Showing papers in "Human Brain Mapping in 2007"

Phase lag index: assessment of functional connectivity from multi channel EEG and MEG with diminished bias from common sources.

Abstract: Objective: To address the problem of volume conduction and active reference electrodes in the assessment of functional connectivity, we propose a novel measure to quantify phase synchronization, the phase lag index (PLI), and compare its performance to the well-known phase coherence (PC), and to the imaginary component of coherency (IC). Methods: The PLI is a measure of the asymmetry of the distribution of phase differences between two signals. The performance of PLI, PC, and IC was examined in (i) a model of 64 globally coupled oscillators, (ii) an EEG with an absence seizure, (iii) an EEG data set of 15 Alzheimer patients and 13 control subjects, and (iv) two MEG data sets. Results: PLI and PC were more sensitive than IC to increasing levels of true synchronization in the model. PC and IC were influenced stronger than PLI by spurious correlations because of common sources. All measures detected changes in synchronization during the absence seizure. In contrast to PC, PLI and IC were barely changed by the choice of different montages. PLI and IC were superior to PC in detecting changes in beta band connectivity in AD patients. Finally, PLI and IC revealed a different spatial pattern of functional connectivity in MEG data than PC. Conclusion: The PLI performed at least as well as the PC in detecting true changes in synchronization in model and real data but, at the same token and like-wise the IC, it was much less affected by the influence of common sources and active reference electrodes.

Bias between MNI and Talairach coordinates analyzed using the ICBM-152 brain template

Abstract: MNI coordinates determined using SPM2 and FSL/FLIRT with the ICBM-152 template were compared to Talairach coordinates determined using a landmark-based Talairach registration method (TAL). Analysis revealed a clear-cut bias in reference frames (origin, orientation) and scaling (brain size). Accordingly, ICBM-152 fitted brains were consistently larger, oriented more nose down, and translated slightly down relative to TAL fitted brains. Whole brain analysis of MNI/Talairach coordi- nate disparity revealed an ellipsoidal pattern with disparity ranging from zero at a point deep within the left hemisphere to greater than 1-cm for some anterior brain areas. MNI/Talairach coordinate dis- parity was generally less for brains fitted using FSL. The mni2tal transform generally reduced MNI/ Talairach coordinate disparity for inferior brain areas but increased disparity for anterior, posterior, and superior areas. Coordinate disparity patterns differed for brain templates (MNI-305, ICBM-152) using the same fitting method (FSL/FLIRT) and for different fitting methods (SPM2, FSL/FLIRT) using the same template (ICBM-152). An MNI-to-Talairach (MTT) transform to correct for bias between MNI and Talairach coordinates was formulated using a best-fit analysis in one hundred high-resolution 3-D MR brain images. MTT transforms optimized for SPM2 and FSL were shown to reduced group mean MNI/Talairach coordinate disparity from a 5-13 mm to 1-2 mm for both deep and superficial brain sites. MTT transforms provide a validated means to convert MNI coordinates to Talairach compatible coordinates for studies using either SPM2 or FSL/FLIRT with the ICBM-152 template. Hum Brain Mapp

Estimating the number of independent components for functional magnetic resonance imaging data.

Abstract: Multivariate analysis methods such as independent component analysis (ICA) have been applied to the analysis of functional magnetic resonance imaging (fMRI) data to study brain function. Because of the high dimensionality and high noise level of the fMRI data, order selection, i.e., estimation of the number of informative components, is critical to reduce over/underfitting in such methods. De- pendence among fMRI data samples in the spatial and temporal domain limits the usefulness of the practical formulations of information-theoretic criteria (ITC) for order selection, since they are based on likelihood of independent and identically distributed (i.i.d.) data samples. To address this issue, we pro- pose a subsampling scheme to obtain a set of effectively i.i.d. samples from the dependent data samples and apply the ITC formulas to the effectively i.i.d. sample set for order selection. We apply the proposed method on the simulated data and show that it significantly improves the accuracy of order selection from dependent data. We also perform order selection on fMRI data from a visuomotor task and show that the proposed method alleviates the over-estimation on the number of brain sources due to the intrin- sic smoothness and the smooth preprocessing of fMRI data. We use the software package ICASSO (Him- berg et al. (2004): Neuroimage 22:1214-1222) to analyze the independent component (IC) estimates at dif- ferent orders and show that, when ICA is performed at overestimated orders, the stability of the IC esti- mates decreases and the estimation of task related brain activations show degradation. Hum Brain Mapp

