Visual activation in functional magnetic resonance imaging at very high field (4 Tesla).

OBJECTIVES: Functional magnetic resonance imaging (fMRI) at very high field strengths provides functional brain mapping with the enhanced signal to noise ratio and the larger blood oxygenation level-dependent (BOLD) effect. We report activated areas in the standard space detected by fMRI at 4 Tesla (T) during simple visual stimulation. MATERIALS AND METHODS: Twelve healthy young subjects were scanned using a 4 T scanner during binocular flashing visual stimulation. Functional images were realigned to the first scan and then spatially normalized. Individual and group data analyses were performed to identify areas of visual activation. RESULTS: Activation of the bilateral primary visual cortex (V1/V2) was observed along the entire calcarine fissure in all subjects. The activated area extended to the extrastriate cortex in all subjects. Activation of the bilateral lateral geniculate nucleus (LGN) was detected in all subjects. The group data showed activation of the bilateral primary visual cortex and the bilateral lateral geniculate nucleus. CONCLUSIONS: Robust activation of the vision-related areas was successfully obtained in all subjects using a 4 T magnetic resonance scanner. These results suggest that fMRI at very high field strengths may be effective in showing visual system physiology, and that it can be a promising method to assess visual function of human subjects.     

Increasing cortical activity in auditory areas through neurofeedback functional magnetic resonance imaging

We report a functional magnetic resonance imaging method to deliver task-specific brain activities as biofeedback signals to guide individuals to increase cortical activity in auditory areas during sound stimulation. A total of 11 study participants underwent multiple functional magnetic resonance imaging scan sessions, while the changes in the activated cortical volume within the primary and secondary auditory areas were fed back to them between scan sessions. On the basis of the feedback information, participants attempted to increase the number of significant voxels during the subsequent trial sessions by adjusting their level of attention to the auditory stimuli. Results showed that the group of individuals who received the feedback were able to increase the activation volume and blood oxygenation level-dependent signal to a greater degree than the control group.     

A high resolution assessment of the repeatability of relative location and intensity of transcranial magnetic stimulation-induced and volitionally induced blood oxygen level-dependent response in the motor cortex.

OBJECTIVE: Using functional magnetic resonance imaging, we assessed variation in location and intensity of blood oxygen level-dependent contrast associated with movements induced by transcranial magnetic stimulation or volition. BACKGROUND: Anatomic location and within-subject repeatability of blood oxygen level-dependent responses induced by transcranial magnetic stimulation comprise critical information to the use of interleaved transcranial magnetic stimulation/functional magnetic resonance imaging as a neuroscience tool. METHODS: Eleven healthy adults were scanned 3 times each at 1.5 T. Interleaved with functional magnetic resonance imaging, 1-Hz transcranial magnetic stimulation was applied over motor cortex. VOL was alternated with transcranial magnetic stimulation over the scans. RESULTS: Intra-subject standard deviations in blood oxygen level-dependent locations ranged between 3 and 6 millimeters, allowing localization to subregions of the motor strip. Coil placement relative to blood oxygen level-dependent location varied more than blood oxygen level-dependent location (sdx = 9.5mm, sdy = 8.7 mm, sdz = 9.0mm) with consistent anterior displacement (dy = 21.8 mm, P = <0.025). Analysis of variance did not detect significant differences between transcranial magnetic stimulation and VOL blood oxygen level-dependent locations or intensities, in contrast to significant intensity differences detected in auditory blood oxygen level dependence. CONCLUSION: The high repeatability of location of transcranial magnetic stimulation-induced blood oxygen level-dependent activation suggests that transcranial magnetic stimulation/functional magnetic resonance imaging stimulation can be used as a precise tool in investigation of cortical mechanisms. The similarity between VOL and transcranial magnetic stimulation suggests that transcranial magnetic stimulation may act through natural brain movement circuits.     

