Multimodal Neuroimaging in Schizophrenia: Description and Dissemination.

In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network's collaborative informatics and neuroimaging suite (COINS).

Modelling the magnetic signature of neuronal tissue.

Neuronal communication in the brain involves electrochemical currents, which produce magnetic fields. Stimulus-evoked brain responses lead to changes in these fields and can be studied using magneto- and electro-encephalography (MEG/EEG). In this paper we model the spatiotemporal distribution of the magnetic field of a physiologically idealized but anatomically realistic neuron to assess the possibility of using magnetic resonance imaging (MRI) for directly mapping the neuronal currents in the human brain. Our results show that the magnetic field several centimeters from the centre of the neuron is well approximated by a dipole source, but the field close to the neuron is not, a finding particularly important for understanding the possible contrast mechanism underlying the use of MRI to detect and locate these currents. We discuss the importance of the spatiotemporal characteristics of the magnetic field in cortical tissue for evaluating and optimizing an experiment based on this mechanism and establish an upper bound for the expected MRI signal change due to stimulus-induced cortical response. Our simulations show that the expected change of the signal magnitude is 1.6% and its phase shift is 1 degrees . An unexpected finding of this work is that the cortical orientation with respect to the external magnetic field has little effect on the predicted MRI contrast. This encouraging result shows that magnetic resonance contrast directly based on the neuronal currents present in the cortex is theoretically a feasible imaging technique. MRI contrast generation based on neuronal currents depends on the dendritic architecture and we obtained high-resolution optical images of cortical tissue to discuss the spatial structure of the magnetic field in grey matter.

Regional brain chemical alterations in young children with autism spectrum disorder.

OBJECTIVE: The authors evaluated regional brain chemistry for evidence of increased neuronal packing density in autism. METHODS: Forty-five 3- to 4-year-old children with autism spectrum disorder (ASD), 13 children with typical development (TD), and 15 children with delayed development (DD) were studied using dual-echo proton echoplanar spectroscopic imaging (32 x 32 matrix-1 cm(3) voxels) to measure brain chemical concentrations and relaxation times. Chemical quantification was corrected for tissue partial volume and relative measures of chemical relaxation (T(2r)) were calculated from the paired echoes. Measures from averaged and individual regions were compared using analysis of variance corrected for multiple comparisons. RESULTS: ASD subjects demonstrated reduced N-acetylaspartate (NAA) (-10%), creatine (Cre) (-8%), and myo-inositol (-13%) concentrations compared to TD controls and prolonged NAA T(2r) relative to TD (7%) and DD (9%) groups. Compared to DD subjects, children with ASD also demonstrated prolonged T(2r) for choline (10%) and Cre (9%). Regional analyses demonstrated subtle patterns of chemical alterations in ASD compared to the TD and DD groups. CONCLUSIONS: Brain chemical abnormalities are present in ASD at 3 to 4 years of age. However, the direction and widespread distribution of these abnormalities do not support hypothesis of diffuse increased neuronal packing density in ASD.

Real-time quantification of T(2)(*) changes using multiecho planar imaging and numerical methods.

Conventional approaches to quantify whole brain T(2)(*) maps use nonlinear regression with intensive computational requirements that therefore likely limit quantitative T(2)(*) mapping for real-time applications. To overcome these limitations an alternative method, NumART(2)(*) (NUMerical Algorithm for Real-time T(2)(*) mapping) that directly calculates T(2)(*) by a linear combination of images obtained at three or more different echo times was developed. NumART(2)(*), linear least-squares, and nonlinear regression techniques were applied to multiecho planar images of the human brain and to simulated data. Although NumART(2)(*) may overestimate T(2)(*), it yields comparable values to regression techniques in cortical and subcortical areas, with only moderate deviations for echo spacings between 18 and 40 ms. NumART(2)(*), like linear regression, requires 2% of the computational time needed for nonlinear regression and compares favorably with linear regression due to its higher precision. The use of NumART(2)(*) for continuous on-line T(2)(*) mapping in real time fMRI studies is shown.

[Fundamentals of functional magnetic resonance imaging in clinical psychology and psychiatry]. / Funktionelle Kernspintomographie in der klinischen Psychologie und Psychiatrie.