Altered functional connectivity in early Alzheimer's disease: A resting‐state fMRI study

Abstract: Previous studies have led to the proposal that patients with Alzheimer's disease (AD) may have disturbed functional connectivity between different brain regions. Furthermore, recent resting-state functional magnetic resonance imaging (fMRI) studies have also shown that low-frequency (<0.08 Hz) fluctuations (LFF) of the blood oxygenation level-dependent signals were abnormal in several brain areas of AD patients. However, few studies have investigated disturbed LFF connectivity in AD patients. By using resting-state fMRI, this study sought to investigate the abnormal functional connectivities throughout the entire brain of early AD patients, and analyze the global distribution of these abnormalities. For this purpose, the authors divided the whole brain into 116 regions and identified abnormal connectivities by comparing the correlation coefficients of each pair. Compared with healthy controls, AD patients had decreased positive correlations between the prefrontal and parietal lobes, but increased positive correlations within the prefrontal lobe, parietal lobe, and occipital lobe. The AD patients also had decreased negative correlations (closer to zero) between two intrinsically anti-correlated networks that had previously been found in the resting brain. By using resting-state fMRI, our results supported previous studies that have reported an anterior-posterior disconnection phenomenon and increased within-lobe functional connectivity in AD patients. In addition, the results also suggest that AD may disturb the correlation/anti-correlation effect in the two intrinsically anti-correlated networks.

Genetic influences on human brain structure: A review of brain imaging studies in twins

Abstract: Twin studies suggest that variation in human brain volume is genetically influenced. The genes involved in human brain volume variation are still largely unknown, but several candidate genes have been suggested. An overview of structural Magnetic Resonance (brain) Imaging studies in twins is presented, which focuses on the influence of genetic factors on variation in healthy human brain volume. Twin studies have shown that genetic effects varied regionally within the brain, with high heritabilities of frontal lobe volumes (90-95%), moderate estimates in the hippocampus (40-69%), and environmental factors influencing several medial brain areas. High heritability estimates of brain structures were revealed for regional amounts of gray matter (density) in medial frontal cortex, Heschl's gyrus, and postcentral gyrus. In addition, moderate to high heritabilities for densities of Broca's area, anterior cingulate, hippocampus, amygdala, gray matter of the parahippocampal gyrus, and white matter of the superior occipitofrontal fasciculus were reported. The high heritability for (global) brain volumes, including the intracranium, total brain, cerebral gray, and white matter, seems to be present throughout life. Estimates of genetic and environmental influences on age-related changes in brain structure in children and adults await further longitudinal twin-studies. For prefrontal cortex volume, white matter, and hippocampus volumes, a number of candidate genes have been identified, whereas for other brain areas, only a few or even a single candidate gene has been found so far. New techniques such as genome-wide scans may become helpful in the search for genes that are involved in the regulation of human brain volume throughout life.

Regulation of emotional responses elicited by threat-related stimuli

Abstract: The capacity to voluntarily regulate emotions is critical for mental health, especially when coping with aversive events. Several neuroimaging studies of emotion regulation found the amygdala to be a target for downregulation and prefrontal regions to be associated with downregulation. To characterize the role of prefrontal regions in bidirectional emotion regulation and to investigate regulatory influences on amygdala activity and peripheral physiological measures, a functional magnetic resonance imaging (fMRI) study with simultaneous recording of self-report, startle eyeblink, and skin conductance responses was carried out. Subjects viewed threat-related pictures and were asked to up- and downregulate their emotional responses using reappraisal strategies. While startle eyeblink responses (in successful regulators) and skin conductance responses were amplified during upregulation, but showed no consistent effect during downregulation, amygdala activity was increased and decreased according to the regulation instructions. Trial-by-trial ratings of regulation success correlated positively with activity in amygdala during upregulation and orbitofrontal cortex during downregulation. Downregulation was characterized by left-hemispheric activation peaks in anterior cingulate cortex, dorsolateral prefrontal cortex, and orbitofrontal cortex and upregulation was characterized by a pattern of prefrontal activation not restricted to the left hemisphere. Further analyses showed significant overlap of prefrontal activation across both regulation conditions, possibly reflecting cognitive processes underlying both up- and downregulation, but also showed distinct activations in each condition. The present study demonstrates that amygdala responses to threat-related stimuli can be controlled through the use of cognitive strategies depending on recruitment of prefrontal areas, thereby changing the subject's affective state.

