Visualisation of changes in regional cerebral blood flow (rCBF) produced by ketamine using long TE gradient-echo sequences: Preliminary results

Autoradiographic studies have shown that low dose ketamine produces increases in regional glucose utilisation and blood flow in the hippocampus, cerebral cortex, and olfactory lobe in the rat brain, probably due to antagonism at the NMDA receptor. Functional MRI using deoxyhaemoglobin contrast can be used to study changes in regional cerebral blood flow (rCBF). Long TE gradient-echo sequences were used to study changes in rCBF produced by low dose ketamine in rats anaesthetised with nitrous oxide, supplemented with either halothane (HAL) or fentanyl/fluanisone/midazolam (FFM) combination. Images from rats in the FFM group showed a 10–14% increase in signal intensity in the hippocampus, cerebral cortex, and olfactory lobe following either a single bolus or a low dose infusion of ketamine (p < .05). These changes were significantly reduced in the HAL group (p < .005). Halothane is known to attenuate the changes in regional glucose utilisation produced by the noncompetitive NMDA antagonist dizocilpine (MK-801), and its effects on ketamine-induced changes in rCBF seen in this study may be due to a similar effect. The potential use of functional MRI in studying the effect of pharmacological interventions on rCBF is discussed.     

On the origin of respiratory artifacts in BOLD-EPI of the human brain

BOLD-based functional MRI (fMRI) can be used to explicitly measure hemodynamic aspects and functions of human neuro-physiology. As fMRI measures changes in regional cerebral blood flow and volume as well as blood oxygenation, rather than neuronal brain activity directly, other processes that may change the above parameters have to be examined closely to assess sensitivity and specificity of fMRI results. Physiological processes that can cause artifacts include cardiac action, breathing and vasomotion. Although there has been substantial research on physiological artifacts and appropriate compensation methods, controversy still remains on the mechanisms that cause the fMRI signal fluctuations. Respiratory-correlated fluctuations may either be induced by changes of the magnetic field homogeneity due to moving organs, intra-thoracic pressure differences, respiration-dependent vasodilation or oxygenation differences. The aim of this study was to characterize the impact of different breathing patterns by varying respiration frequency and/or tidal volume on EPI time courses of the resting human brain. The amount of respiration-related oscillations during three respiration patterns was quantified, and statistically significant differences were obtained in white matter only: p < 0.03 between 6 vs. 12 ml/kg body weight end tidal volume at a respiration frequency of 15/min, p < 0.03 between 12 vs. 6 ml/kg body weight and 15 vs. 10 respiration cycles/min. There was no significant difference between 15 vs. 10 respiration cycles/min at an end tidal volume of 6 ml/kg body weight (p = 0.917). In addition, the respiration-affected brain regions were very similar with EPI readout in the a-p and l-r direction. Based on our results and published literature we hypothesize that venous oxygenation oscillations due to changing intra-thoracic pressure represent a major factor for respiration-related signal fluctuations and increase significantly with increasing end tidal volume in white matter only.     

Identification of activated regions during a language task

Functional magnetic resonance imaging (fMRI) techniques are based on the assumption that changes in neural activity are accompanied by modulation in the blood-oxygenation-level-dependent (BOLD) signal. In addition to conventional increases in BOLD signals, sustained negative BOLD signal changes are occasionally observed in many fMRI experiments, which show regions of cortex that seem to respond in antiphase with primary stimulus. The existence of this so-called negative BOLD response (NBR) has been observed and investigated in many functional studies. Several theoretical mechanisms have been proposed to account for it, but its origin has never been fully explained. In this study, the variability of fMRI activation, including the sources of the negative BOLD signal, during phonological and semantic language tasks, was investigated in six right-handed healthy subjects. We found significant activations in the brain regions, mainly in the left hemisphere, involved in the language stimuli [prominent in the inferior frontal gyrus, approximately Brodmann Areas (BA)7, BA44, BA45 and BA47, and in the precuneus]. Moreover, we observed activations in motor regions [precentral gyrus and supplementary motor area (SMA)], a result that suggests a specific role of these areas (particularly the SMA) in language processing. Functional analysis have also shown that certain brain regions, including the posterior cingulate cortex and the anterior cingulate cortex, have consistently greater activity during resting states compared to states of performing cognitive tasks. In our study, we observed diffuse NBR at the cortical level and a stronger negative response in correspondence to the main sinuses. These phenomena seem to be unrelated to a specific neural activity, appearing to be expressions of a mechanical variation in hemodynamics. We discussed about the importance of these responses that are anticorrelated with the stimulus. Our data suggest that particular care must be considered in the interpretation of fMRI findings, especially in the case of presurgical studies.     

