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Sex differences in blood-oxygenation-level-dependent functional MRI with primary visual stimulation.

OBJECTIVE: The authors evaluated the effect of sex on data derived from activation studies using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (MRI). METHOD: Gradient echo-echo planar imaging was used to measure BOLD signal response in the primary visual cortex in response to binocular photic stimulation in 16 healthy, young subjects (eight women and eight men). RESULTS: BOLD signal response was 38% lower in women than in men, and much of the difference was lateralized to the right hemisphere. CONCLUSIONS: Lower BOLD signal response in women may reflect a sex difference in the brain's response to a primary visual stimulation or in the physiology underlying BOLD functional MRI signal changes.

Adult↗

Functional MRI of human Pavlovian fear conditioning: patterns of activation as a function of learning.

fMRI was used to study human brain activity during Pavlovian fear conditioning. Subjects were exposed to lights that either signaled painful electrical stimulation (CS+), or that did not serve as a warning signal (CS-). Unique patterns of activation developed within anterior cingulate and visual cortices as learning progressed. Training with the CS+ increased active tissue volume and shifted the timing of peak fMRI signal toward CS onset within the anterior cingulate. Within the visual cortex, active tissue volume increased with repeated CS+ presentations, while cross-correlation between the functional time course and CS- presentations decreased. This study demonstrates plasticity of anterior cingulate and visual cortices as a function of learning, and implicates these regions as components of a functional circuit activated in human fear conditioning.

Adult↗

Calibrated functional MRI: mapping the dynamics of oxidative metabolism.

MRI was extended to the measurement of changes in oxidative metabolism in the normal human during functionally induced changes in cellular activity. A noninvasive MRI method that is model-independent calibrates the blood oxygen level dependent (BOLD) signal of functional MRI (fMRI) against perfusion-sensitive MRI, using carbon dioxide breathing as a physiological reference standard. This calibration procedure provides a regional measurement of the expected sensitivity of the fMRI BOLD signal to changes in the cellular activity of the brain. Maps of the BOLD signal calibration factor showed regional heterogeneity, indicating that the magnitude of functionally induced changes in the BOLD signal will be dependent on both the local change in blood flow and the local baseline physiology of the cerebral cortex. BOLD signal magnitude is shown to be reduced by 32% from its expected level by the action of oxygen metabolism. The calibrated fMRI technique was applied to stimulation of the human visual cortex with an alternating radial checkerboard pattern. With this stimulus oxygen consumption increased 16% whereas blood flow increased 45%. Although this result is consistent with previous findings of a significant difference between the increase in blood flow and oxygen consumption, it does indicate clearly that oxidative metabolism is a significant component of the metabolic response of the brain to functionally induced changes in cellular activity.

Brain↗

The neural consequences of repeated cocaine exposure revealed by functional MRI in awake rats.

The use of functional magnetic resonance imaging (fMRI) in animal models of cocaine addiction is an invaluable tool for investigating the neuroadaptations that lead to this psychiatric disorder. We used blood-oxygen-level-dependent (BOLD) MRI in awake rats to identify the neuronal circuits affected by repeated cocaine administration. Rats were given an injection of cocaine (15 mg/kg, i.p.) or its vehicle for 7 days, abstained from injections for 1 week, and challenged with an intracerebroventricular cocaine injection during functional imaging. Acute cocaine produced robust positive BOLD responses across well-known monoamine-enriched brain regions, such as the prefrontal cortex, nucleus accumbens, dorsal striatum, sensory cortex, hippocampus, thalamus, and midbrain areas. However, repeated cocaine administration resulted in lower BOLD responses in the prefrontal cortex, agranular insular cortex, nucleus accumbens, ventral pallidum, and dorsomedial thalamus, among other brain regions. Reductions in BOLD intensity were not associated with variations in cerebrovascular reactivity between drug naive rats and those repeatedly exposed to cocaine. Therefore, the lower metabolic activation in response to cocaine could reflect a reduced neuronal and/or synaptic activity upon repeated administration.

Animals↗

Functional MRI of brain activation by eye blinking.