In the last few years, functional magnetic resonance imaging (fMRI) has become the preferred technique for brain mapping because of its superior spatial and temporal resolution. Other factors that have contributed to the popularity of this imaging method are the increasing availability of scanners and the technological advances made in data acquisition and analysis. This paper describes basic principles of fMRI essential to a comprehension of the capabilities of this complex technology. In particular, it focuses on blood oxygenation level dependent (BOLD) contrast, on the experimental procedures, as well as on possible imaging techniques and statistical analyses. Examples for studying brain-behavior-relationships come from research in the context of emotion in healthy subjects as well as in emotional dysfunctions in psychiatric patients.

Effect of respiratory CO(2) changes on the temporal dynamics of the hemodynamic response in functional MR imaging.

Increasing end-expiratory CO(2) levels (PETCO(2)) increases the dispersion and the time of maximum of the hemodynamic response curve in human primary visual cortex. This was demonstrated using event-related multislice functional magnetic resonance imaging (fMRI) with short repetition time and 3-s flicker light stimulation. Measurements were performed at 5 different PETCO(2) levels between 20 and 60 mmHg using hyperventilation or by adding CO(2) to the inspired air. Between 30 and 60 mmHg the full-width-at-half-maximum of the hemodynamic response curve induced by visual stimulation increased nearly linearly at 130 ms per mmHg PETCO(2). Consistent with previous studies a concomitant decrease of the signal amplitude was observed at PETCO(2) values below 40 mmHg and above 50 mmHg. The relevance of these findings for the temporal resolution of fMRI and especially of event-related methods is discussed.

Interdependence of regional and global cerebral blood flow during visual stimulation: an O-15-butanol positron emission tomography study.

The authors investigated the influence of variations in global cerebral blood flow (gCBF) on regional flow changes during visual stimulation. Global flow was varied using different end-expiratory CO2 values (PETCO2) between 20 and 70 mm Hg. Visual stimulation was performed with a red LED-array flashing at 8 Hz. Blood flow was measured with 0-15-butanol, continuous arterial blood sampling, and positron emission tomography (PET). Global flow changes surpassed the published values of O-15-H2O studies, better fitting the results of the inert gas technique (gCBF at 20, 40, and 70 mm Hg PETCO2 +/- SD was 31 +/- 4, 48 +/- 13, and 160 +/- 50 mL 100 g(-1) min(-1), respectively). The relation between PETCO2 and CBF in the current study was best described by an exponential rather than a linear function. At low PETCO2, the activation-induced flow changes are moderately damped, whereas at high PETCO2, they are nearly lost (deltaCBF (+/-SD): 52% +/- 25%, 68% +/- 22%, 16% +/- 25% at PETCO2 = 20, 40, 70 mm Hg, respectively).

Effect of graded hypo- and hypercapnia on fMRI contrast in visual cortex: quantification of T(*)(2) changes by multiecho EPI.

The sensitivity of functional magnetic resonance imaging (fMRI) in visual cortex to graded hypo- and hypercapnia was quantified in 10 normal subjects using single-shot multiecho echo-planar imaging (Turbo-PEPSI) with eight equidistant echo times (TEs) between 12 and 140 ms. Visual stimulation was combined with controlled hyperventilation and carbon dioxide inhalation to perform fMRI at six levels of end-expiratory pCO(2) (PETCO(2)) between 20 and 70 mm Hg. T(*)(2) in visual cortex during baseline conditions (light off) increased nonlinearly from 20 to 70 mm Hg, from 61.1 +/- 4.2 ms to 72.0 +/- 4.6 ms. Changes in T(*)(2) due to visual stimulation increased 2.1-fold, from 1.2 +/- 0.6 ms at 20 mm Hg to 2.5 +/- 0.7 ms at 50 mm Hg. An almost complete loss of functional contrast was measured at 70 mm Hg. The model of MR signal dephasing by Yablonskiy and Haacke (Mag Reson Med 1994;32:749-763) was used to predict changes in cerebral blood flow (CBF), which were found to be consistent with results from previous positron emission tomography (PET) studies. This study further emphasizes that global CBF changes (due to PETCO(2) changes even in the physiological range) strongly influence fMRI contrast and need to be controlled for.