Impaired functionality of reperfused brain tissue following short transient focal ischemia in rats

Functional magnetic resonance imaging (fMRI) has been applied to study the consequences of transient focal ischemia on neuronal excitability in the rat brain. The experimental paradigm consisted of measuring the changes in local cerebral blood volume (CBV) induced by systemic infusion of the GABA(A) antagonist bicuculline after occlusion of the middle cerebral artery (MCA) for durations of 5, 15, 30 and 60 min using the intraluminal thread model. fMRI studies were carried out 60 min after successful reperfusion of the ischemic territory. Bicuculline-induced dynamic changes in local CBV were assessed in three brain regions: Parietal cortex, caudate putamen and thalamus. The measured CBV response was negatively correlated with the ischemia duration. Additionally, the three regions showed different vulnerability to the transient MCA occlusion, caudate being the most susceptible followed by parietal cortex and thalamus. The fMRI signals weakly correlated with basal CBF and CBV following reperfusion. Our results indicate that fMRI is a sensitive method to assess functional integrity of the brain. Activation maps allow to quantitatively assess the functionally compromized territory at an early stage following the ischemic event prior to the manifestation of pathomorphological changes.     

Functional MRI of the motor cortex using a conventional gradient system: comparison of FLASH and EPI techniques

Gradient echo (GE) and echo planar imaging (EPI) techniques are two different approaches to functional MRI (fMRI). In contrast to GE sequences, the ultra short EPI technique facilitates fMRI experiments with high spatial and temporal resolution or mapping of the whole brain. Although it has become the method of choice for fMRI, EPI is generally restricted to modern scanners with a strong gradient system. The aim of our study was to evaluate the applicability of EPI for fMRI of the motor cortex using a 1.5 T scanner with a conventional gradient system of 10 mT/m (rise time: 1 ms). Therefore, EPI was compared with a well-established high resolution fast low angle shot (FLASH) technique (matrix size 128²). The FLASH technique was applied additionally with a 64² matrix size to exclude influences caused by different spatial resolution, because the EPI sequence was restricted to a 64² matrix size. A total of 35 healthy volunteers were included in this study. The task consisted of clenching and spreading of the right hand. FLASH and EPI techniques were compared regarding geometric distortions as well as qualitative and quantitative fMRI criteria: Mean signal increase between activation and rest and the area of activation were measured within the contralateral, ipsilateral, and supplementary motor cortex. The quality of subtraction images between activation and rest, as well as the quality of z-maps and time course within activated regions of interest, was evaluated visually. EPI revealed significant distortions of the anterior and postior brain margins; lateral distortions (relevant for the motor cortex) could be neglected in most cases. The mean signal increase was significantly higher using FLASH 128² compared to FLASH 64² and EPI 64², whereas the activated areas proved to be smaller in FLASH 128² functional images. Both results can be explained by well-documented partial volume effects, caused by different voxel size. Similar quality of the subtraction images and of the time courses in different regions of interest were found for all techniques under investigation, but slightly reduced quality of z-map in FLASH 128². Within the limits of reproducibility and measurement accuracy, the location of contralateral activation was similar using FLASH and EPI sequences. In conclusion, EPI proved to be a reliable technique for fMRI of the motor cortex, even on an MR scanner with a conventional gradient system.     