Functional magnetic resonance imaging (fMRI) was used to map cortical areas that control eye blinking. T2*-weighted asymmetric spin-echo MRI (or BOLD-blood oxygen level dependent-MRI) was used to detect changes caused by focal variations in blood oxygenation. Six normal volunteers and two cases of dry eye (less than 5-mm Schirmer's test) entered the study. The experimental scheme consisted of three cycles of a two-step sequence: (eyes closed)-(blink or blink inhibition). And to minimize contamination from photic activation, the experiments were carried out in a dark environment and the volunteers reported no light perception during the MR scans. In all eight cases, normal blinking (about one blink every 4 sec) activated areas in the orbitofrontal cortex and in some cases, the visual cortex including the anterior portion of the visual cortex and the primary visual cortex. In severe dry eye, blink-inhibition strongly activated the visual cortex even after irritation due to corneal desiccation was removed by topical anesthesia. The blinking process, especially the rate, appears to be controlled in the orbitofrontal cortex. The significance of visual cortex activation in the dark and in the case of severe dry eye still remains unclear; although it may be associated with attention and arousal.

Adult↗

Functional MRI of the brain principles, applications and limitations.

MRI now allows noninvasive monitoring of brain function with a combined spatial and temporal resolution never achieved by other imaging modalities. Among several methods proposed to evaluate changes in blood volume, flow or oxygenation during mental activity, the most successful is based on the sensitivity of MRI to magnetic effects induced by the modulation of the oxygenation status of hemoglobin (oxy/deoxyhemoglobin) which results from local variations in blood flow. In the brain cortex, such variations may be induced by task activation or by cognitive processes, such as language or mental imagery. Typically, MRI signal is increased by a few percents when brain is activated due to sharp increase in oxygen supply (blood flow). Brain activation maps obtained with MRI using various task paradigms agreed well with previous PET results. However MRI permits direct correlation of function with underlying anatomy within a single imaging modality and repetitive studies on the same individuals. These studies suggest that MRI may be the method of choice in conjunction with other functional techniques, to study mental and cognitive processes underlying the function of the human brain. Clinically, potential applications include presurgical mapping, recovery monitoring of stroke or head injuries, exploration of seizure disorders or monitoring of the effects of neuropharmaceuticals.

Blood Volume↗

Simultaneous EEG and functional MRI of epileptic activity: a case report.

OBJECTIVES: Attempts to localize the source of epileptic activity by linking electroencephalographic (EEG) abnormalities to blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) signal alterations are hampered mainly by EEG distortions during MRI, subject motion, and unknown hemodynamic response characteristics. METHODS: Using T2*-weighted echo-planar imaging at 2.0 T (2 s temporal resolution, 2 x 2 x 4 mm(3) spatial resolution), this work demonstrates strategies to alleviate some of these problems while studying a patient who had ideopathic generalized epilepsy with poly-spike and slow-wave complexes. RESULTS: Continuous EEG recordings during dynamic MRI (500 ms scanning, 1500 ms delay) and post-examination derivation of an EEG reference function for MRI analysis revealed positive BOLD MRI responses with temporal characteristics similar to those obtained for functional challenges. CONCLUSIONS: The ability to map focal epileptic activity and/or associated cognitive processing provides new potential for both epilepsy research and clinical patient management.

Adult↗

Structural and functional MRI reveals multiple retinal layers.

MRI is a noninvasive diagnostic modality that reveals anatomy, physiology, and function in vivo without depth limitation or optical interference. MRI application to the retina, however, remains challenging. We improved spatial resolution to resolve layer-specific structure and functional responses in the retina and confirmed the laminar resolution in an established animal model of retinal degeneration. Structural MRI of normal rat retinas revealed three bands corresponding histologically to (i) the combined ganglion cell layer/inner nuclear layer plus the embedded retinal vessels, (ii) the avascular outer nuclear (photoreceptor) layer and its photoreceptor segments, and (iii) the choroidal vascular layer. Imaging with an intravascular contrast agent (gadolinium-diethylene-tri-amine-pentaacetic acid) enhanced the retinal and choroidal vascular layers bounding the retina, but not the avascular outer nuclear layer and the vitreous. Similarly, blood-oxygen-level-dependent (BOLD) functional MRI revealed layer-specific responses to hyperoxia and hypercapnia. Importantly, layer-specific BOLD responses in the two vascular layers were divergent, suggesting the two vasculatures are differentially regulated. To corroborate sensitivity and specificity, we applied layer-specific MRI to document photoreceptor degeneration in Royal College of Surgeons rats. Consistent with histology, layer-specific MRI detected degeneration of the outer nuclear layer. Surprisingly, MRI revealed increased thickness in the choroidal vascular layer and diminished BOLD responses to hyperoxia and hypercapnia in the Royal College of Surgeons rat retinas, suggesting perturbation of vascular reactivity secondary to photoreceptor loss. We conclude that MRI is a powerful investigative tool capable of resolving lamina-specific structures and functional responses in the retina as well as probing lamina-specific changes in retinal diseases.

