Laura Ceolin, Adam J Schwarz, Alessandro Gozzi, Torsten Reese and Angelo Bifone.
Effects of cocaine on blood flow and oxygen metabolism in the rat brain: implications for phMRI. Magnetic Resonance Imaging 25(6):795–800, 2007.
Abstract The effects of cocaine on cerebral blood flow and tissue oxygen levels in the rat brain were investigated with concurrent laser Doppler flowmetry and fluorescence quenching spectroscopy. Responses elicited by mild hypercapnia were used as calibration to assess the effects of cocaine on oxidative metabolism. Intravenous cocaine challenge of 0.5 mg/kg induced significant increases in tissular oxygenation and perfusion in all regions investigated (primary motor cortex, medial prefrontal cortex and dorsal striatum). Mild hypercapnia, a challenge that affects haemodynamics but not metabolism, elicited comparable changes in blood flow but substantially larger changes in tissue oxygen levels. These differences in tissue oxygen build-up suggest that increased oxidative metabolism is a significant component of the cerebral metabolic response to acute cocaine challenge. The implications for the interpretation of pharmacological MRI data are discussed. The effects of cocaine on cerebral blood flow and tissue oxygen levels in the rat brain were investigated with concurrent laser Doppler flowmetry and fluorescence quenching spectroscopy. Responses elicited by mild hypercapnia were used as calibration to assess the effects of cocaine on oxidative metabolism. Intravenous cocaine challenge of 0.5 mg/kg induced significant increases in tissular oxygenation and perfusion in all regions investigated (primary motor cortex, medial prefrontal cortex and dorsal striatum). Mild hypercapnia, a challenge that affects haemodynamics but not metabolism, elicited comparable changes in blood flow but substantially larger changes in tissue oxygen levels. These differences in tissue oxygen build-up suggest that increased oxidative metabolism is a significant component of the cerebral metabolic response to acute cocaine challenge. The implications for the interpretation of pharmacological MRI data are discussed.
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G D Iannetti and Richard G Wise.
BOLD functional MRI in disease and pharmacological studies: room for improvement?. Magnetic Resonance Imaging 25(6):978–988, 2007.
Abstract In the past decade the use of blood oxygen level-dependent (BOLD) fMRI to investigate the effect of diseases and pharmacological agents on brain activity has increased greatly. BOLD fMRI does not measure neural activity directly, but relies on a cascade of physiological events linking neural activity to the generation of MRI signal. However, most of the disease and pharmacological studies performed so far have interpreted changes in BOLD fMRI as ?brain activation,? ignoring the potential confounds that can arise through drug- or disease-induced modulation of events downstream of the neural activity. This issue is especially serious in diseases (like multiple sclerosis, brain tumours and stroke) and drugs (like anaesthetics or those with a vascular action) that are known to influence these physiological events.Here we provide evidence that, to extract meaningful information on brain activity in patient and pharmacological BOLD fMRI studies, it is important to identify, characterise and possibly correct these influences that potentially confound the results. We suggest a series of experimental measures to improve the interpretability of BOLD fMRI studies. We have ranked these according to their potential information and current practical feasibility.First-line, necessary improvements consist of (1) the inclusion of one or more control tasks, and (2) the recording of physiological parameters during scanning and subsequent correction of possible between-group differences. Second-line, highly recommended importants aim to make the results of a patient or drug BOLD study more interpretable and include the assessment of (1) baseline brain perfusion, (2) vascular reactivity, (3) the inclusion of stimulus-related perfusion fMRI and (4) the recording of electrophysiological responses to the stimulus of interest. Finally, third-line, desirable improvements consist of the inclusion of (1) simultaneous EEG?fMRI, (2) cerebral blood volume and (3) rate of metabolic oxygen consumption measurements and, when relevant, (4) animal studies investigating signalling between neural cells and blood vessels. In the past decade the use of blood oxygen level-dependent (BOLD) fMRI to investigate the effect of diseases and pharmacological agents on brain activity has increased greatly. BOLD fMRI does not measure neural activity directly, but relies on a cascade of physiological events linking neural activity to the generation of MRI signal. However, most of the disease and pharmacological studies performed so far have interpreted changes in BOLD fMRI as ?brain activation,? ignoring the potential confounds that can arise through drug- or disease-induced modulation of events downstream of the neural activity. This issue is especially serious in diseases (like multiple sclerosis, brain tumours and stroke) and drugs (like anaesthetics or those with a vascular action) that are known to influence these physiological events.Here we provide evidence that, to extract meaningful information on brain activity in patient and pharmacological BOLD fMRI studies, it is important to identify, characterise and possibly correct these influences that potentially confound the results. We suggest a series of experimental measures to improve the interpretability of BOLD fMRI studies. We have ranked these according to their potential information and current practical feasibility.First-line, necessary improvements consist of (1) the inclusion of one or more control tasks, and (2) the recording of physiological parameters during scanning and subsequent correction of possible between-group differences. Second-line, highly recommended importants aim to make the results of a patient or drug BOLD study more interpretable and include the assessment of (1) baseline brain perfusion, (2) vascular reactivity, (3) the inclusion of stimulus-related perfusion fMRI and (4) the recording of electrophysiological responses to the stimulus of interest. Finally, third-line, desirable improvements consist of the inclusion of (1) simultaneous EEG?fMRI, (2) cerebral blood volume and (3) rate of metabolic oxygen consumption measurements and, when relevant, (4) animal studies investigating signalling between neural cells and blood vessels.
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Richard G Wise, Brandon J Lujan, Petra Schweinhardt, Guy D Peskett, Richard Rogers and Irene Tracey.
The anxiolytic effects of midazolam during anticipation to pain revealed using fMRI. Magnetic Resonance Imaging 25(6):801–810, 2007.
Abstract Background and PurposeFunctional neuroimaging can distinguish components of the pain experience associated with anticipation to pain from those associated with the experience of pain itself. Anticipation to pain is thought to increase the suffering of chronic pain patients. Inappropriate anxiety, of which anticipation is a component, is also a cause of disability. We present a pharmacological functional magnetic resonance imaging (fMRI) study in which we investigate the selective modulation by midazolam of brain activity associated with anticipation to pain compared to pain itself. Background and PurposeFunctional neuroimaging can distinguish components of the pain experience associated with anticipation to pain from those associated with the experience of pain itself. Anticipation to pain is thought to increase the suffering of chronic pain patients. Inappropriate anxiety, of which anticipation is a component, is also a cause of disability. We present a pharmacological functional magnetic resonance imaging (fMRI) study in which we investigate the selective modulation by midazolam of brain activity associated with anticipation to pain compared to pain itself.
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Heeswijk, B Ruud, Sabrina Laus, Florence D Morgenthaler and Rolf Gruetter.
Relaxivity of Gd-based contrast agents on X nuclei with long intrinsic relaxation times in aqueous solutions. Magnetic Resonance Imaging 25(6):821–825, 2007.
Abstract The relaxivity of commercially available gadolinium (Gd)-based contrast agents was studied for X-nuclei resonances with long intrinsic relaxation times ranging from 6 s to several hundred seconds. Omniscan in pure 13C formic acid had a relaxivity of 2.9 mM?1 s?1, whereas its relaxivity on glutamate C1 and C5 in aqueous solution was ?0.5 mM?1 s?1. Both relaxivities allow the preparation of solutions with a predetermined short T1 and suggest that in vitro substantial sensitivity gains in their measurement can be achieved.6Li has a long intrinsic relaxation time, on the order of several minutes, which was strongly affected by the contrast agents. Relaxivity ranged from ?0.1 mM?1 s?1 for Omniscan to 0.3 for Magnevist, whereas the relaxivity of Gd-DOTP was at 11 mM?1 s?1, which is two orders of magnitude higher. Overall, these experiments suggest that the presence of 0.1- to 10-?M contrast agents should be detectable, provided sufficient sensitivity is available, such as that afforded by hyperpolarization, recently introduced to in vivo imaging. The relaxivity of commercially available gadolinium (Gd)-based contrast agents was studied for X-nuclei resonances with long intrinsic relaxation times ranging from 6 s to several hundred seconds. Omniscan in pure 13C formic acid had a relaxivity of 2.9 mM?1 s?1, whereas its relaxivity on glutamate C1 and C5 in aqueous solution was ?0.5 mM?1 s?1. Both relaxivities allow the preparation of solutions with a predetermined short T1 and suggest that in vitro substantial sensitivity gains in their measurement can be achieved.6Li has a long intrinsic relaxation time, on the order of several minutes, which was strongly affected by the contrast agents. Relaxivity ranged from ?0.1 mM?1 s?1 for Omniscan to 0.3 for Magnevist, whereas the relaxivity of Gd-DOTP was at 11 mM?1 s?1, which is two orders of magnitude higher. Overall, these experiments suggest that the presence of 0.1- to 10-?M contrast agents should be detectable, provided sufficient sensitivity is available, such as that afforded by hyperpolarization, recently introduced to in vivo imaging.