In vivo EPR imaging by using an acyl-protected hydroxylamine to analyze intracerebral oxidative stress in rats after epileptic seizures

EPR imaging by using an acyl-protected hydroxylamine, 1-acetoxy-3-carbamoyl-2,2,5,5-tetramethylpyrrolidine (ACP), in the head of a living rat after kainic acid (KA)-induced epileptic seizures was performed. ACP is a stable non-radical compound, but is easily deprotected with intracellular esterase to yield a hydroxylamine, which is oxidized by intracellular oxidative stress to yield an EPR-detectable nitroxide radical. From in vivo image data, the average values of EPR signal intensity from the hippocampus, striatum, and cerebral cortex were computed. There was no significant difference in cortical signal intensity between the control and KA-treated rats. The signal intensities from the hippocampus and striatum for the KA-treated rats were significantly higher than those for the control. The in vitro study showed that almost the same quantity of ACP moved into all regions of the brain of the control and KA-treated rats. These findings indicate that following a KA-induced seizure, the oxidative stress in the hippocampus and striatum is enhanced, but not so in the cerebral cortex.     

Effects of hypoglycemia on human brain activation measured with fMRI

Functional magnetic resonance imaging (fMRI) was used to measure the effects of acute hypoglycemia caused by passive sensory stimulation on brain activation. Visual stimulation was used to generate blood-oxygen-level-dependent (BOLD) contrast, which was monitored during hyperinsulinemic hypoglycemic and euglycemic clamp studies. Hypoglycemia (50 +/- 1 mg glucose/dl) decreased the fMRI signal relative to euglycemia in 10 healthy human subjects: the fractional signal change was reduced by 28 +/- 12% (P < .05). These changes were reversed when euglycemia was restored. These data provide a basis of comparison for studies that quantify hypoglycemia-related changes in fMRI activity during cognitive tasks based on visual stimuli and demonstrate that variations in blood glucose levels may modulate BOLD signals in the healthy brain.     

Brain oscillatory activity during motor imagery in EEG-fMRI coregistration

The purpose of the present work was to investigate the correlation between topographical changes in brain oscillatory activity and the blood oxygenation level-dependent (BOLD) signal during a motor imagery (MI) task using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) coregistration.     

Therapeutic effect of the NMDA antagonist MK-801 on low-level laser induced retinal injury

The aim of this article was to explore the mechanism of injury in rat retina after constant low-level helium-neon (He-Ne) laser exposure and therapeutic effects of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, on laser-induced retinal injury. He-Ne laser lesions were created in the central retina of adult Wistar Kyoto rats and were followed immediately by intraperitoneal injection of MK-801 (2 mg/kg) or saline, macroscopical and microscopical lesion were observed by funduscope and light microscope. Ultrastructural changes of the degenerating cells were examined by electron microscopy. Photoreceptor apoptosis was evaluated by TdT-mediated dUTP nick end-labeling (TUNEL). mRNA levels were measured by in situ hybridization and NMDA receptor expression was determined by immunohistochemistry. Laser induced damage was histologically quantified by image-analysis morphometry. Electroretinograms (ERGs) were recorded at different time point after the cessation of exposure to constant irradiation. There was no visible bleeding, exudation or necrosis under funduscope. TUNEL and electron microscopy showed photoreceptor apoptosis after irradiation. MK-801-treated animals had significantly fewer TUNEL-positive cells in the photoreceptors than saline-treated animals after exposure to laser. In situ hybridization (ISH) showed that the NMDAR mRNA level of MK-801-treated rats decreased in the inner plexiform layer 6 h after the cessation of exposure to constant irradiation when compared with that of saline-treated rats. So did Immunohistochemistry (IHC). Electroretinogram showed that b-wave amplitudes of MK-801-treated group were higher than that of saline-treated group after laser exposure. These findings suggest that Low level laser may cause the retinal pathological changes under given conditions. High expression of NMDAR is one of the possible mechanisms causing experimental retinal laser injury of rats. MK-801 exhibits the therapeutic effect due to promote the recovery of structure and function of injured retina. Original Text ? Astro, Ltd., 2009.     