Brain activation related to retrosaccades in saccade experiments

In saccade experiments, each trial (e.g. prosaccade/antisaccade) is by definition followed by a saccade, which returns the gaze back to the center (retrosaccade). This event can complicate brain-imaging results when using a simple block-design. We used an event-related functional magnetic resonance imaging design involving prosaccades and antisaccades (testsaccades) to examine brain activation associated with retrosaccades. Testsaccades activated visual and oculomotor-related brain areas. During retrosaccades, these areas were less active than during testsaccades. In the supplementary eye fields, the insula, and striatum, the retrosaccades gave rise to negative blood oxygenation level-dependent responses. In the striatum, these negative responses were equal in size to the positive responses of the testsaccades. This could mask brain activity of testsaccades when not taken into account.     

Quantitative assessment of the balance between oxygen delivery and consumption in the rat brain after transient ischemia with T2 -BOLD magnetic resonance imaging.

The balance between oxygen consumption and delivery in the rat brain after exposure to transient ischemia was quantitatively studied with single-spin echo T2-BOLD (blood oxygenation level-dependent) magnetic resonance imaging at 4.7 T. The rats were exposed to graded common carotid artery occlusions using a modification of the four-vessel model of Pulsinelli. T2, diffusion, and cerebral blood volume were quantified with magnetic resonance imaging, and CBF was measured with the hydrogen clearance method. A transient common carotid artery occlusion below the CBF value of approximately 20 mL x 100 g(-1) x min(-1) was needed to yield a T2 increase of 4.6 +/- 1.2 milliseconds (approximately 9% of cerebral T2) and 6.8 +/- 1.7 milliseconds (approximately 13% of cerebral T2) after 7 and 15 minutes of ischemia, respectively. Increases in CBF of 103 +/- 75% and in cerebral blood volume of 29 +/- 20% were detected in the reperfusion phase. These hemodynamic changes alone could account for only approximately one third of the T2 increase in luxury perfusion, suggesting that a substantial increase in blood oxygen saturation (resulting from reduced oxygen extraction by the brain) is needed to explain the magnetic resonance imaging observation.     

EEG Monitoring during Functional MRI in Animal Models

Summary:  Despite its excellent temporal resolution, electroencephalogram (EEG) has poor spatial resolution to study the participation of different brain areas in epileptic discharges, and the propagation of seizures to subcortical areas is not revealed. Furthermore, EEG provides no information about metabolic changes that occur in the brain before and during the epileptic discharges. Thus, monitoring variations in blood flow and oxygenation in response to epileptic discharges can provide additional complementary information. Functional magnetic resonance imaging (fMRI) technology can be used to study the hemodynamic changes associated with interictal epileptiform discharges or epileptic seizures (i.e., before, during or after them) in experimental animal models and may noninvasively monitor these changes over time. Blood oxygenation level-dependent fMRI has superior spatial resolution compared with other functional imaging modalities and utilizes changes in local magnetic field properties to measure the amount of deoxyhemoglobin in each brain areas as an indicator of brain activity. Simultaneous recording of EEG and fMRI is required to achieve this objective. This article describes methods of acquiring and monitoring EEG during fMRI studies in experimental animals. Particular attention will be paid to methods used to eliminate artifacts induced in the acquired magnetic resonance images by EEG equipment and MR-related artifacts in EEG recordings.     

Recent developments in oximetry and perfusion-based mapping techniques and their role in the surgical treatment of neocortical epilepsy

Detailed understanding of neurovascular coupling during epilepsy is critical for the interpretation of various perfusion-based imaging techniques, such as positron emission tomography, single-photon-emission computed tomography, and functional magnetic resonance imaging, which are used to guide surgical therapy. We used high-resolution intrinsic signal- and voltage-sensitive dye imaging, as well as oxygen-sensitive electrodes, to map the precise spatiotemporal relationship between excitatory and inhibitory neuronal activity, cerebral blood volume, and oximetry during epilepsy. We observed a rapid focal decrease in tissue oxygenation and an increase in deoxygenated hemoglobin in association with both interictal and ictal events. This "epileptic dip" in oxygenation lasts several seconds following both interictal and ictal events, implying that for a period, cerebral blood flow is inadequate to meet metabolic demand. We also observed a rapid focal increase in cerebral blood volume that soon spread to adjacent nonepileptic gyri. Likewise, a diffuse decrease in deoxygenated hemoglobin, related to the blood oxygen level-dependent signal recorded with functional magnetic resonance imaging, spread to adjacent gyri and was poorly localized.     