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Na Zhang, John C Gore, Li M Chen and Malcolm J Avison.
Dependence of BOLD signal change on tactile stimulus intensity in SI of primates. Magnetic Resonance Imaging 25(6):784–794, 2007.
Abstract Recently, we have demonstrated that the fine-digit topography (millimeter sized) previously identified in the primary somatosensory cortex (SI), using electrophysiology and intrinsic signal optical imaging, can also be mapped with submillimeter resolution using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging at high field. In the present study, we have examined the dependence of BOLD signal response on stimulus intensity in two subregions of SI, Areas 3b and 1. In a region(s)-of-interest (ROI) analysis of Area 3b, BOLD signal amplitude increased linearly with increasing amplitude of an 8-Hz vibrotactile stimulus, and BOLD signal was sustained throughout the stimulation period. In contrast, in Area 1, a significant BOLD signal response was only observed with more intense stimuli, and ROI analysis of the dependence of BOLD response showed no significant dependence on stimulus intensity. In addition, activation was not sustained throughout the period of stimulation. Differing responses of Areas 3b and 1 suggest potentially divergent roles for subregions of SI cortices in vibrotactile intensity encoding. Moreover, this study underscores the importance of imaging at small spatial scales. In this case, such high-resolution imaging allows differentiation between area-specific roles in intensity encoding and identifies anatomic targets for detailed electrophysiological studies of somatosensory neuronal populations with different coding properties. These experiments illustrate the value of nonhuman primates for characterizing the dependence of the BOLD signal response on stimulus parameters and on underlying neural response properties. Recently, we have demonstrated that the fine-digit topography (millimeter sized) previously identified in the primary somatosensory cortex (SI), using electrophysiology and intrinsic signal optical imaging, can also be mapped with submillimeter resolution using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging at high field. In the present study, we have examined the dependence of BOLD signal response on stimulus intensity in two subregions of SI, Areas 3b and 1. In a region(s)-of-interest (ROI) analysis of Area 3b, BOLD signal amplitude increased linearly with increasing amplitude of an 8-Hz vibrotactile stimulus, and BOLD signal was sustained throughout the stimulation period. In contrast, in Area 1, a significant BOLD signal response was only observed with more intense stimuli, and ROI analysis of the dependence of BOLD response showed no significant dependence on stimulus intensity. In addition, activation was not sustained throughout the period of stimulation. Differing responses of Areas 3b and 1 suggest potentially divergent roles for subregions of SI cortices in vibrotactile intensity encoding. Moreover, this study underscores the importance of imaging at small spatial scales. In this case, such high-resolution imaging allows differentiation between area-specific roles in intensity encoding and identifies anatomic targets for detailed electrophysiological studies of somatosensory neuronal populations with different coding properties. These experiments illustrate the value of nonhuman primates for characterizing the dependence of the BOLD signal response on stimulus parameters and on underlying neural response properties.
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Nikolaus Weiskopf, Ranganatha Sitaram, Oliver Josephs, Ralf Veit, Frank Scharnowski, Rainer Goebel, Niels Birbaumer, Ralf Deichmann and Klaus Mathiak.
Real-time functional magnetic resonance imaging: methods and applications. Magnetic Resonance Imaging 25(6):989–1003, 2007.
Abstract Functional magnetic resonance imaging (fMRI) has been limited by time-consuming data analysis and a low signal-to-noise ratio, impeding online analysis. Recent advances in acquisition techniques, computational power and algorithms increased the sensitivity and speed of fMRI significantly, making real-time analysis and display of fMRI data feasible. So far, most reports have focused on the technical aspects of real-time fMRI (rtfMRI). Here, we provide an overview of the different major areas of applications that became possible with rtfMRI: online analysis of single-subject data provides immediate quality assurance and functional localizers guiding the main fMRI experiment or surgical interventions. In teaching, rtfMRI naturally combines all essential parts of a neuroimaging experiment, such as experimental design, data acquisition and analysis, while adding a high level of interactivity. Thus, the learning of essential knowledge required to conduct functional imaging experiments is facilitated. rtfMRI allows for brain?computer interfaces (BCI) with a high spatial and temporal resolution and whole-brain coverage. Recent studies have shown that such BCI can be used to provide online feedback of the blood-oxygen-level-dependent signal and to learn the self-regulation of local brain activity. Preliminary evidence suggests that this local self-regulation can be used as a new paradigm in cognitive neuroscience to study brain plasticity and the functional relevance of brain areas, even being potentially applicable for psychophysiological treatment. Functional magnetic resonance imaging (fMRI) has been limited by time-consuming data analysis and a low signal-to-noise ratio, impeding online analysis. Recent advances in acquisition techniques, computational power and algorithms increased the sensitivity and speed of fMRI significantly, making real-time analysis and display of fMRI data feasible. So far, most reports have focused on the technical aspects of real-time fMRI (rtfMRI). Here, we provide an overview of the different major areas of applications that became possible with rtfMRI: online analysis of single-subject data provides immediate quality assurance and functional localizers guiding the main fMRI experiment or surgical interventions. In teaching, rtfMRI naturally combines all essential parts of a neuroimaging experiment, such as experimental design, data acquisition and analysis, while adding a high level of interactivity. Thus, the learning of essential knowledge required to conduct functional imaging experiments is facilitated. rtfMRI allows for brain?computer interfaces (BCI) with a high spatial and temporal resolution and whole-brain coverage. Recent studies have shown that such BCI can be used to provide online feedback of the blood-oxygen-level-dependent signal and to learn the self-regulation of local brain activity. Preliminary evidence suggests that this local self-regulation can be used as a new paradigm in cognitive neuroscience to study brain plasticity and the functional relevance of brain areas, even being potentially applicable for psychophysiological treatment.
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Andrew M Peters, Matthew J Brookes, Frank G Hoogenraad, Penny A Gowland, Susan T Francis, Peter G Morris and Richard Bowtell.
T₂* measurements in human brain at 1.5, 3 and 7 T. Magnetic Resonance Imaging 25(6):748–753, 2007.
Abstract Measurements have been carried out in six subjects at magnetic fields of 1.5, 3 and 7 T, with the aim of characterizing the variation of T2* with field strength in human brain. Accurate measurement of T2* in the presence of macroscopic magnetic field inhomogeneity is problematic due to signal decay resulting from through-slice dephasing. The approach employed here allowed the signal decay due to through-slice dephasing to be characterized and removed from data, thus facilitating an accurate measurement of T2* even at ultrahigh field. Using double inversion recovery turbo spin-echo images for tissue classification, an analysis of T2* relaxation times in cortical grey matter and white matter was carried out, along with an evaluation of the variation of T2* with field strength in the caudate nucleus and putamen. The results show an approximately linear increase in relaxation rate R2* with field strength for all tissues, leading to a greater range of relaxation times across tissue types at 7 T that can be exploited in high-resolution T2*-weighted imaging. Measurements have been carried out in six subjects at magnetic fields of 1.5, 3 and 7 T, with the aim of characterizing the variation of T2* with field strength in human brain. Accurate measurement of T2* in the presence of macroscopic magnetic field inhomogeneity is problematic due to signal decay resulting from through-slice dephasing. The approach employed here allowed the signal decay due to through-slice dephasing to be characterized and removed from data, thus facilitating an accurate measurement of T2* even at ultrahigh field. Using double inversion recovery turbo spin-echo images for tissue classification, an analysis of T2* relaxation times in cortical grey matter and white matter was carried out, along with an evaluation of the variation of T2* with field strength in the caudate nucleus and putamen. The results show an approximately linear increase in relaxation rate R2* with field strength for all tissues, leading to a greater range of relaxation times across tissue types at 7 T that can be exploited in high-resolution T2*-weighted imaging.
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Marco Bozzali and Andrea Cherubini.
Diffusion tensor MRI to investigate dementias: a brief review. Magnetic Resonance Imaging 25(6):969–977, 2007.
