrophils. These data further support possible beneficial actions of microglial cells in the injured brain.

Oxygenation and hematocrit dependence of transverse relaxation rates of blood at 3T.

Knowledge of the transverse relaxation rates R2 and R u20092* of blood is relevant for quantitative assessment of functional MRI (fMRI) results, including calibration of blood oxygenation and measurement of tissue oxygen extraction fractions (OEFs). In a temperature controlled circulation system, these rates were measured for blood in vitro at 3T under conditions akin to the physiological state. Single spin echo (SE) and gradient echo (GRE) sequences were used to determine R2 and R u20092* , respectively. Both rates varied quadratically with deoxygenation, and changes in R u20092* were found to be due predominantly to changes in R2. These data were used to estimate intravascular blood oxygenation level dependent (BOLD) contributions during visual activation. Due to the large R u20092* in venous blood, intravascular SE BOLD signal changes were larger than GRE effects at echo times above 30 ms. When including extravascular effects to estimate the total BOLD effect, GRE BOLD dominated due to the large tissue volume fraction. Magn Reson Med 58:592–596, 2007.

Effects of hematocrit and oxygen saturation level on blood spin‐lattice relaxation

In the present study blood T1 was determined as a function of hematocrit and oxygen saturation. T1 showed a significant linear dependency on both of these parameters. In addition, oxygen dissolved in blood plasma in hyperoxygenated blood resulted in relaxation enhancement, comparable in size to that due to the change in oxygenation state of hemoglobin. As blood T1 is a key factor for quantification of flow with arterial spin labeling methods, the influence of T1 variation in the physiological range of hematocrit and oxygen saturation to flow determination is discussed. Magn Reson Med 49:568–571, 2003.

Proton transfer ratio, lactate, and intracellular pH in acute cerebral ischemia

The amide proton transfer ratio (APTR) from the asymmetry of the Z‐spectrum was determined in rat brain tissue during and after unilateral middle cerebral artery occlusion (MCAo). Cerebral lactate (Lac) as determined by 1H NMR spectroscopy, water diffusion, and T1ρ were quantified as well. Lac concentrations were used to estimate intracellular pH (pHi) in the brain during the MCA occlusion. A decrease in APTR during occlusion indicated acidification from 7.1 to 6.79 ± 0.19 (a drop by 0.3 ± 0.2 pH units), whereas pHi computed from Lac concentration was 6.3 ± 0.2 (a drop by 0.8 ± 0.2 pH units). Despite the disagreement between the two methods in terms of the size of the change in the absolute pHi during ischemia, ΔAPTR and pHi (and Lac concentration) displayed a strong correlation during the MCAo. Diffusion and T1ρ indicated cytotoxic edema following MCA occlusion; however, APTR returned slowly toward the values determined in the contralateral hemisphere post‐ischemia. These data argue that the APTR during ischemia is affected not only by pHi but by other physicochemical factors as well, and indicates different aspects of pathology in the post‐ischemic brain compared to those that influence water diffusion and T1ρ. Magn Reson Med 57:647–653, 2007.

A metabolomics perspective of human brain tumours

During the past decade or so, a wealth of information about metabolites in various human brain tumour preparations (cultured cells, tissue specimens, tumours inu2003vivo) has been accumulated by global profiling tools. Such holistic approaches to cellular biochemistry have been termed metabolomics. Inherent and specific metabolic profiles of major brain tumour cell types, as determined by proton nuclear magnetic resonance spectroscopy (1Hu2003MRS), have also been used to define metabolite phenotypes in tumours inu2003vivo. This minireview examines the recent advances in the field of human brain tumour metabolomics research, including advances in MRS and mass spectrometry technologies, and data analysis.

Exchange-influenced T2ρ contrast in human brain images measured with adiabatic radio frequency pulses

Transverse relaxation in the rotating frame (T2ρ) is the dominant relaxation mechanism during an adiabatic Carr–Purcell (CP) spin‐echo pulse sequence when no delays are used between pulses in the CP train. The exchange‐induced and dipolar interaction contributions (T2ρ,ex and T2ρ,dd) depend on the modulation functions of the adiabatic pulses used. In this work adiabatic pulses having different modulation functions were utilized to generate T2ρ contrast in images of the human occipital lobe at magnetic field of 4 T. T2ρ time constants were measured using an adiabatic CP pulse sequence followed by an imaging readout. For these measurements, adiabatic full passage pulses of the hyperbolic secant HSn (n = 1 or 4) family having significantly different amplitude—and frequency—modulation functions were used with no time delays between pulses. A dynamic averaging (DA) mechanism (e.g., chemical exchange and diffusion in the locally different magnetic susceptibilities) alone was insufficient to fully describe differences in brain tissue water proton T2ρ time constants. Measurements of the apparent relaxation time constants (T u20092† ) of brain tissue water as a function of the time between centers of pulses (τcp) at 4 and 7 T permitted separation of the DA contribution from that of dipolar relaxation. The methods presented assess T2ρ relaxation influenced by DA in tissue and provide a means to generate T2ρ contrast in MRI. Magn Reson Med 53:823–829, 2005.