Activation of frontoparietal cortices during memorized triple-step sequences of saccadic eye movements: an fMRI study.

To determine the cortical areas controlling memory-guided sequences of saccadic eye movements, we performed functional magnetic resonance imaging (fMRI) in six healthy adults. Subjects had to perform a memorized sequence of three saccades in darkness, after a triple-step stimulus of successively flashed laser targets. To assess the differential contribution of saccadic subfunctions, we applied several control conditions, such as central fixation with or without triple-step visual stimulation, self-paced saccades in darkness, visually guided saccades and single memory-guided saccades. Triple-step saccades strongly activated the regions of the frontal eye fields, the adjacent ventral premotor cortex, the supplementary eye fields, the anterior cingulate cortex and several posterior parietal foci in the superior parietal lobule, the precuneus, and the middle and posterior portion of the intraparietal sulcus, the probable location of the human parietal eye field. Comparison with the control conditions showed that the right intraparietal sulcus and parts of the frontal and supplementary eye fields are more involved in the execution of triple-step saccades than in the other saccade tasks. In accordance with evidence from clinical lesion studies, we propose that the supplementary eye field essentially controls the triggering of memorized saccadic sequences, whereas activation near the middle portion of the right intraparietal sulcus appears to reflect the necessary spatial computations, including the use of extraretinal information (efference copy) about a saccadic eye displacement for updating the spatial representation of the second or third target of the triple-step sequence.

Subjective ratings of pain correlate with subcortical-limbic blood flow: an fMRI study.

Studies investigating the cerebral representations of pain using functional imaging techniques failed to elucidate the affective aspects of pain. This investigation used functional magnetic resonance imaging to measure pain-related changes in cerebral activity during painful stimulation with a strong affective component. Vascular pain was induced via balloon dilatation of a dorsal foot vein of healthy volunteers. The subjects rated their perceived pain uninterruptedly during imaging, allowing cerebral activity to be correlated with both stimulus function (boxcar) and, more importantly, subjective ratings reflecting individual pain experience. The findings indicated signal increases in subcortical-limbic regions, particularly in the amygdala. This region is suggested to be involved in the affective dimension of pain.

A new approach to measure single-event related brain activity using real-time fMRI: feasibility of sensory, motor, and higher cognitive tasks.

Real-time fMRI is a rapidly emerging methodology that enables monitoring changes in brain activity during an ongoing experiment. In this article we demonstrate the feasibility of performing single-event sensory, motor, and higher cognitive tasks in real-time on a clinical whole-body scanner. This approach requires sensitivity optimized fMRI methods: Using statistical parametric mapping we quantified the spatial extent of BOLD contrast signal changes as a function of voxel size and demonstrate that sacrificing spatial resolution and readout bandwidth improves the detection of signal changes in real time. Further increases in BOLD contrast sensitivity were obtained by using real-time multi-echo EPI. Real-time image analysis was performed using our previously described Functional Imaging in REal time (FIRE) software package, which features real-time motion compensation, sliding window correlation analysis, and automatic reference vector optimization. This new fMRI methodology was validated using single-block design paradigms of standard visual, motor, and auditory tasks. Further, we demonstrate the sensitivity of this method for online detection of higher cognitive functions during a language task using single-block design paradigms. Finally, we used single-event fMRI to characterize the variability of the hemodynamic impulse response in primary and supplementary motor cortex in consecutive trials using single movements. Real-time fMRI can improve reliability of clinical and research studies and offers new opportunities for studying higher cognitive functions.

Evaluation of motion and realignment for functional magnetic resonance imaging in real time.

Functional magnetic resonance imaging in real time is an emerging tool for the assessment of dynamic changes in brain activation. The short response latency (tens of seconds) renders the technique more sensitive to motion artifacts. Motion correction in real time requires computationally efficient algorithms which can be executed on a complete 3D data set within a single time of repetition cycle. In this study, a method to evaluate motion and realign functional images in real time implemented on standard imaging hardware is introduced. The detection of activity in correlation maps is improved, and artifactual edge enhancements are reduced. As the estimation of large movements is stable, this algorithm is attractive for clinical studies with uncooperative patients. Magn Reson Med 45:167-171, 2001.