Linear age-correlated functional development of right inferior fronto-striato-cerebellar networks during response inhibition and anterior cingulate during error-related processes

Abstract: Inhibitory and performance-monitoring functions have been shown to develop throughout adolescence. The developmental functional magnetic resonance imaging (fMRI) literature on inhibitory control, however, has been relatively inconsistent with respect to functional development of prefrontal cortex in the progression from childhood to adulthood. Age-related performance differences between adults and children have been shown to be a confound and may explain inconsistencies in findings. The development of error-related processes has not been studied so far using fMRI. The aim of this study was to investigate the neural substrates of the development of inhibitory control and error-related functions by use of an individually adjusted task design that forced subjects to fail on 50% of trials, and therefore controlled for differences in task difficulty and performance between different age groups. Event-related fMRI was used to compare brain activation between 21 adults and 26 children/adolescents during successful motor inhibition and inhibition failure. Adults compared with children/adolescents showed increased brain activation in right inferior prefrontal cortex during successful inhibition and in anterior cingulate during inhibition failure. A whole-brain age-regression analysis between 10 and 42 years showed progressive age-related changes in activation in these two brain regions, with additional changes in thalamus, striatum, and cerebellum. Age-correlated brain regions correlated with each other and with inhibitory performance, suggesting they form developing fronto-striato-thalamic and fronto-cerebellar neural pathways for inhibitory control. This study shows developmental specialization of the integrated function of right inferior prefrontal cortex, basal ganglia, thalamus, and cerebellum for inhibitory control and of anterior cingulate gyrus for error-related processes.

A functional MRI study of happy and sad affective states induced by classical music

Abstract: The present study investigated the functional neuroanatomy of transient mood changes in response to Western classical music. In a pilot experiment, 53 healthy volunteers (mean age: 32.0; SD = 9.6) evaluated their emotional responses to 60 classical musical pieces using a visual analogue scale (VAS) ranging from 0 (sad) through 50 (neutral) to 100 (happy). Twenty pieces were found to accurately induce the intended emotional states with good reliability, consisting of 5 happy, 5 sad, and 10 emotionally unevocative, neutral musical pieces. In a subsequent functional magnetic resonance imaging (fMRI) study, the blood oxygenation level dependent (BOLD) signal contrast was measured in response to the mood state induced by each musical stimulus in a separate group of 16 healthy participants (mean age: 29.5; SD = 5.5). Mood state ratings during scanning were made by a VAS, which confirmed the emotional valence of the selected stimuli. Increased BOLD signal contrast during presentation of happy music was found in the ventral and dorsal striatum, anterior cingulate, parahippocampal gyrus, and auditory association areas. With sad music, increased BOLD signal responses were noted in the hippocampus/amygdala and auditory association areas. Presentation of neutral music was associated with increased BOLD signal responses in the insula and auditory association areas. Our findings suggest that an emotion processing network in response to music integrates the ventral and dorsal striatum, areas involved in reward experience and movement; the anterior cingulate, which is important for targeting attention; and medial temporal areas, traditionally found in the appraisal and processing of emotions.

Comparison of different cortical connectivity estimators for high-resolution EEG recordings.

Abstract: The aim of this work is to characterize quantitatively the performance of a body of techniques in the frequency domain for the estimation of cortical connectivity from high-resolution EEG recordings in different operative conditions commonly encountered in practice. Connectivity pattern estimators investigated are the Directed Transfer Function (DTF), its modification known as direct DTF (dDTF) and the Partial Directed Coherence (PDC). Predefined patterns of cortical connectivity were simulated and then retrieved by the application of the DTF, dDTF, and PDC methods. Signal-to-noise ratio (SNR) and length (LENGTH) of EEG epochs were studied as factors affecting the reconstruction of the imposed connectivity patterns. Reconstruction quality and error rate in estimated connectivity patterns were evaluated by means of some indexes of quality for the reconstructed connectivity pattern. The error functions were statistically analyzed with analysis of variance (ANOVA). The whole methodology was then applied to high-resolution EEG data recorded during the well-known Stroop paradigm. Simulations indicated that all three methods correctly estimated the simulated connectivity patterns under reasonable conditions. However, performance of the methods differed somewhat as a function of SNR and LENGTH factors. The methods were generally equivalent when applied to the Stroop data. In general, the amount of available EEG affected the accuracy of connectivity pattern estimations. Analysis of 27 s of nonconsecutive recordings with an SNR of 3 or more ensured that the connectivity pattern could be accurately recovered with an error below 7% for the PDC and 5% for the DTF. In conclusion, functional connectivity patterns of cortical activity can be effectively estimated under general conditions met in most EEG recordings by combining high-resolution EEG techniques, linear inverse estimation of the cortical activity, and frequency domain multivariate methods such as PDC, DTF, and dDTF.