Abstract Diffusion tensor magnetic resonance imaging (DT-MRI) is a powerful quantitative technique with the ability to detect in vivo microscopic characteristics and abnormalities of brain tissue. It has been successfully applied to a number of neurological conditions, such as stroke, multiple sclerosis and brain tumors, providing information otherwise inaccessible on the pathological substrates. DT-MRI has also been used to study patients with cognitive decline, mainly those with Alzheimer's disease. Several image-analysis approaches have been employed, including region of interest, histogram, voxel-based analyses and DT-MRI-based tractography. Specific patterns of spatial distribution of tissue damage and correlations with neuropsychological measures have been reported. This review focuses on the use of DT-MRI to investigate dementias. The main clinical results and the different methods of image analysis will be overviewed and discussed. Diffusion tensor magnetic resonance imaging (DT-MRI) is a powerful quantitative technique with the ability to detect in vivo microscopic characteristics and abnormalities of brain tissue. It has been successfully applied to a number of neurological conditions, such as stroke, multiple sclerosis and brain tumors, providing information otherwise inaccessible on the pathological substrates. DT-MRI has also been used to study patients with cognitive decline, mainly those with Alzheimer's disease. Several image-analysis approaches have been employed, including region of interest, histogram, voxel-based analyses and DT-MRI-based tractography. Specific patterns of spatial distribution of tissue damage and correlations with neuropsychological measures have been reported. This review focuses on the use of DT-MRI to investigate dementias. The main clinical results and the different methods of image analysis will be overviewed and discussed.
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Axel Oeltermann, Mark A Augath and Nikos K Logothetis.
Simultaneous recording of neuronal signals and functional NMR imaging. Magnetic Resonance Imaging 25(6):760–774, 2007.
Abstract We recently directly examined the relationship between blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signals and neural activity by simultaneously acquiring electrophysiological and fMRI data from monkeys in a 4.7-T vertical scanner (Logothetis NK, Pauls J, Augath MA, Trinath T, Oeltermann A. Neurophysiological investigation of the basis of the fMRI signal. Nature 2001;412:150?157). Acquisition of electrical signals in the microvolt range required extensive development of new recording hardware, including electrodes, microdrives, signal conditioning and interference compensation devices. Here, we provide a detailed description of the interference compensation system that can be used to record field and action potentials intracortically within a high-field scanner. We recently directly examined the relationship between blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signals and neural activity by simultaneously acquiring electrophysiological and fMRI data from monkeys in a 4.7-T vertical scanner (Logothetis NK, Pauls J, Augath MA, Trinath T, Oeltermann A. Neurophysiological investigation of the basis of the fMRI signal. Nature 2001;412:150?157). Acquisition of electrical signals in the microvolt range required extensive development of new recording hardware, including electrodes, microdrives, signal conditioning and interference compensation devices. Here, we provide a detailed description of the interference compensation system that can be used to record field and action potentials intracortically within a high-field scanner.
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Fahad Sultan, Mark Augath and Nikos Logothetis.
BOLD sensitivity to cortical activation induced by microstimulation: comparison to visual stimulation. Magnetic Resonance Imaging 25(6):754–759, 2007.
Abstract Electrical microstimulation via intracortical electrodes is a widely used method for deducing functions of the brain. In this study, we compared the spatial extent and amplitude of BOLD responses evoked by intracortical electrical stimulation in primary visual cortex with BOLD activations evoked by visual stimulation. The experiments were performed in anesthetized rhesus monkeys. Visual stimulation yielded activities larger than predicted from the well-established visual magnification factor. However, electrical microstimulation yielded an even greater spread of the BOLD response. Our results confirm that the effects of electrical microstimulation extend beyond the brain region expected to be excited by direct current spread. Electrical microstimulation via intracortical electrodes is a widely used method for deducing functions of the brain. In this study, we compared the spatial extent and amplitude of BOLD responses evoked by intracortical electrical stimulation in primary visual cortex with BOLD activations evoked by visual stimulation. The experiments were performed in anesthetized rhesus monkeys. Visual stimulation yielded activities larger than predicted from the well-established visual magnification factor. However, electrical microstimulation yielded an even greater spread of the BOLD response. Our results confirm that the effects of electrical microstimulation extend beyond the brain region expected to be excited by direct current spread.
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Annalena Venneri.
Imaging treatment effects in Alzheimer's disease. Magnetic Resonance Imaging 25(6):953–968, 2007.
Abstract Alzheimer's disease (AD) is the commonest form of degenerative dementia and is characterised by progressive cognitive decline. Despite extensive research, the cause of AD is unknown and there is no cure at present. Of the deficits found in AD, that affecting the cholinergic neurotransmitter system is the best established and the only one translated into symptomatic treatment. Cholinergic enhancement with cholinesterase inhibitor (ChEI) drugs has been achieved and their efficacy and safety ascertained by conventional clinical trials. The mechanism of action of these drugs, however, is not well understood. Imaging with SPECT, PET, MRI and fMRI after treatment has clarified what happens in the brains of those AD patients treated with ChEI drugs. Studies with these techniques have identified increases in brain blood flow and glucose metabolism, restoration of nicotinic receptor function and re-establishment of task-related regional brain activation in response to cognitive stimulation after treatment. Structural MRI studies have explained, to some degree, why only a proportion of patients benefits from ChEI treatment and there is some evidence that some ChEI drugs might be neuroprotective.There are, however, many unsolved problems. Timing of treatment intervention to obtain maximum response and the determinants of treatment response are mostly unknown. It is also unclear whether administration of treatment in those patients who have no potential for response accelerates disease progression. These issues cannot be solved by conventional clinical trials. Pharmacoimaging studies could assist the development and refinement of drugs to treat those diseases, such as AD, which affect the central nervous system. Alzheimer's disease (AD) is the commonest form of degenerative dementia and is characterised by progressive cognitive decline. Despite extensive research, the cause of AD is unknown and there is no cure at present. Of the deficits found in AD, that affecting the cholinergic neurotransmitter system is the best established and the only one translated into symptomatic treatment. Cholinergic enhancement with cholinesterase inhibitor (ChEI) drugs has been achieved and their efficacy and safety ascertained by conventional clinical trials. The mechanism of action of these drugs, however, is not well understood. Imaging with SPECT, PET, MRI and fMRI after treatment has clarified what happens in the brains of those AD patients treated with ChEI drugs. Studies with these techniques have identified increases in brain blood flow and glucose metabolism, restoration of nicotinic receptor function and re-establishment of task-related regional brain activation in response to cognitive stimulation after treatment. Structural MRI studies have explained, to some degree, why only a proportion of patients benefits from ChEI treatment and there is some evidence that some ChEI drugs might be neuroprotective.There are, however, many unsolved problems. Timing of treatment intervention to obtain maximum response and the determinants of treatment response are mostly unknown. It is also unclear whether administration of treatment in those patients who have no potential for response accelerates disease progression. These issues cannot be solved by conventional clinical trials. Pharmacoimaging studies could assist the development and refinement of drugs to treat those diseases, such as AD, which affect the central nervous system.
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Adam J Schwarz, Alessandro Gozzi, Torsten Reese, Christian A Heidbreder and Angelo Bifone.
Pharmacological modulation of functional connectivity: the correlation structure underlying the phMRI response to d-amphetamine modified by selective dopamine D₃ receptor antagonist SB277011A. Magnetic Resonance Imaging 25(6):811–820, 2007.
Abstract Pharmacological MRI (phMRI) experiments utilise fMRI time series methods to map the central effect of pharmaceutical compounds. The typical univariate maps may, however, integrate the effects of several different neurotransmitter systems or underlying mechanisms. The results may thus be spatially and/or mechanistically nonspecific. Intersubject correlation analysis based on the phMRI response amplitude can more directly identify patterns of functional connectivity underlying the central effects of an acutely administered compound. In this article, we extend this approach to experiments where the effects of one compound in modulating the response to another are of interest. Specifically, we show a modulation of the correlation structure of a probe compound (d-amphetamine) by pretreatment with the selective dopamine D3 receptor antagonist SB277011A in the rat. The strongest modifications in the correlation patterns occurred in connection with the ventral tegmental area, the source of mesolimbic dopamine projections and a key substrate in the reward system. Pharmacological MRI (phMRI) experiments utilise fMRI time series methods to map the central effect of pharmaceutical compounds. The typical univariate maps may, however, integrate the effects of several different neurotransmitter systems or underlying mechanisms. The results may thus be spatially and/or mechanistically nonspecific. Intersubject correlation analysis based on the phMRI response amplitude can more directly identify patterns of functional connectivity underlying the central effects of an acutely administered compound. In this article, we extend this approach to experiments where the effects of one compound in modulating the response to another are of interest. Specifically, we show a modulation of the correlation structure of a probe compound (d-amphetamine) by pretreatment with the selective dopamine D3 receptor antagonist SB277011A in the rat. The strongest modifications in the correlation patterns occurred in connection with the ventral tegmental area, the source of mesolimbic dopamine projections and a key substrate in the reward system.