Origins of intersubject variability of blood oxygenation level dependent and arterial spin labeling fMRI: implications for quantification of brain activity

Accurate localization of brain activity using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been challenged because of the large BOLD signal within distal veins. Arterial spin labeling (ASL) techniques offer greater sensitivity to the microvasculature but possess low temporal resolution and limited brain coverage. In this study, we show that the physiological origins of BOLD and ASL depend on whether percent change or statistical significance is being considered. For BOLD and ASL fMRI data collected during a simple unilateral hand movement task, we found that in the area of the contralateral motor cortex the centre of gravity (CoG) of the intersubject coefficient of variation (CV) of BOLD fMRI was near the brain surface for percent change in signal, whereas the CoG of the intersubject CV for Z-score was in close proximity of sites of brain activity for both BOLD and ASL. These findings suggest that intersubject variability of BOLD percent change is vascular in origin, whereas the origin of inter-subject variability of Z-score is neuronal for both BOLD and ASL. For longer duration tasks (12 s or greater), however, there was a significant correlation between BOLD and ASL percent change, which was not evident for short duration tasks (6 s). These findings suggest that analyses directly comparing percent change in BOLD signal between pre-defined regions of interest using short duration stimuli, as for example in event-related designs, may be heavily weighted by large-vessel responses rather than neuronal responses.     

Neurophysiological and functional MRI evidence of reorganization of cortical motor areas in cerebral arteriovenous malformation

Functional magnetic resonance imaging (fMRI) research has shown that brain arteriovenous malformations (AVMs) lead to reorganization of cortical motor areas. Since it is known that blood oxygenation level-dependent signal in fMRI may be influenced by the hemodynamic perturbation associated with the presence of the AVM, in the present study, a combined exploration with fMRI and transcranial magnetic stimulation was performed in a patient with a right rolandic AVM in order to explore the relationship between neuronal and hemodynamic activity. The combined protocol of investigation adopted in this study was able to provide significant information regarding neuronal activity of the different cortical areas that partake to post-lesional reorganization.     

Neonatal auditory activation detected by functional magnetic resonance imaging

The objective of this study was to detect auditory cortical activation in non-sedated neonates employing functional magnetic resonance imaging (fMRI). Using echo-planar functional brain imaging, subjects were presented with a frequency-modulated pure tone; the BOLD signal response was mapped in 5 mm-thick slices running parallel to the superior temporal gyrus. Twenty healthy neonates (13 term, 7 preterm) at term and 4 adult control subjects. Blood oxygen level-dependent (BOLD) signal in response to auditory stimulus was detected in all 4 adults and in 14 of the 20 neonates. FMRI studies of adult subjects demonstrated increased signal in the superior temporal regions during auditory stimulation. In contrast, signal decreases were detected during auditory stimulation in 9 of 14 newborns with BOLD response. fMRI can be used to detect brain activation with auditory stimulation in human infants.     

Mapping of the cerebral response to acetazolamide using graded asymmetric spin echo EPI

Cerebral vascular reactivity in different regions of the rat brain was quantitatively characterized by spatial and temporal measurements of blood oxygenation level-dependent (BOLD)-fMRI signals following intravenous administration of the carbonic anhydrase inhibitor acetazolamide: this causes cerebral vasodilatation through a cerebral extracellular acidosis that spares neuronal metabolism and vascular smooth muscle function, thus separating vascular and cerebral metabolic events. An asymmetric spin echo-echo planar imaging (ASE-EPI) pulse sequence sensitised images selectively to oxygenation changes in the microvasculature; use of a surface coil receiver enhanced image signal-to-noise ratios (SNRs). Image SNRs and hardware integrity were verified by incorporating quality assurance procedures; cardiorespiratory stability in the physiological preparations were monitored and maintained through the duration of the experiments. These conditions made it possible to apply BOLD contrast fMRI to map regional changes in cerebral perfusion in response to acetazolamide administration. Thus, fMRI findings demonstrated cerebral responses to acetazolamide that directly paralleled the known physiological actions of acetazolamide and whose time courses were similar through all regions of interest, consistent with acetazolamide's initial distribution in brain plasma, where it affects cerebral haemodynamics by acting at cerebral capillary endothelial cells. However, marked variations in the magnitude of the responses suggested relative perfusion deficits in the hippocampus and white matter regions correlating well with their relatively low vascularity and the known vulnerability of the hippocampus to ischaemic damage.     