Aging↗

Functional MRI and its applications to the clinical neurosciences.

Functional magnetic resonance imaging (fMRI) is an emerging methodology for studying regional brain function in vivo at relatively high spatial and temporal resolution. Because MRI methods are comparatively inexpensive and entirely noninvasive, fMRI has rapidly become one of the most popular approaches for brain mapping in cognitive and systems neuroscience. There has also been great interest in using fMRI to assist in clinical diagnosis and management, with promising demonstrations of feasibility in a number of applications. Both resting and task-specific regional brain activity can be measured, primarily utilizing alterations in regional cerebral blood flow (CBF) as a surrogate marker for neural function. This article reviews the biophysical and physiological bases of fMRI and its applications to the clinical neurosciences, with particular attention to potential challenges of fMRI under pathophysiological conditions. Carefully controlled prospective evaluation of clinical fMRI in its various potential applications will be required for fMRI to be validated as a clinically useful tool. Because the technology for fMRI is widely available, its impact could be substantial.

Animals↗

Modeling hemodynamic response for analysis of functional MRI time-series.

The standard Gaussian function is proposed for the hemodynamic modulation function (HDMF) of functional magnetic resonance imaging (fMRI) time-series. Unlike previously proposed parametric models, the Gaussian model accounts independently for the delay and dispersion of the hemodynamic responses and provides a more flexible and mathematically convenient model. A suboptimal noniterative scheme to estimate the hemodynamic parameters is presented. The ability of the Gaussian function to represent the HDMF of brain activation is compared with Poisson and Gamma models. The proposed model seems valid because the lag and dispersion values of hemodynamic responses rendered by the Gaussian model are in the ranges of their previously reported values in recent optical and fMR imaging studies. An extension of multiple regression analysis to incorporate the HDMF is presented. The detected activity patterns exhibit improvements with hemodynamic correction. The proposed model and efficient parameter estimation scheme facilitated the investigation of variability of hemodynamic parameters of human brain activation. The hemodynamic parameters estimated over different brain regions and across different stimuli showed significant differences. Measurement of hemodynamic parameters over the brain during sensory or cognitive stimulation may reveal vital information on physiological events accompanying neuronal activation and functional variability of the human brain, and should lead to the investigation of more accurate and complex models.

Brain↗

Inadequacy of motion correction algorithms in functional MRI: role of susceptibility-induced artifacts.

Functional MR (fMR) has been useful in providing insight into the localization and detection of neural cortical activity. However, patient head motion is inevitable over the course of most fMR experiments. Although methods to align the control and activation fMR images may correct for some of this motional error, they will be incomplete in correcting for those that depend on spatial orientation. MR signal amplitude of structures that lie along air-tissue interfaces, for example, are sensitive to susceptibility errors introduced by their reorientation with respect to the main magnetic field. This analysis, using phantoms, cadaver brain, and volunteers, has shown that this reorientation between control and activation images can create regions of "false activation" that increase in area with rotation. Anatomic regions that are expected to be most affected by these susceptibility-induced magnetic field homogeneity variations are those adjacent to bone or air, such as the mesial and inferior temporal lobes and the inferior and anterior frontal lobes. Interpretation of "activation" in these areas on fMR studies must be performed with careful consideration of this important source of error.

Algorithms↗

A spatio-temporal regression model for the analysis of functional MRI data.