Brain maturation in adolescence: concurrent changes in neuroanatomy and neurophysiology.

Abstract: Adolescence to early adulthood is a period of dramatic transformation in the healthy human brain. However, the relationship between the concurrent structural and functional changes remains unclear. We investigated the impact of age on both neuroanatomy and neurophysiology in the same healthy subjects (n = 138) aged 10 to 30 years using magnetic resonance imaging (MRI) and resting electroencephalography (EEG) recordings. MRI data were segmented into gray and white matter images and parcellated into large-scale regions of interest. Absolute EEG power was quantified for each lobe for the slow-wave, alpha and beta frequency bands. Gray matter volume was found to decrease across the age bracket in the frontal and parietal cortices, with the greatest change occurring in adolescence. EEG activity, particularly in the slow-wave band, showed a similar curvilinear decline to gray matter volume in corresponding cortical regions. An inverse pattern of curvilinearly increasing white matter volume was observed in the parietal lobe. We suggest that the reduction in gray matter primarily reflects a reduction of neuropil, and that the corresponding elimination of active synapses is responsible for the observed reduction in EEG power.

Frontoparietal cortical activity of methamphetamine-dependent and comparison subjects performing a delay discounting task.

Abstract: Relative to individuals who do not have addictive disorders, drug abusers exhibit greater devaluation of rewards as a function of their delay ("delay discounting"). The present study sought to extend this finding to methamphetamine (MA) abusers and to help understand its neural basis. MA abusers (n = 12) and control subjects who did not use illicit drugs (n = 17) participated in tests of delay discounting with hypothetical money rewards. We then used a derived estimate of each individual's delay discounting to generate a functional magnetic resonance imaging probe task consisting of three conditions: "hard choices," requiring selections between "smaller, sooner" and "larger, later" alternatives that were similarly valued given the individual's delay discounting; "easy choices," in which alternatives differed dramatically in value; and a "no choice" control condition. MA abusers exhibited more delay discounting than control subjects (P no choice" contrast revealed significant effects in the ventrolateral prefrontal cortex, dorsolateral prefrontal cortex (DLPFC), dorsal anterior cingulate cortex, and areas surrounding the intraparietal sulcus (IPS). With group comparisons limited to these clusters, the "hard choice > easy choice" contrast indicated significant group differences in task-related activity within the left DLPFC and right IPS; qualitatively similar nonsignificant effects were present in the other clusters tested. Whereas control subjects showed less recruitment associated with easy than with hard choices, MA abusers generally did not. Correlational analysis did not indicate a relationship between this anomaly in frontoparietal recruitment and greater degree of delay discounting exhibited by MA abusers. Therefore, while apparent inefficiency of cortical processing related to decision-making in MA abusers may contribute to the neural basis of enhanced delay discounting by this population, other factors remain to be identified.

Parieto-occipital sources account for the increase in alpha activity with working memory load.

Abstract: The role of oscillatory alpha activity (8-13 Hz) in cognitive processing remains an open question. It has been debated whether alpha activity plays a direct role in the neuronal processing required for a given task or whether it reflects idling and/or functional inhibition. Recent electroencephalography (EEG) studies have demonstrated that alpha activity increases parametrically with load during retention in working memory paradigms. While it is known that the parieto-occipital cortex is involved in the generation of the spontaneous alpha oscillations, it remains unknown where the sources of the memory-dependent alpha activity are located. We recorded brain activity using magnetoencephalography (MEG) from human subjects performing a Sternberg memory task where faces were used as stimuli. Spectral analysis revealed a parametric increase in alpha activity with memory load over posterior brain areas. We then applied a source reconstruction technique that allowed us to map the parametric increase in alpha activity to the anatomical magnetic resonance (MR) images of the subject. The primary sources of the memory-dependent alpha activity were in the vicinity of the parieto-occipital sulcus. This region is not directly involved in working memory maintenance of faces. Our findings are consistent with the notion that alpha activity reflects disengagement or inhibition of the visual dorsal stream. We propose that the disengagement reflected in alpha power serves to suppress visual input in order to devote resources to structures responsible for working memory maintenance.