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Soléakhéna Ken, Giancarlo Di Gennaro, Giovanni Giulietti, Fabio Sebastiano, Diego De Carli, Girolamo Garreffa, Claudio Colonnese, Roberto Passariello, Jean-Albert Lotterie and Bruno Maraviglia.
Quantitative evaluation for brain CT/MRI coregistration based on maximization of mutual information in patients with focal epilepsy investigated with subdural electrodes. Magnetic Resonance Imaging 25(6):883–888, 2007.
Abstract Patients with drug-resistant focal epilepsy may require intracranial investigations with subdural electrodes. These must be correctly localized with respect to the brain cortical surface and require appropriate monitoring. For this purpose, coregistration techniques, which fuse preimplantation 3D magnetic resonance imaging scans with postimplantation computed tomography scans, have been implemented. In order to reduce localization errors due to the fusion process, we used a coregistration method based on the maximization of mutual information (MI) in 11 patients with extratemporal epilepsy who were invasively investigated. Our registration method is based on three processing steps: rigid-body transformation for coregistration, computation of MI as a similarity measure and the use of the Downhill Simplex optimization method. After consistency analysis, the shift of the registration method reached 0.14±0.27 mm in translation and 0.03±0.14° in rotation, and the accuracies assessed on voxels of skull surface and voxels of the center of the brain volume were 1.42±0.61 and 1.15±0.53 mm, respectively. The accuracy of the fusion process reached submillimeter range, and results were considered reliable for surgical planning in all studied patients. Patients with drug-resistant focal epilepsy may require intracranial investigations with subdural electrodes. These must be correctly localized with respect to the brain cortical surface and require appropriate monitoring. For this purpose, coregistration techniques, which fuse preimplantation 3D magnetic resonance imaging scans with postimplantation computed tomography scans, have been implemented. In order to reduce localization errors due to the fusion process, we used a coregistration method based on the maximization of mutual information (MI) in 11 patients with extratemporal epilepsy who were invasively investigated. Our registration method is based on three processing steps: rigid-body transformation for coregistration, computation of MI as a similarity measure and the use of the Downhill Simplex optimization method. After consistency analysis, the shift of the registration method reached 0.14±0.27 mm in translation and 0.03±0.14° in rotation, and the accuracies assessed on voxels of skull surface and voxels of the center of the brain volume were 1.42±0.61 and 1.15±0.53 mm, respectively. The accuracy of the fusion process reached submillimeter range, and results were considered reliable for surgical planning in all studied patients.
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Axel Oeltermann, Shih-Pi Ku and Nikos K Logothetis.
A novel functional magnetic resonance imaging compatible search-coil eye-tracking system. Magnetic Resonance Imaging 25(6):913–922, 2007.
Abstract Measuring eye movements (EMs) using the search-coil eye-tracking technique is superior to video-based infrared methods [Collewijn H, van der Mark F, Jansen TC. Precise recording of human eye movements. Vision Res 1975;15(3):447-50], which suffer from the instability of pupil size, blinking behavior and lower temporal resolution. However, no conventional functional magnetic resonance imaging (fMRI)-compatible search-coil eye tracker exists. The main problems for such a technique are the interaction between the transmitter coils and the magnetic gradients used for imaging as well as the limited amount of space in a scanner. Here we present an approach to overcome these problems and we demonstrate a method to record EMs in an MRI scanner using a search coil. The system described has a spatial resolution of 0.07° (visual angle) and a high temporal resolution (22 kHz). The transmitter coils are integrated into the visual presentation system and the control/analysis unit is portable, which enables us to integrate the eye tracker with an MRI scanner. Our tests demonstrate low noise in the recorded eye traces and scanning with minimal artifact. Furthermore, the induced current in the search coil caused by the RF pulses does not lead to measurable heating. Altogether, this MR-compatible search-coil eye tracker can be used to precisely monitor EMs with high spatial and temporal resolution during fMRI. It can therefore be of great importance for studies requiring accurate fixation of a target, or measurement and study of the subject's oculomotor system. Measuring eye movements (EMs) using the search-coil eye-tracking technique is superior to video-based infrared methods [Collewijn H, van der Mark F, Jansen TC. Precise recording of human eye movements. Vision Res 1975;15(3):447-50], which suffer from the instability of pupil size, blinking behavior and lower temporal resolution. However, no conventional functional magnetic resonance imaging (fMRI)-compatible search-coil eye tracker exists. The main problems for such a technique are the interaction between the transmitter coils and the magnetic gradients used for imaging as well as the limited amount of space in a scanner. Here we present an approach to overcome these problems and we demonstrate a method to record EMs in an MRI scanner using a search coil. The system described has a spatial resolution of 0.07° (visual angle) and a high temporal resolution (22 kHz). The transmitter coils are integrated into the visual presentation system and the control/analysis unit is portable, which enables us to integrate the eye tracker with an MRI scanner. Our tests demonstrate low noise in the recorded eye traces and scanning with minimal artifact. Furthermore, the induced current in the search coil caused by the RF pulses does not lead to measurable heating. Altogether, this MR-compatible search-coil eye tracker can be used to precisely monitor EMs with high spatial and temporal resolution during fMRI. It can therefore be of great importance for studies requiring accurate fixation of a target, or measurement and study of the subject's oculomotor system.
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Cornelia Laule, Shannon Heather Kolind, Thorarin Albert Bjarnason, David Kwok Boon Li and Alex Lloyd MacKay.
In vivo multiecho T₂ relaxation measurements using variable TR to decrease scan time. Magnetic Resonance Imaging 25(6):834–839, 2007.
Abstract Multiecho T2 relaxation measurements to determine geometric mean T2 (GMT2) and myelin water fraction (MWF) are lengthy, resulting in increased motion artefacts from patient discomfort and reduced patient compliance. The goal of this study was to shorten the acquisition time for multiecho T2 measurements without affecting T1 weighting by varying TR across k-space. Six phantoms and 10 healthy volunteers were imaged with both a constant TR and a variable TR multiecho T2 sequence. T1 weighting was determined by TR at the center of k-space; for variable TR measurement, TR was shortened linearly from the center to the edges of k-space. Phantoms showed excellent agreement for proton density and GMT2 between constant and variable TR measurements. No significant differences were found in proton density or MWF for any of the brain structures between the two measurements. The average GMT2 over all structures between the two experiments was not significantly different. In summary, with the variable TR approach, scan time was reduced by >20%, with minimal loss of image resolution and no significant affect on proton density, MWF or GMT2. Multiecho T2 relaxation measurements to determine geometric mean T2 (GMT2) and myelin water fraction (MWF) are lengthy, resulting in increased motion artefacts from patient discomfort and reduced patient compliance. The goal of this study was to shorten the acquisition time for multiecho T2 measurements without affecting T1 weighting by varying TR across k-space. Six phantoms and 10 healthy volunteers were imaged with both a constant TR and a variable TR multiecho T2 sequence. T1 weighting was determined by TR at the center of k-space; for variable TR measurement, TR was shortened linearly from the center to the edges of k-space. Phantoms showed excellent agreement for proton density and GMT2 between constant and variable TR measurements. No significant differences were found in proton density or MWF for any of the brain structures between the two measurements. The average GMT2 over all structures between the two experiments was not significantly different. In summary, with the variable TR approach, scan time was reduced by >20%, with minimal loss of image resolution and no significant affect on proton density, MWF or GMT2.
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Josef Pfeuffer, Amir Shmuel, Georgios A Keliris, Thomas Steudel, Hellmut Merkle and Nikos K Logothetis.
Functional MR imaging in the awake monkey: effects of motion on dynamic off-resonance and processing strategies. Magnetic Resonance Imaging 25(6):869–882, 2007.