Water diffusion in a rat glioma during ganciclovir-thymidine kinase gene therapy-induced programmed cell death in vivo: correlation with cell density.

To study the characteristics of diffusion magnetic resonance imaging (MRI) contrast in a rat brain BT4C glioma during progression of ganciclovir (GCV)‐thymidine kinase gene therapy‐induced programmed cell death (PCD) in vivo.

Manganese-enhanced magnetic resonance imaging of mossy fiber plasticity in vivo

Mn(2+)-enhanced magnetic resonance imaging (MEMRI) was used to characterize activity-dependent plasticity in the mossy fiber pathway after intraperitoneal kainic acid (KA) injection. Enhancement of the MEMRI signal in the dentate gyrus and the CA3 subregion of the hippocampus was evident 3 to 5 days after injection of MnCl(2) into the entorhinal cortex both in control and KA-injected rats. In volume-rendered three-dimensional reconstructions, Mn(2+)-induced signal enhancement revealed the extent of the mossy fiber pathway throughout the septotemporal axis of the dentate gyrus. An increase in the number of Mn(2+)-enhanced pixels in the dentate gyrus and CA3 subfield of rats with KA injection correlated (P < 0.05) with histologically verified mossy fiber sprouting. These data demonstrate that MEMRI can be used to detect specific changes at the cellular level during activity-dependent plasticity in vivo. The present findings also suggest that MEMRI signal changes can serve as an imaging marker of epileptogenesis.

Determination of regional brain temperature using proton magnetic resonance spectroscopy to assess brain–body temperature differences in healthy human subjects

Proton magnetic resonance spectroscopy (1H MRS) was used to determine brain temperature in healthy volunteers. Partially water‐suppressed 1H MRS data sets were acquired at 3T from four different gray matter (GM)/white matter (WM) volumes. Brain temperatures were determined from the chemical‐shift difference between the CH3 of N‐acetyl aspartate (NAA) at 2.01 ppm and water. Brain temperatures in 1H MRS voxels of 2 × 2 × 2 cm3 showed no substantial heterogeneity. The volume‐averaged temperature from single‐voxel spectroscopy was compared with body temperatures obtained from the oral cavity, tympanum, and temporal artery regions. The mean brain parenchyma temperature was 0.5°C cooler than readings obtained from three extra‐brain sites (P < 0.01). 1H MRS imaging (MRSI) data were acquired from a slice encompassing the single‐voxel volumes to assess the ability of spectroscopic imaging to determine regional brain temperature within the imaging slice. Brain temperature away from the center of the brain determined by MRSI differed from that obtained by single‐voxel MRS in the same brain region, possibly due to a poor line width (LW) in MRSI. The data are discussed in the light of proposed brain–body temperature gradients and the use of 1H MRSI to monitor brain temperature in pathologies, such as brain trauma. Magn Reson Med 57:59–66, 2007.

Effects of oxygen saturation on BOLD and arterial spin labelling perfusion fMRI signals studied in a motor activation task.

Effects of oxygen availability on blood oxygenation level dependent (BOLD) and arterial spin labelling (ASL) perfusion functional magnetic resonance imaging (fMRI) signal changes upon motor activation were studied. Mild hypoxic hypoxia was induced by reducing the inspired oxygen content (FIO(2)) to 12%, decreasing blood oxygen saturation (Y) from 0.99 +/- 0.01 to 0.85 +/- 0.03. The fMRI signal characteristics were determined during finger tapping. BOLD activation volume decreased as a function of declining Y in the brain structures involved in execution of the motor task, however, the BOLD signal increase in activated parenchyma was not influenced by Y. ASL fMRI showed that the baseline CBF of 61.8 +/- 3.6 ml/100 g/min was not affected by hypoxic hypoxia. Similar to the BOLD fMRI, the volume of motor cortex areas displaying increase in perfusion by ASL fMRI decreased, but the signal change due to perfusion increase was not influenced in hypoxia. The present fMRI results show distinct patterns of haemodynamic and metabolic responses in the brain to motor task between normoxia and hypoxia. On one hand, neither BOLD nor ASL fMRI signal changes are influenced by hypoxia during motor activation. On the other hand, hypoxia attenuates increase in both BOLD and perfusion fMRI signals upon finger tapping from the levels determined in normoxia. These observations indicate that haemodynamic and metabolic responses may be heterogeneous in brain during execution of motor functions in mild hypoxia.