Identification of Alzheimer disease risk by functional magnetic resonance imaging

BACKGROUND: Functional magnetic resonance imaging plays a promising role in the preclinical characterization of Alzheimer disease (AD) for use in early diagnosis and in preventive drug trials. OBJECTIVE: To determine whether functional magnetic resonance imaging can reliably distinguish risk groups for AD among cognitively normal middle-aged adults. DESIGN: Cross-sectional case-control study. SETTING: University of California, San Diego, Alzheimer Disease Research Center participants and San Diego community volunteers. PARTICIPANTS: Twenty cognitively normal individuals (10 high risk and 10 low risk), aged 58 to 65 years, were divided into 2 groups based on the presence or absence of the apolipoprotein E epsilon4 allele and a positive family history of AD. MAIN OUTCOME MEASURES: Word pairs were presented in a blocked design alternating between conditions of novel pairs, repeated pairs, and fixation. Whole-brain differences in blood oxygenation level-dependent brain responses between conditions were compared across risk groups. RESULTS: Compared with the low-risk group, the high-risk group showed many areas of differential blood oxygenation level-dependent response in regions commonly associated with AD pathology (eg, the left medial temporal lobe). Furthermore, different patterns of association between left medial temporal lobe activity and memory performance were demonstrated. CONCLUSIONS: Results support a theory of up-regulation in neuronal memory systems in people at risk for AD many years before the typical age at disease onset. They further demonstrate that functional magnetic resonance imaging is a viable technique to identify persons at risk for AD.     

Noninvasive functional imaging of human brain using light.

Analysis of photon transit time for low-power light passing into the head, and through both skull and brain, of human subjects allowed for tomographic imaging of cerebral hemoglobin oxygenation based on photon diffusion theory. In healthy adults, imaging of changes in hemoglobin saturation during hand movement revealed focal, contralateral increases in motor cortex oxygenation with spatial agreement to activation maps determined by functional magnetic resonance imaging; in ill neonates, imaging of hemoglobin saturation revealed focal regions of low oxygenation after acute stroke, with spatial overlap to injury location determined by computed tomography scan. Because such slow optical changes occur over seconds and co-localize with magnetic resonance imaging vascular signals whereas fast activation-related optical changes occur over milliseconds and co-localize with EEG electrical signals, optical methods offer a single modality for exploring the spatio-temporal relationship between electrical and vascular responses in the brain in vivo, as well as for mapping cortical activation and oxygenation at the bedside in real-time for clinical monitoring.     

Emotion processing in Parkinson's disease: a blood oxygenation level-dependent functional magnetic resonance imaging study

Parkinson's disease is a neurodegenerative disorder caused by loss of dopamine neurons in the substantia nigra pars compacta. Tremor, rigidity, and bradykinesia are the major symptoms of the disease. These motor impairments are often accompanied by affective and emotional dysfunctions which have been largely studied over the last decade. The aim of this study was to investigate emotional processing organization in the brain of patients with Parkinson's disease and to explore whether there are differences between recognition of different types of emotions in Parkinson's disease. We examined 18 patients with Parkinson's disease(8 men, 10 women) with no history of neurological or psychiatric comorbidities. All these patients underwent identical brain blood oxygenation level-dependent functional magnetic resonance imaging for emotion evaluation. Blood oxygenation level-dependent functional magnetic resonance imaging results revealed that the occipito-temporal cortices, insula, orbitofrontal cortex, basal ganglia, and parietal cortex which are involved in emotion processing, were activated during the functional control. Additionally, positive emotions activate larger volumes of the same anatomical entities than neutral and negative emotions. Results also revealed that Parkinson's disease associated with emotional disorders are increasingly recognized as disabling as classic motor symptoms. These findings help clinical physicians to recognize the emotional dysfunction of patients with Parkinson's disease.     

Cerebral perfusion response to hyperoxia.