Abstract Functional MR imaging of the alert, behaving monkey is being used more and more often to detect activation patterns and guide electrophysiological research investigating the neural basis of behavior. Several labs have reported fMRI data from the awake monkey, but none of them has studied and systematically corrected the effects of monkeys' motion on fMRI time series. In this study, a significant refinement of acquisition and correction strategies is reported that can be used to minimize magnetic susceptibility artifacts induced by respiration and by jaw and body movement. Real-time acquisition of sensor signals (e.g., signals induced by jaw and body movement) and MR navigator data were combined to optimize fMRI signal-correction strategies. Within trials, the artifact-induced off-resonance changes were small and mainly reflected the effects of respiration; between trials, movements caused major changes of global frequency and shim (>20 Hz/cm). Several methods were used to assess the stability of the fMRI series: k-space analysis (?dynamic intensity and off-resonance changes in k-space?, dubbed DICK and DORK) and image analysis using a Laplace operator and a center-of-mass metric. The variability between trials made it essential to correct for inter-trial variations. On the other hand, images were sufficiently stable with our approach to perform fMRI evaluations on single trials before averaging of trials. Different motion correction strategies were compared: DORK, McFLIRT (rigid body model with three translations and three rotations) and 2D image alignment based on a center-of-mass detection (in-plane translation). The latter yielded the best results and proved to be fast and robust for intra- and inter-trial alignment. Finally, fMRI in the behaving monkey was tested for spatial and temporal reproducibility on a trial-to-trial basis. Highly activated voxels also displayed good reproducibility between trials. On average, the BOLD amplitude response to a short 3-s visual stimulus was close to 2%. Functional MR imaging of the alert, behaving monkey is being used more and more often to detect activation patterns and guide electrophysiological research investigating the neural basis of behavior. Several labs have reported fMRI data from the awake monkey, but none of them has studied and systematically corrected the effects of monkeys' motion on fMRI time series. In this study, a significant refinement of acquisition and correction strategies is reported that can be used to minimize magnetic susceptibility artifacts induced by respiration and by jaw and body movement. Real-time acquisition of sensor signals (e.g., signals induced by jaw and body movement) and MR navigator data were combined to optimize fMRI signal-correction strategies. Within trials, the artifact-induced off-resonance changes were small and mainly reflected the effects of respiration; between trials, movements caused major changes of global frequency and shim (>20 Hz/cm). Several methods were used to assess the stability of the fMRI series: k-space analysis (?dynamic intensity and off-resonance changes in k-space?, dubbed DICK and DORK) and image analysis using a Laplace operator and a center-of-mass metric. The variability between trials made it essential to correct for inter-trial variations. On the other hand, images were sufficiently stable with our approach to perform fMRI evaluations on single trials before averaging of trials. Different motion correction strategies were compared: DORK, McFLIRT (rigid body model with three translations and three rotations) and 2D image alignment based on a center-of-mass detection (in-plane translation). The latter yielded the best results and proved to be fast and robust for intra- and inter-trial alignment. Finally, fMRI in the behaving monkey was tested for spatial and temporal reproducibility on a trial-to-trial basis. Highly activated voxels also displayed good reproducibility between trials. On average, the BOLD amplitude response to a short 3-s visual stimulus was close to 2%.
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Petra Ritter, Robert Becker, Christine Graefe and Arno Villringer.
Evaluating gradient artifact correction of EEG data acquired simultaneously with fMRI. Magnetic Resonance Imaging 25(6):923–932, 2007.
Abstract Simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) has become a widely used application in spite of EEG perturbations due to electromagnetic interference in the MR environment. The most prominent and disturbing artifacts in the EEG are caused by the alternating magnetic fields (gradients) of the MR scanner. Different methods for gradient artifact correction have been developed. Here we propose an approach for the systematic evaluation and comparison of these gradient artifact correction methods. Exemplarily, we evaluate different algorithms all based on artifact template subtraction ? the currently most established means of gradient artifact removal. We introduce indices for the degree of gradient artifact reduction and physiological signal preservation. The combination of both indices was used as a measure for the overall performance of gradient artifact removal and was shown to be useful in identifying problems during artifact removal. We demonstrate that the evaluation as proposed here allows to reveal frequency-band specific performance differences among the algorithms. This emphasizes the importance of carefully selecting the artifact correction method appropriate for the respective case. Simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) has become a widely used application in spite of EEG perturbations due to electromagnetic interference in the MR environment. The most prominent and disturbing artifacts in the EEG are caused by the alternating magnetic fields (gradients) of the MR scanner. Different methods for gradient artifact correction have been developed. Here we propose an approach for the systematic evaluation and comparison of these gradient artifact correction methods. Exemplarily, we evaluate different algorithms all based on artifact template subtraction ? the currently most established means of gradient artifact removal. We introduce indices for the degree of gradient artifact reduction and physiological signal preservation. The combination of both indices was used as a measure for the overall performance of gradient artifact removal and was shown to be useful in identifying problems during artifact removal. We demonstrate that the evaluation as proposed here allows to reveal frequency-band specific performance differences among the algorithms. This emphasizes the importance of carefully selecting the artifact correction method appropriate for the respective case.
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Luigi Bianchi, Lucia Rita Quitadamo, Maria Grazia Marciani, Bruno Maraviglia, Manuel Abbafati and Girolamo Garreffa.
How the NPX data format handles EEG data acquired simultaneously with fMRI. Magnetic Resonance Imaging 25(6):1011–1014, 2007.
Abstract There is a growing interest in combining EEG and (f)MRI data as they provide complementary information: EEG is characterized by a high temporal resolution but poor spatial one, while fMRI is characterized by a high spatial resolution but low temporal one. However, while a standard file format for storing EEG data is available since over a decade, it does not fulfill the needs of modern protocols and devices such as those involved in simultaneous EEG and fMRI recordings. The main reasons are the limited bit resolution, some difficulties encountered in handling and storing acquisition events or trace markers for off-line analyses and the impossibility to add some protocol-specific information that is not considered in the actual data formats. This, among others, hinders the release of free analysis software and makes it difficult to share data across different laboratories as every research unit develops its own tools according to its needs, stores data in proprietary formats and a lot of time is spent building software applications for converting data from one format to another. The NPX (NeuroPhysiological signals in eXtensible Markup Language) data format was defined to overcome these and other limitations, and here its main characteristics are reported as well as how some typical problems occurring in simultaneous EEG?fMRI recordings are also treated. Many tools based on the NPX technology can be freely downloaded, including a tool for removing artifacts occurring during simultaneous EEG?fMRI recordings. There is a growing interest in combining EEG and (f)MRI data as they provide complementary information: EEG is characterized by a high temporal resolution but poor spatial one, while fMRI is characterized by a high spatial resolution but low temporal one. However, while a standard file format for storing EEG data is available since over a decade, it does not fulfill the needs of modern protocols and devices such as those involved in simultaneous EEG and fMRI recordings. The main reasons are the limited bit resolution, some difficulties encountered in handling and storing acquisition events or trace markers for off-line analyses and the impossibility to add some protocol-specific information that is not considered in the actual data formats. This, among others, hinders the release of free analysis software and makes it difficult to share data across different laboratories as every research unit develops its own tools according to its needs, stores data in proprietary formats and a lot of time is spent building software applications for converting data from one format to another. The NPX (NeuroPhysiological signals in eXtensible Markup Language) data format was defined to overcome these and other limitations, and here its main characteristics are reported as well as how some typical problems occurring in simultaneous EEG?fMRI recordings are also treated. Many tools based on the NPX technology can be freely downloaded, including a tool for removing artifacts occurring during simultaneous EEG?fMRI recordings.
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Alessandro Gozzi, Laura Ceolin, Adam Schwarz, Torsten Reese, Simone Bertani, Valerio Crestan and Angelo Bifone.
A multimodality investigation of cerebral hemodynamics and autoregulation in pharmacological MRI. Magnetic Resonance Imaging 25(6):826–833, 2007.
Abstract Pharmacological MRI (phMRI) methods have been widely applied to assess the central hemodynamic response to pharmacological intervention as a surrogate for changes in the underlying neuronal activity. However, many psychoactive drugs can also affect cardiovascular parameters, including arterial blood pressure (BP). Abrupt changes in BP or the anesthetic agents used in preclinical phMRI may impair cerebral blood flow (CBF) autoregulation mechanisms, potentially introducing confounds in the phMRI response. Moreover, relative cerebral blood volume (rCBV), often measured in small-animal phMRI studies, may be sensitive to BP changes even in the presence of intact autoregulation. We applied laser Doppler flowmetry and MRI to measure changes in CBF and microvascular CBV induced by increasing doses of intravenous norepinephrine (NE) challenge in the halothane-anesthetized rat. NE is a potent vasopressor that does not cross the blood?brain barrier and mimics the rapid BP changes typically observed with acute drug challenges. We found that CBF autoregulation was maintained over a BP range of 60?120 mmHg. Under these conditions, no significant central rCBV responses were observed, suggesting that microvascular rCBV changes in response to abrupt changes in perfusion pressure are negligible within the autoregulatory range. Larger BP responses were accompanied by significant changes in both CBV and CBF that might confound the interpretation of phMRI results. Pharmacological MRI (phMRI) methods have been widely applied to assess the central hemodynamic response to pharmacological intervention as a surrogate for changes in the underlying neuronal activity. However, many psychoactive drugs can also affect cardiovascular parameters, including arterial blood pressure (BP). Abrupt changes in BP or the anesthetic agents used in preclinical phMRI may impair cerebral blood flow (CBF) autoregulation mechanisms, potentially introducing confounds in the phMRI response. Moreover, relative cerebral blood volume (rCBV), often measured in small-animal phMRI studies, may be sensitive to BP changes even in the presence of intact autoregulation. We applied laser Doppler flowmetry and MRI to measure changes in CBF and microvascular CBV induced by increasing doses of intravenous norepinephrine (NE) challenge in the halothane-anesthetized rat. NE is a potent vasopressor that does not cross the blood?brain barrier and mimics the rapid BP changes typically observed with acute drug challenges. We found that CBF autoregulation was maintained over a BP range of 60?120 mmHg. Under these conditions, no significant central rCBV responses were observed, suggesting that microvascular rCBV changes in response to abrupt changes in perfusion pressure are negligible within the autoregulatory range. Larger BP responses were accompanied by significant changes in both CBV and CBF that might confound the interpretation of phMRI results.