Relationship between task-related gamma oscillations and BOLD signal: new insights from combined fMRI and intracranial EEG.

Abstract: Cognitive neuroscience relies on two sets of techniques to map the neural networks underlying cognition in humans: recordings of either regional metabolic changes (fMRI or PET) or fluctuations in the neural electromagnetic fields (EEG and MEG) Despite major advances in the last few years, an explicit linkage between the two is still missing and the neuroimaging community faces two complementary but unrelated sets of functional descriptions of the human brain Such an explicit framework, linking the two approaches in potentially complex cognitive tasks and in a variety of brain regions would permit to combine them into fine spatio-temporally-grained human brain mapping procedures We combined fMRI and intra-cranial EEG recordings of the same epileptic patients during a semantic decision task and found a close spatial correspondence between regions of fMRI activations and recording sites showing EEG energy modulations in the gamma range (>40 Hz) Our findings further support previous findings that gamma band modulations co-localize with BOLD variations and also indicate that fMRI may be used as a constraint to improve source reconstruction of gamma band EEG responses

Abnormal activation of the social brain during face perception in autism.

Abstract: ASD involves a fundamental impairment in processing social-communicative information from faces. Several recent studies have challenged earlier findings that individuals with autism spec- trum disorder (ASD) have no activation of the fusiform gyrus (fusiform face area, FFA) when viewing faces. In this study, we examined activation to faces in the broader network of face-processing modules that comprise what is known as the social brain. Using 3T functional resonance imaging, we measured BOLD signal changes in 10 ASD subjects and 7 healthy controls passively viewing nonemotional faces. We replicated our original findings of significant activation of face identity-processing areas (FFA and inferior occipital gyrus, IOG) in ASD. However, in addition, we identified hypoactivation in a more widely distributed network of brain areas involved in face processing (including the right amygdala, inferior frontal cortex (IFC), superior temporal sulcus (STS), and face-related somatosensory and pre- motor cortex). In ASD, we found functional correlations between a subgroup of areas in the social brain that belong to the mirror neuron system (IFC, STS) and other face-processing areas. The severity of the social symptoms measured by the Autism Diagnostic Observation Schedule was correlated with the right IFC cortical thickness and with functional activation in that area. When viewing faces, adults with ASD show atypical patterns of activation in regions forming the broader face-processing network and social brain, outside the core FFA and IOG regions. These patterns suggest that areas belonging to the mirror neuron system are involved in the face-processing disturbances in ASD. Hum Brain Mapp 28:441-449, 2007. V C 2006 Wiley-Liss, Inc.

Prefrontal cortex activity is reduced in gambling and nongambling substance users during decision-making

Abstract: Objective: Poor decision-making is a hallmark of addiction, whether to substances or activities. Performance on a widely used test of decision-making, the Iowa Gambling Task (IGT), can discriminate controls from persons with ventral medial frontal lesions, substance-dependence, and pathological gambling. Positron emission tomography (PET) studies indicate that substance-dependent individuals show altered prefrontal activity on the task. Here we adapted the IGT to an fMRI setting to test the hy- pothesis that defects in ventral medial and prefrontal processing are associated with impaired decisions that involve risk but may differ depending on whether substance dependence is comorbid with gam- bling problems. Method: 18 controls, 14 substance-dependent individuals (SD), and 16 SD with gam- bling problems (SDPG) underwent fMRI while performing a modified version of the IGT. Result: Group differences were observed in ventral medial frontal, right frontopolar, and superior frontal cortex dur- ing decision-making. Controls showed the greatest activity, followed by SDPG, followed by SD. Conclu- sion: Our results support a hypothesis that defects in ventral medial frontal processing lead to impaired decisions that involve risk. Reductions in right prefrontal activity during decision-making appear to be modulated by the presence of gambling problems and may reflect impaired working memory, stimulus reward valuation, or cue reactivity in substance-dependent individuals. Hum Brain Mapp 28:1276-1286, 2007. V C 2007 Wiley-Liss, Inc.

Spatiotemporal analysis of the cortical sources of the steady-state visual evoked potential.