Graded levels of supplemental inspired oxygen were investigated for their viability as a noninvasive method of obtaining intravascular magnetic resonance image contrast. Administered hyperoxia has been shown to be effective as a blood oxygenation level-dependent contrast agent for magnetic resonance imaging (MRI); however, it is known that high levels of inspired fraction of oxygen result in regionally decreased perfusion in the brain potentially confounding the possibility of using hyperoxia as a means of measuring blood flow and volume. Although the effects of hypoxia on blood flow have been extensively studied, the hyperoxic regime between normoxia and 100% inspired oxygen has been only intermittently studied. Subjects were studied at four levels of hyperoxia induced during a single session while perfusion was measured using arterial spin labelling MRI. Reductions in regional perfusion of grey matter were found to occur even at moderate levels of hyperoxia; however, perfusion changes at all oxygen levels were relatively mild (less than 10%) supporting the viability of hyperoxia-induced contrast.     

Biophysical and physiological origins of blood oxygenation level-dependent fMRI signals

After its discovery in 1990, blood oxygenation level-dependent (BOLD) contrast in functional magnetic resonance imaging (fMRI) has been widely used to map brain activation in humans and animals. Since fMRI relies on signal changes induced by neural activity, its signal source can be complex and is also dependent on imaging parameters and techniques. In this review, we identify and describe the origins of BOLD fMRI signals, including the topics of (1) effects of spin density, volume fraction, inflow, perfusion, and susceptibility as potential contributors to BOLD fMRI, (2) intravascular and extravascular contributions to conventional gradient-echo and spin-echo BOLD fMRI, (3) spatial specificity of hemodynamic-based fMRI related to vascular architecture and intrinsic hemodynamic responses, (4) BOLD signal contributions from functional changes in cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of O(2) utilization (CMRO(2)), (5) dynamic responses of BOLD, CBF, CMRO(2), and arterial and venous CBV, (6) potential sources of initial BOLD dips, poststimulus BOLD undershoots, and prolonged negative BOLD fMRI signals, (7) dependence of stimulus-evoked BOLD signals on baseline physiology, and (8) basis of resting-state BOLD fluctuations. These discussions are highly relevant to interpreting BOLD fMRI signals as physiological means.     

Spatiotemporal evolution of functional hemodynamic changes and their relationship to neuronal activity.

Brain imaging techniques such as functional magnetic resonance imaging (fMRI) have provided a wealth of information about brain organization, but their ability to investigate fine-scale functional architecture is limited by the spatial specificity of the hemodynamic responses upon which they are based. We investigated the spatiotemporal evolution of hemodynamic responses in rat somatosensory cortex to electrical hindpaw stimulation. We combined the advantages of optical intrinsic signal imaging and spectroscopy to produce high-resolution two-dimensional maps of functional changes in tissue oxygenation and blood volume. Cerebral blood flow changes were measured with laser-Doppler flowmetry, and simultaneously recorded field potentials allowed comparison between hemodynamic changes and underlying neuronal activity. For the first 2 to 3 secs of activation, hemodynamic responses overlapped in a central parenchymal focus. Over the next several seconds, cerebral blood volume changes propagated retrograde into feeding arterioles, and oxygenation changes anterograde into draining veins. By 5 to 6 secs, responses localized primarily in vascular structures distant from the central focus. The peak spatial extent of the hemodynamic response increased linearly with synaptic activity. This spatial spread might be because of lateral subthreshold activation or passive vascular overspill. These results imply early microvascular changes in volume and oxygenation localize to activated neural columns, and that spatial specificity will be optimal within a 2- to 3-sec window after neuronal activation.     

Class information predicts activation by object fragments in human object areas

Object-related areas in the ventral visual system in humans are known from imaging studies to be preferentially activated by object images compared with noise or texture patterns. It is unknown, however, which features of the object images are extracted and represented in these areas. Here we tested the extent to which the representation of visual classes used object fragments selected by maximizing the information delivered about the class. We tested functional magnetic resonance imaging blood oxygenation level-dependent activation of highly informative object features in low- and high-level visual areas, compared with noninformative object features matched for low-level image properties. Activation in V1 was similar, but in the lateral occipital area and in the posterior fusiform gyrus, activation by "informative" fragments was significantly higher for three object classes. Behavioral studies also revealed high correlation between performance and fragments information. The results show that an objective class-information measure can predict classification performance and activation in human object-related areas.     