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Diego De Carli, Girolamo Garreffa, Claudio Colonnese, Giovanni Giulietti, Ludovica Labruna, Ennio Briselli, Soléakhéna Ken, Maria Antonietta Macrì and Bruno Maraviglia.
Identification of activated regions during a language task. Magnetic Resonance Imaging 25(6):933–938, 2007.
Abstract 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. 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.
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Michael F Shanks, William J McGeown, Katrina E Forbes-McKay, Gordon D Waiter, Mario Ries and Annalena Venneri.
Regional brain activity after prolonged cholinergic enhancement in early Alzheimer's disease. Magnetic Resonance Imaging 25(6):848–859, 2007.
Abstract This functional magnetic resonance imaging (fMRI) study examined changes in brain activation after prolonged (20 weeks) and stabilized treatment with the cholinesterase inhibitor galantamine in a small group of patients with very mild Alzheimer's disease (AD). Two cognitive activation paradigms were chosen: one requiring semantic association and the other relying on attention and requiring target detection. A group of age- and education-matched healthy controls was also scanned for comparison. A modest (but not statistically significant) improvement in behavioral scores after treatment was observed in both fMRI tasks. There were brain activation increases in the semantic association task after treatment, and the differences in brain activation present in the comparison of AD patients' baseline images with those of controls were not detectable after treatment. In the target detection task, regions that were activated in the elderly controls but not in the baseline images of the AD group also showed significant activation after treatment.Overall, however, the increases were modest and might reflect the heterogeneity of clinical response to treatment in this small group. Future pharmacological fMRI studies should include clinical response as a factor in the analysis of cholinergic enhancement effects in AD patients. This functional magnetic resonance imaging (fMRI) study examined changes in brain activation after prolonged (20 weeks) and stabilized treatment with the cholinesterase inhibitor galantamine in a small group of patients with very mild Alzheimer's disease (AD). Two cognitive activation paradigms were chosen: one requiring semantic association and the other relying on attention and requiring target detection. A group of age- and education-matched healthy controls was also scanned for comparison. A modest (but not statistically significant) improvement in behavioral scores after treatment was observed in both fMRI tasks. There were brain activation increases in the semantic association task after treatment, and the differences in brain activation present in the comparison of AD patients' baseline images with those of controls were not detectable after treatment. In the target detection task, regions that were activated in the elderly controls but not in the baseline images of the AD group also showed significant activation after treatment.Overall, however, the increases were modest and might reflect the heterogeneity of clinical response to treatment in this small group. Future pharmacological fMRI studies should include clinical response as a factor in the analysis of cholinergic enhancement effects in AD patients.
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Anne Catherin Zappe, Johannes Reichold, Cyrill Burger, Bruno Weber, Alfred Buck, Josef Pfeuffer and Nikos K Logothetis.
Quantification of cerebral blood flow in nonhuman primates using arterial spin labeling and a two-compartment model. Magnetic Resonance Imaging 25(6):775–783, 2007.
Abstract Noninvasive absolute quantification of cerebral blood flow (CBF) with high spatial resolution is still a challenging task. Arterial spin labeling (ASL) is a promising magnetic resonance imaging (MRI) method for accurate perfusion quantification. However, modeling of ASL data is far from being standardized and has not been investigated in great detail. In this study, two-compartment modeling of monkey ASL data in three physiological conditions (baseline, sensory activated and globally elevated CBF) is reported. Absolute perfusion and arterial transit times were derived for gray matter (GM) and white matter (WM) separately. The uncertainties of the model's result were determined by Monte Carlo simulations. The fitted CBF values for GM were 133 ml/min/100 ml at baseline condition, 165 ml/min/100 ml during visual stimulation and 234 ml/min/100 ml for globally elevated CBF after intravenous injection of acetazolamide. The ratio of GM to WM CBF was 2.5 at baseline and was found to decrease to 1.6 after application of acetazolamide. The corresponding arterial transit times decreased from 742 to 607 ms in GM and from 985 to 875 ms in WM. Monte Carlo simulations showed that absolute CBF values can be determined with an error of 11?15%, while the arterial transit time values have a coefficient of variation of 25?31%. With an alternative acquisition scheme, the precision of the arterial transit times can be improved significantly. The CBF values in the occipital lobe of the monkey brain quantified with ASL are higher than previously reported in positron emission tomography studies. Noninvasive absolute quantification of cerebral blood flow (CBF) with high spatial resolution is still a challenging task. Arterial spin labeling (ASL) is a promising magnetic resonance imaging (MRI) method for accurate perfusion quantification. However, modeling of ASL data is far from being standardized and has not been investigated in great detail. In this study, two-compartment modeling of monkey ASL data in three physiological conditions (baseline, sensory activated and globally elevated CBF) is reported. Absolute perfusion and arterial transit times were derived for gray matter (GM) and white matter (WM) separately. The uncertainties of the model's result were determined by Monte Carlo simulations. The fitted CBF values for GM were 133 ml/min/100 ml at baseline condition, 165 ml/min/100 ml during visual stimulation and 234 ml/min/100 ml for globally elevated CBF after intravenous injection of acetazolamide. The ratio of GM to WM CBF was 2.5 at baseline and was found to decrease to 1.6 after application of acetazolamide. The corresponding arterial transit times decreased from 742 to 607 ms in GM and from 985 to 875 ms in WM. Monte Carlo simulations showed that absolute CBF values can be determined with an error of 11?15%, while the arterial transit time values have a coefficient of variation of 25?31%. With an alternative acquisition scheme, the precision of the arterial transit times can be improved significantly. The CBF values in the occipital lobe of the monkey brain quantified with ASL are higher than previously reported in positron emission tomography studies.
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Christoph Juchem, Nikos K Logothetis and Josef Pfeuffer.
¹H-MRS of the macaque monkey primary visual cortex at 7 T: strategies and pitfalls of shimming at the brain surface. Magnetic Resonance Imaging 25(6):902–912, 2007.
Abstract Magnetic resonance spectroscopy (MRS) is ideally suited for physiology?neurochemistry experiments with the living brain and particularly for studies on the primary visual cortex (striate cortex or area V1). Yet, the highly convoluted form of the human V1 has thus far prevented the performance of MRS investigations that are spatially confined within the gray matter of this area. Typically, these studies are compromised by partial volume contaminations originating from white matter tissue, cerebrospinal fluid and other cortical areas. In this study, was exploited the relative flatness of V1 in macaques to enable single-voxel 1H-MRS from a small volume (5?1.6?5 mm3, 40 ?l) that was entirely confined within the V1 gray matter of anesthetized monkeys. Linewidths of 13.5±1.9 Hz and 13.0±1.3 Hz for water and creatine, respectively, were achieved with a two-step shimming strategy for voxels at the brain surface. The quality of the obtained results paves the way for further neuroscientific research, including studies on the cortical microcircuits and the dynamic longitudinal changes occurring during cortical reorganization and plasticity. Magnetic resonance spectroscopy (MRS) is ideally suited for physiology?neurochemistry experiments with the living brain and particularly for studies on the primary visual cortex (striate cortex or area V1). Yet, the highly convoluted form of the human V1 has thus far prevented the performance of MRS investigations that are spatially confined within the gray matter of this area. Typically, these studies are compromised by partial volume contaminations originating from white matter tissue, cerebrospinal fluid and other cortical areas. In this study, was exploited the relative flatness of V1 in macaques to enable single-voxel 1H-MRS from a small volume (5?1.6?5 mm3, 40 ?l) that was entirely confined within the V1 gray matter of anesthetized monkeys. Linewidths of 13.5±1.9 Hz and 13.0±1.3 Hz for water and creatine, respectively, were achieved with a two-step shimming strategy for voxels at the brain surface. The quality of the obtained results paves the way for further neuroscientific research, including studies on the cortical microcircuits and the dynamic longitudinal changes occurring during cortical reorganization and plasticity.