Functional imaging of conditioned aversive emotional responses in antisocial personality disorder.

Individuals with antisocial personality disorder (n = 12) and healthy controls (n = 12) were examined for cerebral regional activation involved in the processing of negative affect. A differential aversive classical conditioning paradigm was applied with odors as unconditioned stimuli and faces as conditioned stimuli. Functional magnetic resonance imaging (fMRI) based on echo-planar imaging was used while cerebral activity was studied during habituation, acquisition, and extinction. Individually defined cerebral regions were analyzed. Both groups indicated behavioral conditioning following subjective ratings of emotional valence to conditioned stimuli. Differential effects were found during acquisition in the amygdala and dorsolateral prefrontal cortex. Controls showed signal decreases, patients signal increases. These preliminary results revealed unexpected signal increases in cortical/subcortical areas of patients. The increases may result from an additional effort put in by these individuals to form negative emotional associations, a pattern of processing that may correspond to their characteristic deviant emotional behavior.

Gender differences in regional cerebral activity during sadness.

Functional magnetic resonance imaging and echo-planar-imaging were used to investigate affect related gender differences in regional cerebral activity. The experiment was conducted using a standardized mood induction procedure. Blood-oxygen-level-dependent effect was measured in 13 male and 13 female healthy subjects, during both moods of happiness and sadness, respectively. Parallel to earlier neuroimaging findings, our results show brain activity in the amygdala of males during negative affect. Females failed to demonstrate a similar activation pattern despite matched subjective ratings of negative affect to males. Results point to differential regional cerebral correlates of emotional experience in males and females, which is suggestive of a more focal and subcortical processing of sadness in men.

Modeling brain compartmental lactate response to metabolic challenge: a feasibility study.

Magnetic resonance spectroscopy has been used to characterize abnormal brain lactate response in panic disorder (PD) subjects following lactate infusion. The present study integrated water quantification and tissue segmentation to evaluate compartmental lactate response within brain and cerebrospinal fluid (CSF). As there is evidence of brain parenchymal pH changes during lactate infusion, water scans were collected at baseline and post-infusion to address brain water stability. Water levels remained essentially stable across the protocol suggesting internal water provides an improved reference signal for measuring dynamic changes in response to metabolic challenge paradigms such as lactate infusion. To model brain lactate changes by compartments, we took the null hypothesis that lactate rises occur only in tissue. The approach referenced lactate amplitude (potentially from both compartments) to 'voxel' water (water scan corrected for differential T(2) between CSF brain at long-echo times - synonymous to a short-echo water scan). If the magnitude of lactate rise in CSF was equal to or greater than brain, voxels with substantial CSF fractions should demonstrate an equivalent or elevated response to voxels comprised only of tissue. The magnitude of lactate increases paralleled voxel tissue fraction suggesting the abnormal lactate rise observed in PD is tissue-based. The feasibility of lactate quantification and compartmental modeling are discussed.

Functional magnetic resonance imaging in real time (FIRE): sliding-window correlation analysis and reference-vector optimization.

New algorithms for correlation analysis are presented that allow the mapping of brain activity from functional MRI (fMRI) data in real time during the ongoing scan. They combine the computation of the correlation coefficients between measured fMRI time-series data and a reference vector with "detrending", a technique for the suppression of non-stimulus-related signal components, and the "sliding-window technique". Using this technique, which limits the correlation computation to the last N measurement time points, the sensitivity to changes in brain activity is maintained throughout the whole experiment. For increased sensitivity in activation detection a fast and robust optimization of the reference vector is proposed, which takes into account a realistic model of the hemodynamic response function to adapt the parameterized reference vector to the measured data. Based on the described correlation method, real-time fMRI experiments using visual stimulation paradigms have been performed successfully on a clinical MR scanner, which was linked to an external workstation for image analysis.

Broca's region subserves imagery of motion: a combined cytoarchitectonic and fMRI study.