Development of a functional magnetic resonance imaging protocol for intraoperative localization of critical temporoparietal language areas

The aim of this study was to evaluate the use of functional magnetic resonance imaging as an alternative to intraoperative electrocortical stimulation mapping for the localization of critical language areas in the temporoparietal region. We investigated several requirements that functional magnetic resonance imaging must fulfill for clinical implementation: high predictive power for the presence as well as the absence of critical language function in regions of the brain, user-independent statistical methodology, and high spatial accuracy. Thirteen patients with temporal lobe epilepsy performed four different functional magnetic resonance imaging language tasks (ie, verb generation, picture naming, verbal fluency, and sentence comprehension) before epilepsy surgery that included intraoperative electrocortical stimulation mapping. To assess the optimal statistical threshold for functional magnetic resonance imaging, images were analyzed with three different statistical thresholds. Functional magnetic resonance imaging information was read into a surgical guidance system for identification of cortical areas of interest. Intraoperative electrocortical stimulation mapping was recorded by video camera, and stimulation sites were digitized. Next, a computer algorithm indicated whether significant functional magnetic resonance imaging activation was present or absent within the immediate vicinity (<6.4mm) of intraoperative electrocortical stimulation mapping sites. In 2 patients, intraoperative electrocortical stimulation mapping failed during surgery. Intraoperative electrocortical stimulation mapping detected critical language areas in 8 of the remaining 11 patients. Correspondence between functional magnetic resonance imaging and intraoperative electrocortical stimulation mapping depended heavily on statistical threshold and varied between patients and tasks. In 7 of 8 patients, sensitivity of functional magnetic resonance imaging was 100% with a combination of 3 functional magnetic resonance imaging tasks (ie, functional magnetic resonance imaging correctly detected all critical language areas with high spatial accuracy). In 1 patient, sensitivity was 38%; in this patient, functional magnetic resonance imaging was included in a larger area found with intraoperative electrocortical stimulation mapping. Overall, specificity was 61%. Functional magnetic resonance imaging reliably predicted the absence of critical language areas within the region exposed during surgery, indicating that such areas can be safely resected without the need for intraoperative electrocortical stimulation mapping. The presence of functional magnetic resonance imaging activity at noncritical language sites limited the predictive value of functional magnetic resonance imaging for the presence of critical language areas to 51%. Although this precludes current replacement of intraoperative electrocortical stimulation mapping, functional magnetic resonance imaging can at present be used to speed up intraoperative electrocortical stimulation mapping procedures and to guide the extent of the craniotomy.     

Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson's disease.

Functional magnetic resonance imaging (fMRI) was performed in patients with Parkinson's disease during deep brain stimulation of the subthalamic nucleus (three patients) and during deep brain stimulation of the ventral intermedius nucleus of the thalamus (one patient). All showed an increase in blood oxygenation level-dependent signal in the subcortical regions ipsilateral to the stimulated nucleus. This effect cannot be simply explained by a mechanism of depolarization blockade; rather, it is caused by overstimulation of the target nucleus, resulting in the suppression of its spontaneous activity. We confirm that fMRI during deep brain stimulation is a safe method with considerable potential for elucidating the functional connectivity of the stimulated nuclei.     