Abstract: This study aimed to characterize the neural generators of the steady-state visual evoked potential (SSVEP) to repetitive, 6 Hz pattern-reversal stimulation. Multichannel scalp recordings of SSVEPs and dipole modeling techniques were combined with functional magnetic resonance imaging (fMRI) and retinotopic mapping in order to estimate the locations of the cortical sources giving rise to the SSVEP elicited by pattern reversal. The time-varying SSVEP scalp topography indicated contributions from two major cortical sources, which were localized in the medial occipital and mid-temporal regions of the contralateral hemisphere. Colocalization of dipole locations with fMRI activation sites indicated that these two major sources of the SSVEP were located in primary visual cortex (V1) and in the motion sensitive (MT/V5) areas, respectively. Minor contributions from mid-occipital (V3A) and ventral occipital (V4/V8) areas were also considered. Comparison of SSVEP phase information with timing information collected in a previous transient VEP study (Di Russo et al. [2005] Neuroimage 24:874-886) suggested that the sequence of cortical activation is similar for steady-state and transient stimulation. These results provide a detailed spatiotemporal profile of the cortical origins of the SSVEP, which should enhance its use as an efficient clinical tool for evaluating visual-cortical dysfunction as well as an investigative probe of the cortical mechanisms of visual-perceptual processing.

Neural systems connecting interoceptive awareness and feelings.

Abstract: In many theories of emotions the representations of bodily responses play an important role for subjective feelings. We tested the hypothesis that the perception of bodily states is positively related to the experienced intensity of feelings as well as to the activity of first-order and second-order brain structures involved in the processing of feelings. Using a heartbeat perception task, subjects were separated into groups with either high or poor interoceptive awareness. During emotional picture presentation we measured high-density EEG and used spatiotemporal current density reconstruction to identify regions involved in both interoceptive awareness and emotion processing. We observed a positive relation between interoceptive awareness and the experienced intensity of emotions. Furthermore, the P300 amplitudes to pleasant and unpleasant pictures were enhanced for subjects with high interoceptive awareness. The source reconstruction revealed that interoceptive awareness is related to an enhanced activation in both first-order structures (insula, somatosensory cortices) and second-order structures (anterior cingulate, prefrontal cortices). We conclude that the perception of bodily states is a crucial determinant for the processing and the subjective experience of feelings.

Real-Time fMRI Using Brain-State Classification

Abstract: We have implemented a real-time functional magnetic resonance imaging system based on multivariate classification. This approach is distinctly different from spatially localized real-time imple- mentations, since it does not require prior assumptions about functional localization and individual performance strategies, and has the ability to provide feedback based on intuitive translations of brain state rather than localized fluctuations. Thus this approach provides the capability for a new class of experimental designs in which real-time feedback control of the stimulus is possible—rather than using a fixed paradigm, experiments can adaptively evolve as subjects receive brain-state feedback. In this report, we describe our implementation and characterize its performance capabilities. We observed � 80% classification accuracy using whole brain, block-design, motor data. Within both left and right motor task conditions, important differences exist between the initial transient period produced by task switching (changing between rapid left or right index finger button presses) and the subsequent stable period during sustained activity. Further analysis revealed that very high accuracy is achievable during stable task periods, and that the responsiveness of the classifier to changes in task condition can be much faster than signal time-to-peak rates. Finally, we demonstrate the versatility of this implementa- tion with respect to behavioral task, suggesting that our results are applicable across a spectrum of cog- nitive domains. Beyond basic research, this technology can complement electroencephalography-based brain computer interface research, and has potential applications in the areas of biofeedback rehabilita- tion, lie detection, learning studies, virtual reality-based training, and enhanced conscious awareness. Hum Brain Mapp 28:1033-1044, 2007. V C 2006 Wiley-Liss, Inc.

Dissociation of response inhibition and performance monitoring in the stop signal task using event-related fMRI

Abstract: We examined the neural substrate of motor response inhibition and performance monitoring in the stop signal task (SST) using event-related functional magnetic resonance imaging (fMRI). The SST involves a go task and the occasional requirement to stop the go response. We posit that both the go and the stop phases of the SST involve components of inhibition and performance monitoring. The goal of this study was to determine whether inhibition and performance monitoring during go and stop phases of the task activated different networks. We isolated go-phase activities underlying response withholding, monitoring, and sensorimotor processing and contrasted these with successful inhibition to identify the substrate of response inhibition. Error detection activity was isolated using trials in which a stop signal appeared but the response was executed. These trials were modeled as a hand-specific go trial followed by error processing. Cognitive go-phase processes included response withholding and monitoring and activated right prefrontal and midline networks. Response withdrawal additionally activated right inferior frontal gyrus and basal ganglia (caudate). Error detection invoked by failed inhibition activated dorsal anterior cingulate cortex (dACC) and right middle frontal Brodmann's area 9. Our results confirm that there are distinct aspects of inhibition and performance monitoring functions which come into play at various phases within a given trial of the SST, and that these are separable using fMRI.