Broca's region in the dominant cerebral hemisphere is known to mediate the production of language but also contributes to comprehension. Here, we report the differential participation of Broca's region in imagery of motion in humans. Healthy volunteers were studied with functional magnetic resonance imaging (fMRI) while they imagined movement trajectories following different instructions. Imagery of right-hand finger movements induced a cortical activation pattern including dorsal and ventral portions of the premotor cortex, frontal medial wall areas, and cortical areas lining the intraparietal sulcus in both cerebral hemispheres. Imagery of movement observation and of a moving target specifically activated the opercular portion of the inferior frontal cortex. A left-hemispheric dominance was found for egocentric movements and a right-hemispheric dominance for movement characteristics in space. To precisely localize these inferior frontal activations, the fMRI data were coregistered with cytoarchitectonic maps of Broca's areas 44 and 45 in a common reference space. It was found that the activation areas in the opercular portion of the inferior frontal cortex were localized to area 44 of Broca's region. These activations of area 44 can be interpreted to possibly demonstrate the location of the human analogue to the so-called mirror neurones found in inferior frontal cortex of nonhuman primates. We suggest that area 44 mediates higher-order forelimb movement control resembling the neuronal mechanisms subserving speech.

A fronto-parietal circuit for object manipulation in man: evidence from an fMRI-study.

Functional magnetic resonance imaging (fMRI) was used to localize brain areas active during manipulation of complex objects. In one experiment subjects were required to manipulate complex objects for exploring their macrogeometric features as compared to manipulation of a simple smooth object (a sphere). In a second experiment subjects were asked to manipulate complex objects and to silently name them upon recognition as compared to manipulation of complex not recognizable objects without covert naming. Manipulation of complex objects resulted in an activation of ventral premotor cortex [Brodmann's area (BA) 44], of a region in the intraparietal sulcus (most probably corresponding to the anterior intraparietal area in the monkey), of area SII and of a sector of the superior parietal lobule. When the objects were covertly named additional activations were found in the opercular part of BA 44 and in the pars triangularis of the inferior frontal gyrus (BA 45). We suggest that a fronto-parietal circuit for manipulation of objects exists in humans and involves basically the same areas as in the monkey. It is proposed that area SII analyses the intrinsic object characteristics whilst the superior parietal lobule is related to kinaesthesia.

Dyslexic children have abnormal brain lactate response to reading-related language tasks.

BACKGROUND AND PURPOSE: Children with dyslexia have difficulty learning to recognize written words owing to subtle deficits in oral language related to processing sounds and accessing words automatically. The purpose of this study was to compare regional changes in brain lactate between dyslexic children and control subjects during oral language activation. METHODS: Brain lactate metabolism was measured during four different cognitive tasks (three language tasks and one nonlanguage task) in six dyslexic boys and in seven control subjects (age- and IQ-matched right-handed boys who are good readers) using a fast MR spectroscopic imaging technique called proton echo-planar spectroscopic imaging (1-cm3 voxel resolution). The area under the N-acetylaspartate (NAA) and lactate peaks was measured to calculate the lactate/NAA ratio in each voxel. RESULTS: Dyslexic boys showed a greater area of brain lactate elevation (2.33+/-SE 0.843 voxels) as compared with the control group (0.57+/-SE 0.30 voxels) during a phonological task in the left anterior quadrant. No significant differences were observed in the nonlanguage tasks. CONCLUSION: Dyslexic and control children differ in brain lactate metabolism when performing language tasks, but do not differ in nonlanguage auditory tasks.

Cerebral midline structures in bimanual coordination.

In six healthy right-handed volunteers, we compared the cerebral activation pattern related to unimanual right- and left-hand movements and to bimanual in-phase and anti-phase movements using functional magnetic resonance imaging (fMRI). Internally paced unimanual finger-to-thumb opposition movements led to a strong contralateral activation of primary sensorimotor areas in all six subjects. Midline activity was lateralized to the left side during right-hand movements, but to both sides during left-hand movements. Activity patterns of bimanual in-phase movements resembled the combined activity patterns of the two unimanual conditions: right and left hemispheric activations of the primary sensorimotor cortices and predominantly left-sided medial frontal activity. In contrast, during anti-phase movements, we observed a clear increase in activity, in both right and left frontal midline areas and in right hemispheric, mainly dorsolateral premotor areas compared to in-phase movements. These results indicate that frontal midline activity is not specific for bimanual movements per se. It can already be involved during simple unimanual movements but becomes progressively more involved during more complex aspects of movement control.