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Gil G Westmeyer and Alan Jasanoff.
Genetically controlled MRI contrast mechanisms and their prospects in systems neuroscience research. Magnetic Resonance Imaging 25(6):1004–1010, 2007.
Abstract Application of MRI contrast agents to neural systems research is complicated by the need to deliver agents past the blood?brain barrier or into cells, and the difficulty of targeting agents to specific brain structures or cell types. In the future, these barriers may be wholly or partially overcome using genetic methods for producing and directing MRI contrast. Here we review MRI contrast mechanisms that have used gene expression to manipulate MRI signal in cultured cells or in living animals. We discuss both fully genetic systems involving endogenous biosynthesis of contrast agents, and semi-genetic systems in which expressed proteins influence the localization or activity of exogenous contrast agents. We close by considering which contrast-generating mechanisms might be most suitable for applications in neuroscience, and we ask how genetic control machinery could be productively combined with existing molecular agents to enable next-generation neuroimaging experiments. Application of MRI contrast agents to neural systems research is complicated by the need to deliver agents past the blood?brain barrier or into cells, and the difficulty of targeting agents to specific brain structures or cell types. In the future, these barriers may be wholly or partially overcome using genetic methods for producing and directing MRI contrast. Here we review MRI contrast mechanisms that have used gene expression to manipulate MRI signal in cultured cells or in living animals. We discuss both fully genetic systems involving endogenous biosynthesis of contrast agents, and semi-genetic systems in which expressed proteins influence the localization or activity of exogenous contrast agents. We close by considering which contrast-generating mechanisms might be most suitable for applications in neuroscience, and we ask how genetic control machinery could be productively combined with existing molecular agents to enable next-generation neuroimaging experiments.
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Louis Lemieux, Afraim Salek-Haddadi, Torben E Lund, Helmut Laufs and David Carmichael.
Modelling large motion events in fMRI studies of patients with epilepsy. Magnetic Resonance Imaging 25(6):894–901, 2007.
Abstract EEG-correlated fMRI can provide localisation information on the generators of epileptiform discharges in patients with focal epilepsy. To increase the technique's clinical potential, it is important to consider ways of optimising the yield of each experiment while minimizing the risk of false-positive activation. Head motion can lead to severe image degradation and result in false-positive activation and is usually worse in patients than in healthy subjects. We performed general linear model fMRI data analysis on simultaneous EEG?fMRI data acquired in 34 cases with focal epilepsy. Signal changes associated with large inter-scan motion events (head jerks) were modelled using modified design matrices that include ?scan nulling? regressors. We evaluated the efficacy of this approach by mapping the proportion of the brain for which F-tests across the additional regressors were significant. In 95% of cases, there was a significant effect of motion in 50% of the brain or greater; for the scan nulling effect, the proportion was 36%; this effect was predominantly in the neocortex. We conclude that careful consideration of the motion-related effects in fMRI studies of patients with epilepsy is essential and that the proposed approach can be effective. EEG-correlated fMRI can provide localisation information on the generators of epileptiform discharges in patients with focal epilepsy. To increase the technique's clinical potential, it is important to consider ways of optimising the yield of each experiment while minimizing the risk of false-positive activation. Head motion can lead to severe image degradation and result in false-positive activation and is usually worse in patients than in healthy subjects. We performed general linear model fMRI data analysis on simultaneous EEG?fMRI data acquired in 34 cases with focal epilepsy. Signal changes associated with large inter-scan motion events (head jerks) were modelled using modified design matrices that include ?scan nulling? regressors. We evaluated the efficacy of this approach by mapping the proportion of the brain for which F-tests across the additional regressors were significant. In 95% of cases, there was a significant effect of motion in 50% of the brain or greater; for the scan nulling effect, the proportion was 36%; this effect was predominantly in the neocortex. We conclude that careful consideration of the motion-related effects in fMRI studies of patients with epilepsy is essential and that the proposed approach can be effective.
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Alain Smolders, Federico De Martino, Noël Staeren, Paul Scheunders, Jan Sijbers, Rainer Goebel and Elia Formisano.
Dissecting cognitive stages with time-resolved fMRI data: a comparison of fuzzy clustering and independent component analysis. Magnetic Resonance Imaging 25(6):860–868, 2007.
Abstract In combination with cognitive tasks entailing sequences of sensory and cognitive processes, event-related acquisition schemes allow using functional MRI to examine not only the topography but also the temporal sequence of cortical activation across brain regions (time-resolved fMRI). In this study, we compared two data-driven methods ? fuzzy clustering method (FCM) and independent component analysis (ICA) ? in the context of time-resolved fMRI data collected during the performance of a newly devised visual imagery task. We analyzed a multisubject fMRI data set using both methods and compared their results in terms of within- and between-subject consistency and spatial and temporal correspondence of obtained maps and time courses. Both FCM and spatial ICA allowed discriminating the contribution of distinct networks of brain regions to the main cognitive stages of the task (auditory perception, mental imagery and behavioural response), with good agreement across methods. Whereas ICA worked optimally on the original time series, averaging with respect to the task onset (and thus introducing some a priori information on the stimulation protocol) was found to be indispensable in the case of FCM. On averaged time series, FCM led to a richer decomposition of the spatio-temporal patterns of activation and allowed a finer separation of the neurocognitive processes subserving the mental imagery task.This study confirms the efficacy of the two examined methods in the data-driven estimation of hemodynamic responses in time-resolved fMRI studies and provides empirical guidelines to their use. In combination with cognitive tasks entailing sequences of sensory and cognitive processes, event-related acquisition schemes allow using functional MRI to examine not only the topography but also the temporal sequence of cortical activation across brain regions (time-resolved fMRI). In this study, we compared two data-driven methods ? fuzzy clustering method (FCM) and independent component analysis (ICA) ? in the context of time-resolved fMRI data collected during the performance of a newly devised visual imagery task. We analyzed a multisubject fMRI data set using both methods and compared their results in terms of within- and between-subject consistency and spatial and temporal correspondence of obtained maps and time courses. Both FCM and spatial ICA allowed discriminating the contribution of distinct networks of brain regions to the main cognitive stages of the task (auditory perception, mental imagery and behavioural response), with good agreement across methods. Whereas ICA worked optimally on the original time series, averaging with respect to the task onset (and thus introducing some a priori information on the stimulation protocol) was found to be indispensable in the case of FCM. On averaged time series, FCM led to a richer decomposition of the spatio-temporal patterns of activation and allowed a finer separation of the neurocognitive processes subserving the mental imagery task.This study confirms the efficacy of the two examined methods in the data-driven estimation of hemodynamic responses in time-resolved fMRI studies and provides empirical guidelines to their use.
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Istvan Csapo, Christopher M Holland and Charles R G Guttmann.
Image registration framework for large-scale longitudinal MRI data sets: strategy and validation. Magnetic Resonance Imaging 25(6):889–893, 2007.