Neuroimaging endophenotypes: Strategies for finding genes influencing brain structure and function

Abstract: It is vitally important to identify the genetic determinants of complex brain-related disorders such as autism, dementia, mood disorders, and schizophrenia. However, the search for genes predis- posing individuals to these illnesses has been hampered by their genetic and phenotypic complexity and by reliance upon phenomenologically based qualitative diagnostic systems. Neuroimaging endo- phenotypes are quantitative indicators of brain structure or function that index genetic liability for an illness. These indices will significantly improve gene discovery and help us to understand the func- tional consequences of specific genes at the level of systems neuroscience. Here, we review the feasibil- ity of using neuroanatomic and neuropsychological measures as endophenotypes for brain-related dis- orders. Specifically, we examine specific indices of brain structure or function that are genetically influ- enced and associated with neurological and psychiatric illness. In addition, we review genetic approaches that capitalize on the use of quantitative traits, including those derived from brain images. Hum Brain Mapp 28:488-501, 2007. V C 2007 Wiley-Liss, Inc.

Impaired functional connectivity at EEG alpha and theta frequency bands in major depression

Abstract: Recent reports on functional brain imaging in major depression have lead to an assumption that observed psychopathology might be related to an altered brain functional connectivity. Our hypothesis was that an increase in brain functional connectivity occurs in major depression. As a measure of functional connectivity, the EEG structural synchrony approach was used in 12 medication-free depressive outpatients and 10 control subjects. Differences in the number and strength of structurally synchronized EEG patterns were compared between groups. In depressive patients, the number and strength of short cortex functional connections were significantly larger for the left than for the right hemisphere, while the number and strength of long functional connections were significantly larger for the right than for the left hemisphere. Some of the functional connections were positively correlated with the severity of depression, thus being predictive. These were short-range anterior, posterior, and left hemisphere functional connections for the alpha frequency band and short-range anterior functional connections for the theta frequency band. Topology of the most representative functional connections among all patients with major depression indicated that right anterior and left posterior brain parts may discriminate depressive patients from healthy controls. The obtained data support our hypothesis that there is an increase in brain functional connectivity in major depression. This finding was interpreted within the semantic framework, where different specialization of left (monosemantic context) and right (polysemantic context) hemispheres is functionally insufficient in patients with depression.

Neural correlates of verbal feedback processing: an fMRI study employing overt speech.

Abstract: Speakers use external auditory feedback to monitor their own speech. Feedback distortion has been found to increase activity in the superior temporal areas. Using fMRI, the present study investigates the neural correlates of processing verbal feedback without distortion. In a blocked design, the following conditions were presented: (1) overt picture-naming, (2) overt picture-naming while pink noise was presented to mask external feedback, (3) covert picture-naming, (4) listening to the picture names (previously recorded from participants' own voices), and (5) listening to pink noise. The results show that auditory feedback processing involves a network of different areas related to general performance monitoring and speech-motor control. These include the cingulate cortex and the bilateral insula, supplementary motor area, bilateral motor areas, cerebellum, thalamus and basal ganglia. Our findings suggest that the anterior cingulate cortex, which is often implicated in error-processing and conflict-monitoring, is also engaged in ongoing speech monitoring. Furthermore, in the superior temporal gyrus, we found a reduced response to speaking under normal feedback conditions. This finding is interpreted in the framework of a forward model according to which, during speech production, the sensory consequence of the speech-motor act is predicted to attenuate the sensitivity of the auditory cortex.