The standard method for analyzing functional magnetic resonance imaging (fMRI) data applies the general linear model to the time series of each voxel separately. Such a voxelwise approach, however, does not consider the spatial autocorrelation between neighboring voxels in its model formulation and parameter estimation. We propose a spatio-temporal regression analysis for detecting activation in fMRI data. Its main features are that (1) each voxel has a regression model that involves the time series of the neighboring voxels together with its own, (2) the regression coefficient assigned to the center voxel is estimated so that the time series of these multiple voxels will best fit the model, (3) a generalized least squares (GLS) method was employed instead of the ordinary least squares (OLS) to put intrinsic autocorrelation structures into the model, and (4) the underlying spatial and temporal correlation structures are modeled using a separable model which expresses the combined correlation structures as a product of the two. We evaluated the statistical power of our model in comparison with voxelwise OLS/GLS models and a multivoxel OLS model. Our model's power to detect clustered activation was higher than that of the two voxelwise models and comparable to that of the multivoxel OLS. We examined the usefulness and goodness of fit of our model using real experimental data. Our model successfully detected neural activity in expected brain regions and realized better fit than the other models. These results suggest that our spatio-temporal regression model can serve as a reliable analysis suited for the nature of fMRI data.

Adult↗

Anatomy of verbal memory: a functional MRI study.

The recent advent of new functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI) makes it possible to examine cerebral activations in healthy individuals. In the present study, we attempted to examine the anatomical distribution of neocortical and mediotemporal activations in control subjects during episodic memory tasks over 24 h. BOLD (blood oxygenation-level-dependent) fMRI data were collected from 10 control subjects. Twenty-two contiguous images covering the whole brain were acquired using an EPI echoplanar sequence. Subjects were instructed to learn a list of 17 words, and to recall it immediately and after a 24-h interval. Individual and group analyses were performed using SPM96. The results demonstrated that a similar left occipito-temporofrontal network was activated during both immediate and 24-h-delayed retrieval conditions. In addition, the 24-h-delayed retrieval also activated a larger parietal region and the right hippocampus. These findings suggest that fMRI is a reliable method with which to perform anatomical studies.

Adult↗

Multistable representation of speech forms: a functional MRI study of verbal transformations.

We used functional magnetic resonance imaging (fMRI) to localize the brain areas involved in the imagery analogue of the verbal transformation effect, that is, the perceptual changes that occur when a speech form is cycled in rapid and continuous mental repetition. Two conditions were contrasted: a baseline condition involving the simple mental repetition of speech sequences, and a verbal transformation condition involving the mental repetition of the same items with an active search for verbal transformation. Our results reveal a predominantly left-lateralized network of cerebral regions activated by the verbal transformation task, similar to the neural network involved in verbal working memory: the left inferior frontal gyrus, the left supramarginal gyrus, the left superior temporal gyrus, the anterior part of the right cingulate cortex, and the cerebellar cortex, bilaterally. Our results strongly suggest that the imagery analogue of the verbal transformation effect, which requires percept analysis, form interpretation, and attentional maintenance of verbal material, relies on a working memory module sharing common components of speech perception and speech production systems.

Adult↗

Functional MRI of amblyopia before and after levodopa.

Functional magnetic resonance imaging (fMRI) was applied to five older amblyopes with monocular amblyopia before and after levodopa treatment. During the experiment, images were acquired in two runs with visual stimulation delivered through the sound and the amblyopic eyes, respectively. The experiment was performed on each of the subjects, before and after their oral administration of levodopa/carbidopa (0.5/0.12 mg/kg) three times per day for 7 weeks. Our study demonstrated that there was no effect on the spatial extent of the visual cortical activation during the sound eye stimulation (P=0.17), but some improvement during the amblyopic eye stimulation (P=0.06). The volume ratio between the amblyopic and sound eye stimulation significantly increased after the treatment (P<0.05). This finding supports the previous studies of levodopa effect on amblyopia at the visual cortical level, and suggests that fMRI can be a useful tool in assessing changes of visual cortical activity after the treatment

Adolescent↗

Memory lateralization in medial temporal lobe epilepsy assessed by functional MRI.