Haemodynamic and neural responses to hypercapnia in the awake rat

The relationship between localized changes in brain activity and metabolism, and the blood oxygenation level-dependent (BOLD) signal used in functional magnetic resonance imaging studies is not fully understood. One source of complexity is that stimulus-elicited changes in the BOLD signal arise both from changes in oxygen consumption due to increases in activity and purely 'haemodynamic' changes such as increases in cerebral blood flow. It is well established that robust cortical haemodynamic changes can be elicited by increasing the concentration of inspired CO(2) (inducing hypercapnia) and it is widely believed that these haemodynamic changes occur without significant effects upon neural activity or cortical metabolism. Hypercapnia is therefore commonly used as a calibration condition in functional magnetic resonance imaging studies to enable estimation of oxidative metabolism from subsequent stimulus-evoked functional magnetic resonance imaging BOLD signal changes. However, there is little research that has investigated in detail the effects of hypercapnia upon all components of the haemodynamic response (changes in cerebral blood flow, volume and oxygenation) in addition to recording neural activity. In awake animals, we used optical and electrophysiological techniques to measure cortical haemodynamic and field potential responses to hypercapnia (60 s, 5% CO(2)). The main findings are that firstly, in the awake rat, the temporal structure of the haemodynamic response to hypercapnia differs from that reported previously in anaesthetized preparations in that the response is more rapid. Secondly, there is evidence that hypercapnia alters ongoing neural activity in awake rats by inducing periods of cortical desynchronization and this may be associated with changes in oxidative metabolism.     

Motion standstill leads to activation of inferior parietal lobe

Previous studies on motion perception revealed motion-processing brain areas sensitive to changes in luminance and texture (low-level) and changes in salience (high-level). The present functional magnetic resonance imaging (fMRI) study focused on motion standstill. This phenomenon, occurring at fast presentation frequencies of visual moving objects that are perceived as static, has not been previously explored by neuroimaging techniques. Thirteen subjects were investigated while perceiving apparent motion at 4 Hz, at 30 Hz (motion standstill), isoluminant static and flickering stimuli, fixation cross, and blank screen, presented randomly and balanced for rapid event-related fMRI design. Blood oxygenation level-dependent (BOLD) signal in the occipito-temporal brain region MT/V5 increased during apparent motion perception. Here we could demonstrate that brain areas like the posterior part of the right inferior parietal lobule (IPL) demonstrated higher BOLD-signal during motion standstill. These findings suggest that the activation of higher-order motion areas is elicited by apparent motion at high presentation rates (motion standstill). We interpret this observation as a manifestation of an orienting reaction in IPL towards stimulus motion that might be detected but not resolved by other motion-processing areas (i.e., MT/V5).     

Functional magnetic resonance imaging and magnetoencephalography differences associated with APOEepsilon4 in young healthy adults

Functional neural alterations are present in middle-aged to late-aged healthy individuals carrying the epsilon4 allele of the apolipoprotein E (APOEepsilon4) gene, a known risk factor for Alzheimer's disease. Neural activity was measured in young adults with and without the epsilon4 allele (APOEepsilon4+ and APOEepsilon4-) by functional magnetic resonance imaging and magnetoencephalography while performing a visual working memory task on two separate days. Greater activity was observed in frontal areas and cingulate gyri in APOEepsilon4+ participants by both functional magnetic resonance imaging and magnetoencephalography with regional blood oxygenation level-dependent responses correlating with increased theta band power. The findings suggest that the presence of the APOEepsilon4 allele has physiological consequences before aging that may contribute to risk for Alzheimer's disease.     

Neural correlates of formal thought disorder in schizophrenia: preliminary findings from a functional magnetic resonance imaging study

BACKGROUND: Formal thought disorder (FTD) is a core symptom of schizophrenia, but its pathophysiology is little understood. We examined the neural correlates of FTD using functional magnetic resonance imaging. METHODS: Blood oxygenation level-dependent contrast was measured using functional magnetic resonance imaging while 6 patients with schizophrenia and 6 control subjects spoke about 7 Rorschach inkblots for 3 minutes each. In patients, varying degrees of thought-disordered speech were elicited during each "run." In a within-subject design, the severity of positive FTD was correlated with the level of blood oxygenation level-dependent contrast in the 2 runs that showed the highest variance of FTD in each patient. RESULTS: The severity of positive FTD in patients was negatively correlated (P<.001) with signal changes in the left superior and middle temporal gyri. Positive correlations were evident in the cerebellar vermis, the right caudate body, and the precentral gyrus. CONCLUSIONS: The severity of positive FTD was inversely correlated with the level of activity in the Wernicke area, a region implicated in the production of coherent speech. Reduced activity in this area might contribute to the articulation of incoherent speech. Because of the small sample size, these findings should be considered preliminary.