Functional MR imaging of visual and motor cortex stimulation at high temporal resolution using a flash technique on a standard 1.5 tesla scanner

Functional magnetic resonance imaging (fMRI) was performed on a conventional 1.5 T scanner by means of a modified FLASH-technique at temporal resolutions of 80 and 320 ms. The method's stability was assessed by phantom measurements and by investigation of three volunteers resulting in a low amplitude (3%) periodic (4 s) signal modulation for the in vivo measurements, which was not observable in the phantom experiments. fMRI activation studies of motor and visual cortices of four adjacent slices were carried out on 12 healthy right-handed volunteers. Stimulation was performed by a triggered single white light flash or single finger-to-thumb opposition movement, respectively. Event-related response of visual and motor activation was traced over 10.24 s with a temporal resolution of 320 ms for the four slice measurements. Brain activation maps were calculated by correlation of measured signal time courses with a time-shifted boxcar function. Activation was quantified by calculation of percentual signal change in relation to the baseline. Observed signal magnitudes were about 5–7% in visual and about 8–12% in primary motor cortex. While photic response was delayed by about 2 s, motor stimulation showed an instantaneous increase of the MR signal. MR signal responses for both stimuli had decayed completely after about 5 s. Our results show that event-related fMRI enables mapping of brain function at sufficient spatial resolution with a temporal resolution of up to 80 ms on a conventional scanner.     

Functional MRI involving painful stimulation of the ankle and the effect of physiotherapy joint mobilization

We examined whether cerebral activation due to secondary hyperalgesia resulting from intrajoint capsaicin injection could be detected using functional magnetic resonance imaging (fMRI) in alpha-chloralose anesthetized rats. We also examined whether we could detect analgesic changes in the central nervous system response to pain as a result of physiotherapy joint manipulation. Robust activation of areas of the brain known to be associated with the processing of pain, namely the anterior cingulate (bilateral), frontal cortex (bilateral) and sensory motor cortex (contralateral), was found in all animals following injection of 25 microl of capsaicin (128 microg/ml in 7.5% DMSO) into the plantar surface of the rat hindpaw (n = 7) and 75 microL into the ankle joint (n = 13). Significantly greater activation was observed when capsaicin was injected into the plantar surface of the hindpaw compared to the ankle joint. Mechanical allodynia and secondary hyperalgesia following capsaicin injection into the ankle joint also resulted in activation of the same brain regions. Trends toward decreased areas of activation in brain regions associated with pain in animals following physiotherapy joint mobilization were observed.     

Signal characteristics of FLAIR related to water content: comparison with conventional spin echo imaging in infarcted rat brain

To examine the correlation between tissue water content and signal intensity on fluid-attenuated inversion recovery (FLAIR) images, we analyzed infarcted rat brain, verified the results by theoretical simulation, and compared them with conventional spin-echo images. We produced brain infarction with cavitation in five rats by middle cerebral artery occlusion. After in vivo MRI, histologic sections of the MRI plane were obtained. We measured the signal intensity of regions on FLAIR and spin-echo images, and measured the area of cavitation on histologic sections. We plotted curves of cavity percentage to signal intensity. Theoretical values were calculated using a two-compartment model. On the curve of cavity area to signal intensity, the signal on FLAIR images peaked in tissues with 20% to 30% area of cavitation. On the theoretical curve, the signal on FLAIR images peaked at 90% tissue water content. These results seem to be characteristic of FLAIR.     

The effect of sensorimotor activation on functional connectivity mapping with MRI

The correlations in the fluctuations in the blood oxygenation level-dependent (BOLD) MRI signal between anatomically distinct regions of the cortex that are known components of functional systems have been previously studied as possible indicators of functional connectivity. The objective of this study was to examine the effect of sensorimotor brain activity, as assessed by task-based functional magnetic resonance imaging (fMRI), on functional connectivity indices in the same region. Regions of activation for sequential finger motion were determined using a task-based, block-design fMRI study. Functional connectivity measurements based on interregional correlations were acquired at rest and during continuous, sequential finger motion. Connectivity indices were determined using normalized mean correlations within and between three regions of interest activated for the finger motion task. Connectivity indices were also determined for a control region that was not activated for the task. Continuous motor tasks performed during BOLD measurements did not significantly affect the functional connectivity as compared to the connectivity at rest within or between regions known to be activated by the task. However, there appeared to be a trend suggesting a slight reduction in connectivity indices during the motor task. The connectivity within and between those areas not activated for the task remained unchanged between conditions. These results suggest that in the motor system investigated, the recruitment of neurons to perform a specific task may moderately reduce the degree of hemodynamic coupling within and between regions.     