PURPOSE: To determine the utility of functional magnetic resonance imaging (fMRI) in preoperative lateralization of memory function in patients with medial temporal lobe epilepsy (MTLE). METHODS: Nine patients with MTLE underwent standard preoperative assessment including video-EEG and intracarotid amytal testing (IAT). fMRI was performed while subjects encoded four types of stimuli (patterns, faces, scenes, and words). Activation maps were created for each subject representing areas more active for novel than for repeated stimuli. Regions of interest were drawn around the MTL in individual subjects, suprathreshold voxels were counted, and an asymmetry index was calculated. RESULTS: In eight of nine subjects, lateralization of memory encoding by fMRI was concordant with that obtained from the IAT. Group-level analysis demonstrated greater activation in the MTL contralateral to the seizure focus such that in the left MTLE group, verbal encoding engaged the right MTL, whereas in the right MTLE group, nonverbal encoding engaged the left MTL. CONCLUSIONS: fMRI is a valid tool for assessing of memory lateralization in patients with MTLE and may therefore allow noninvasive preoperative evaluation of memory lateralization. FMRI revealed that memory encoding may be reorganized to the contralateral MTL in patients with MTLE.

Adult↗

Functional MRI and the study of human consciousness.

Functional brain imaging offers new opportunities for the study of that most pervasive of cognitive conditions, human consciousness. Since consciousness is attendant to so much of human cognitive life, its study requires secondary analysis of multiple experimental datasets. Here, four preprocessed datasets from the National fMRI Data Center are considered: Hazeltine et al., Neural activation during response competition; Ishai et al., The representation of objects in the human occipital and temporal cortex; Mechelli et al., The effects of presentation rate during word and pseudoword reading; and Postle et al., Activity in human frontal cortex associated with spatial working memory and saccadic behavior. The study of consciousness also draws from multiple disciplines. In this article, the philosophical subdiscipline of phenomenology provides initial characterization of phenomenal structures conceptually necessary for an analysis of consciousness. These structures include phenomenal intentionality, phenomenal superposition, and experienced temporality. The empirical predictions arising from these structures require new interpretive methods for their confirmation. These methods begin with single-subject (preprocessed) scan series, and consider the patterns of all voxels as potential multivariate encodings of phenomenal information. Twenty-seven subjects from the four studies were analyzed with multivariate methods, revealing analogues of phenomenal structures, particularly the structures of temporality. In a second interpretive approach, artificial neural networks were used to detect a more explicit prediction from phenomenology, namely, that present experience contains and is inflected by past states of awareness and anticipated events. In all of 21 subjects in this analysis, nets were successfully trained to extract aspects of relative past and future brain states, in comparison with statistically similar controls. This exploratory study thus concludes that the proposed methods for "neurophenomenology" warrant further application, including the exploration of individual differences, multivariate differences between cognitive task conditions, and exploration of specific brain regions possibly contributing to the observations. All of these attractive questions, however, must be reserved for future research.

Cognition↗

Frontostriatal abnormalities in adolescents with bipolar disorder: preliminary observations from functional MRI.

OBJECTIVE: This study investigated whether the functional abnormalities in prefrontal systems observed in adult bipolar disorder are manifested in adolescents with this illness. METHOD: Ten adolescents with bipolar disorder and 10 healthy comparison subjects participated in a color-naming Stroop task during event-related functional magnetic resonance imaging. RESULTS: Signal increases in the left putamen and thalamus were significantly greater in the bipolar disorder group than in the healthy group. Age correlated positively with signal increases in the bilateral rostroventral prefrontal cortex and the striatum in the healthy group but not in the bipolar disorder group. In the bipolar disorder subjects, depressive symptoms correlated positively with signal increases in the ventral striatum. CONCLUSIONS: These findings suggest the presence of dysfunction in the subcortical portions of the frontostriatal circuits in adolescents with bipolar disorder. The absence of the prefrontal abnormalities that were observed previously in adults and the absence of the age-related increases in prefrontal activity observed in normal comparison subjects suggest that a developmental disturbance in prefrontal function may emerge in bipolar disorder over the course of adolescence.

Adolescent↗