Abstract Advanced magnetic resonance imaging (MRI) studies often require the transformation of large numbers of images into a common space. Calculating transformations that relate each image to every other and applying them to the images on demand are theoretically possible; however, these can be computationally prohibitive. Therefore, relating each image to only one other image, then linking those transforms together to relate any two images in the database, may be an efficient alternative. Evaluated were the feasibility and validity of image registration to bring intraindividual MR images into mutual correspondence for longitudinal analysis through the concatenation of precomputed transforms. A longitudinal data set of 10 multiple sclerosis patients with nine serial dual-echo spin-echo, 1.5-T MRI scans was used. Intrasubject registrations were performed stepwise between consecutive images and direct from each time point to the baseline. Consecutive transforms were concatenated and evaluated against direct registrations by comparing the resulting transformed images (using Pearson correlation coefficient). Confounding variables such as time between scans, brain atrophy, and change in lesion load were evaluated. We found the images resampled with the direct and the concatenated transforms to be highly correlated, and there was no significant difference between methods. Differences in brain parenchymal fraction (a measure of brain atrophy) showed significant inverse correlation with the correspondence of the resampled images. Results indicate that concatenating multiple transforms that link two images together produces near-identical results to that of direct registration; thus, this method is both useful and valid. Advanced magnetic resonance imaging (MRI) studies often require the transformation of large numbers of images into a common space. Calculating transformations that relate each image to every other and applying them to the images on demand are theoretically possible; however, these can be computationally prohibitive. Therefore, relating each image to only one other image, then linking those transforms together to relate any two images in the database, may be an efficient alternative. Evaluated were the feasibility and validity of image registration to bring intraindividual MR images into mutual correspondence for longitudinal analysis through the concatenation of precomputed transforms. A longitudinal data set of 10 multiple sclerosis patients with nine serial dual-echo spin-echo, 1.5-T MRI scans was used. Intrasubject registrations were performed stepwise between consecutive images and direct from each time point to the baseline. Consecutive transforms were concatenated and evaluated against direct registrations by comparing the resulting transformed images (using Pearson correlation coefficient). Confounding variables such as time between scans, brain atrophy, and change in lesion load were evaluated. We found the images resampled with the direct and the concatenated transforms to be highly correlated, and there was no significant difference between methods. Differences in brain parenchymal fraction (a measure of brain atrophy) showed significant inverse correlation with the correspondence of the resampled images. Results indicate that concatenating multiple transforms that link two images together produces near-identical results to that of direct registration; thus, this method is both useful and valid.
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Robert V Mulkern, Steven J Haker and Stephan E Maier.
Complimentary aspects of diffusion imaging and fMRI: II. Elucidating contributions to the fMRI signal with diffusion sensitization. Magnetic Resonance Imaging 25(6):939–952, 2007.
Abstract Tissue water molecules reside in different biophysical compartments. For example, water molecules in the vasculature reside for variable periods of time within arteries, arterioles, capillaries, venuoles and veins, and may be within blood cells or blood plasma. Water molecules outside of the vasculature, in the extravascular space, reside, for a time, either within cells or within the interstitial space between cells. Within these different compartments, different types of microscopic motion that water molecules may experience have been identified and discussed. These range from Brownian diffusion to more coherent flow over the time scales relevant to functional magnetic resonance imaging (fMRI) experiments, on the order of several 10s of milliseconds. How these different types of motion are reflected in magnetic resonance imaging (MRI) methods developed for ?diffusion? imaging studies has been an ongoing and active area of research. Here we briefly review the ideas that have developed regarding these motions within the context of modern ?diffusion? imaging techniques and, in particular, how they have been accessed in attempts to further our understanding of the various contributions to the fMRI signal changes sought in studies of human brain activation. Tissue water molecules reside in different biophysical compartments. For example, water molecules in the vasculature reside for variable periods of time within arteries, arterioles, capillaries, venuoles and veins, and may be within blood cells or blood plasma. Water molecules outside of the vasculature, in the extravascular space, reside, for a time, either within cells or within the interstitial space between cells. Within these different compartments, different types of microscopic motion that water molecules may experience have been identified and discussed. These range from Brownian diffusion to more coherent flow over the time scales relevant to functional magnetic resonance imaging (fMRI) experiments, on the order of several 10s of milliseconds. How these different types of motion are reflected in magnetic resonance imaging (MRI) methods developed for ?diffusion? imaging studies has been an ongoing and active area of research. Here we briefly review the ideas that have developed regarding these motions within the context of modern ?diffusion? imaging techniques and, in particular, how they have been accessed in attempts to further our understanding of the various contributions to the fMRI signal changes sought in studies of human brain activation.
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Jozien B M Goense, Anne-Catherin Zappe and Nikos K Logothetis.
High-resolution fMRI of macaque V1. Magnetic Resonance Imaging 25(6):740–747, 2007.
Abstract To understand the physiological mechanisms underlying the blood-oxygenation-level-dependent (BOLD) signal, the acquisition of data must be optimized to achieve the maximum possible spatial resolution and specificity. The term ?specificity? implies the selective enhancement of signals originating in the parenchyma, and thus best reflecting actual neural activity. Such spatial specificity is a prerequisite for imaging aimed at the elucidation of interactions between cortical micromodules, such as columns and laminae. In addition to the optimal selection of functional magnetic resonance imaging pulse sequences, accurate superposition of activation patterns onto corresponding anatomical scans, preferably acquired during the same experimental session, is necessary. At high resolution, exact functional-to-structural registration is of critical importance, because even small differences in geometry, that arise when different sequences are used for functional and anatomical scans, can lead to misallocation of activation and erroneous interpretation of data. In the present study, we used spin-echo (SE) echo planar imaging (EPI) for functional scans, since the SE-BOLD signal is sensitive to the capillary response, together with SE-EPI anatomical reference scans. The combination of these acquisition methods revealed a clear spatial colocalization of the largest fractional changes with the Gennari line, suggesting peak activity in Layer IV. Notably, this very same layer coincided with the largest relaxivity changes as observed in steady-state cerebral blood volume measurements, using the intravascular agent monocrystalline iron oxide nanoparticles (MION). To understand the physiological mechanisms underlying the blood-oxygenation-level-dependent (BOLD) signal, the acquisition of data must be optimized to achieve the maximum possible spatial resolution and specificity. The term ?specificity? implies the selective enhancement of signals originating in the parenchyma, and thus best reflecting actual neural activity. Such spatial specificity is a prerequisite for imaging aimed at the elucidation of interactions between cortical micromodules, such as columns and laminae. In addition to the optimal selection of functional magnetic resonance imaging pulse sequences, accurate superposition of activation patterns onto corresponding anatomical scans, preferably acquired during the same experimental session, is necessary. At high resolution, exact functional-to-structural registration is of critical importance, because even small differences in geometry, that arise when different sequences are used for functional and anatomical scans, can lead to misallocation of activation and erroneous interpretation of data. In the present study, we used spin-echo (SE) echo planar imaging (EPI) for functional scans, since the SE-BOLD signal is sensitive to the capillary response, together with SE-EPI anatomical reference scans. The combination of these acquisition methods revealed a clear spatial colocalization of the largest fractional changes with the Gennari line, suggesting peak activity in Layer IV. Notably, this very same layer coincided with the largest relaxivity changes as observed in steady-state cerebral blood volume measurements, using the intravascular agent monocrystalline iron oxide nanoparticles (MION).
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Matthew G Skinner, Shannon H Kolind and Alex L MacKay.
The effect of varying echo spacing within a multiecho acquisition: better characterization of long T₂ components. Magnetic Resonance Imaging 25(6):840–847, 2007.
Abstract A 48-echo pulse sequence with five different echo-spacing combinations was examined to determine how one can most effectively measure the T2 relaxation characteristics of cerebral tissue containing a long T2 component. For each scan, the first 32 echoes had an echo spacing of 10 ms, while the spacing for Echoes 33?48 (?TE2) was 10, 20, 30, 40 or 50 ms.In an in vivo study using 10 normal volunteers, it was found that the resolution of T2 distribution peaks for both myelin water (?20 ms) and intracellular/extracellular (IE) water (?80 ms) improved as ?TE2 increased. The geometric mean T2 values of the main peak agreed within the error for all ?TE2 values.A phantom study simulated T2 relaxation distributions that are expected in the brains of patients with demyelinating diseases. For phantoms in which the T2 values of the IE and lesion (200?500 ms) water compartments were separated by at least a factor of 3, each compartment in the distribution was better resolved when ?TE2=40 or 50 ms.On the basis of these results, we recommend the use of extended ?TE2 values for imaging patients with lesions, without the risk of losing valuable short T2 information. A 48-echo pulse sequence with five different echo-spacing combinations was examined to determine how one can most effectively measure the T2 relaxation characteristics of cerebral tissue containing a long T2 component. For each scan, the first 32 echoes had an echo spacing of 10 ms, while the spacing for Echoes 33?48 (?TE2) was 10, 20, 30, 40 or 50 ms.In an in vivo study using 10 normal volunteers, it was found that the resolution of T2 distribution peaks for both myelin water (?20 ms) and intracellular/extracellular (IE) water (?80 ms) improved as ?TE2 increased. The geometric mean T2 values of the main peak agreed within the error for all ?TE2 values.A phantom study simulated T2 relaxation distributions that are expected in the brains of patients with demyelinating diseases. For phantoms in which the T2 values of the IE and lesion (200?500 ms) water compartments were separated by at least a factor of 3, each compartment in the distribution was better resolved when ?TE2=40 or 50 ms.On the basis of these results, we recommend the use of extended ?TE2 values for imaging patients with lesions, without the risk of losing valuable short T2 information.
URL, DOI