Correlations and dissociations between BOLD signal and P300 amplitude in an auditory oddball task: a parametric approach to combining fMRI and ERP

A parametric method is proposed to examine the relationship between neuronal activity, measured with event related potentials (ERPs), and the hemodynamic response, observed with functional magnetic resonance imaging (fMRI), during an auditory oddball paradigm. After verifying that the amplitude of the evoked response P300 increases as the probability of oddball target presentation decreases, we explored the corresponding effect of target frequency on the fMRI signal. We predicted and confirmed that some regions that showed activation changes following each oddball are affected by the rate of presentation of the oddballs, or the probability of an oddball target. We postulated that those regions that increased activation with decreasing probability might be responsible for the corresponding changes in the P300 amplitude. fMRI regions that correlated with the amplitude of the P300 wave were supramarginal gyri, thalamus, insula and right medial frontal gyrus, and are presumably sources of the P300 wave. Other regions, such as anterior and posterior cingulate cortex, were activated during the oddball paradigm but their fMRI signal changes were not correlated with the P300 amplitudes. This study thus shows how combining fMRI and ERP in a parametric design identifies task-relevant sources of activity and allows separation of regions that have different response properties.     

Application of magnetic resonance imaging to the measurement of neurodegeneration in rat brain: MRI data correlate strongly with histology and enzymatic analysis.

Focal brain ischemia was induced by middle cerebral artery occlusion in the rat. The volume of cerebral damage was determined 2 days later by MRI in vivo and in the same animals histologically. The edema volume as measured by MRI and the histologically determined infarction was highly correlated. As a consequence, the neuroprotective effect of the N-methyl-D-aspartate (NMDA) receptor antagonists CGP 40116 and MK 801 were similar with both methods. Excitotoxic neurodegeneration in the rat striatum was induced by direct injection of quinolinic acid. The degree of damage was evaluated in vivo 1 day later by quantitative MRI, and 7 days later by measuring the activities of neuronal marker enzymes choline acetyltransferase and glutamic acid decarboxylase. Striatal damage assessed using the three approaches was highly correlated. Cerebroprotective efficacy of the NMDA receptor antagonist CGP 40116 was indistinguishable based on all methods. MRI was more reproducible than the enzymatic methods and was faster and simpler than histologic examination for routine analysis of excitotoxic damage and cerebroprotection in vivo in a pharmaceutical research environment.     

Percept-related activity in the human somatosensory system: functional magnetic resonance imaging studies

In this paper, we review blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies addressing the neural correlates of touch, thermosensation, pain and the mechanisms of their cognitive modulation in healthy human subjects. There is evidence that fMRI signal changes can be elicited in the parietal cortex by stimulation of single mechanoceptive afferent fibers at suprathreshold intensities for conscious perception. Positive linear relationships between the amplitude or the spatial extents of BOLD fMRI signal changes, stimulus intensity and the perceived touch or pain intensity have been described in different brain areas. Some recent fMRI studies addressed the role of cortical areas in somatosensory perception by comparing the time course of cortical activity evoked by different kinds of stimuli with the temporal features of touch, heat or pain perception. Moreover, parametric single-trial functional MRI designs have been adopted in order to disentangle subprocesses within the nociceptive system.

Available evidence suggest that studies that combine fMRI with psychophysical methods may provide a valuable approach for understanding complex perceptual mechanisms and top-down modulation of the somatosensory system by cognitive factors specifically related to selective attention and to anticipation. The brain networks underlying somatosensory perception are complex and highly distributed. A deeper understanding of perceptual-related brain mechanisms therefore requires new approaches suited to investigate the spatial and temporal dynamics of activation in different brain regions and their functional interaction.