Neural characteristics of successful and less successful speech and word learning in adults

Abstract: A remarkable characteristic of the human nervous system is its ability to learn to integrate novel (foreign) complex sounds into words. However, the neural changes involved in how adults learn to integrate novel sounds into words and the associated individual differences are largely unknown. Unlike English, most languages of the world use pitch patterns to mark individual word meaning. We report a study assessing the neural correlates of learning to use these pitch patterns in words by English-speaking adults who had no previous exposure to such usage. Before and after training, subjects discriminated pitch patterns of the words they learned while blood oxygenation levels were measured using fMRI. Subjects who mastered the learning program showed increased activation in the left posterior superior temporal region after training, while subjects who plateaued at lower levels showed increased activation in the right superior temporal region and right inferior frontal gyrus, which are associated with nonlinguistic pitch processing, and prefrontal and medial frontal areas, which are associated with increased working memory and attentional efforts. Furthermore, we found brain activation differences even before training between the two subject groups, including the superior temporal region. These results demonstrate an association between range of neural changes and degrees of language learning, specifically implicating the physiologic contribution of the left dorsal auditory cortex in learning success.

Unified structural equation modeling approach for the analysis of multisubject, multivariate functional MRI data

Abstract: The ultimate goal of brain connectivity studies is to propose, test, modify, and compare certain directional brain pathways. Path analysis or structural equation modeling (SEM) is an ideal statistical method for such studies. In this work, we propose a two-stage unified SEM plus GLM (General Linear Model) approach for the analysis of multisubject, multivariate functional magnetic resonance imaging (fMRI) time series data with subject-level covariates. In Stage 1, we analyze the fMRI multivariate time series for each subject individually via a unified SEM model by combining longitudinal pathways represented by a multivariate autoregressive (MAR) model, and contemporaneous pathways represented by a conventional SEM. In Stage 2, the resulting subject-level path coefficients are merged with subject-level covariates such as gender, age, IQ, etc., to examine the impact of these covariates on effective connectivity via a GLM. Our approach is exemplified via the analysis of an fMRI visual attention experiment. Furthermore, the significant path network from the unified SEM analysis is compared to that from a conventional SEM analysis without incorporating the longitudinal information as well as that from a Dynamic Causal Modeling (DCM) approach.

Dose-dependent attenuation of auditory phantom perception (tinnitus) by PET-guided repetitive transcranial magnetic stimulation

Abstract: Recent data suggest that chronic tinnitus is a "phantom auditory perception" caused by maladaptive neuroplasticity and subsequent hyperactivity in an extended neuronal network including the primary auditory cortex, higher-order association areas, and parts of the limbic system. It was suggested that attenuation of this tinnitus-associated hyperactivity may offer a rational option for lasting tinnitus reduction. Here, we tested the hypothesis that tinnitus loudness can be attenuated by low-frequency repetitive transcranial magnetic stimulation (rTMS) individually navigated to cortical areas with excessive tinnitus-related activity as assessed by [(15)O]H(2)O positron-emission tomography (PET). Nine patients with chronic tinnitus underwent this combined functional imaging and rTMS-study. Group analysis of the PET data showed tinnitus-related increases of regional cerebral blood flow in the left middle and inferior temporal as well as right temporoparietal cortex and posterior cingulum. Repetitive TMS was performed at 1 Hz and 120% of the motor threshold for 5, 15, and 30 min, navigated to the individual maximum of tinnitus-related cortical hyperactivity. A noncortical stimulation site with the same distance to the ear served as sham control. Tinnitus loudness was reduced after temporoparietal, PET-guided low-frequency rTMS. This reduction, lasting up to 30 min, was dependent on the number of stimuli applied, differed from sham stimulation, and was negatively correlated with the length of the medical history of tinnitus in our patients. These data show the feasibility and effectiveness of rTMS guided by individual functional imaging to induce a lasting, dose-dependent attenuation of tinnitus. Of note, these effects were related to stimulation of cortical association areas, not primary auditory cortex, emphasizing the crucial role of higher-order sensory processing in the pathophysiology of chronic tinnitus.

Relationship between regional hemodynamic activity and simultaneously recorded EEG-theta associated with mental arithmetic-induced workload.

Abstract: Theta increases with workload and is associated with numerous processes including working memory, problem solving, encoding, or self monitoring. These processes, in turn, involve numerous structures of the brain. However, the relationship between regional brain activity and the occurrence of theta remains unclear. In the present study, simultaneous EEG-fMRI recordings were used to investigate the functional topography of theta. EEG-theta was enhanced by mental arithmetic-induced workload. For the EEG-constrained fMRI analysis, theta-reference time-series were extracted from the EEG, reflecting the strength of theta occurrence during the time course of the experiment. Theta occurrence was mainly associated with activation of the insular cortex, hippocampus, superior temporal areas, cingulate cortex, superior parietal, and frontal areas. Though observation of temporal and insular activation is in accord with the theory that theta specifically reflects encoding processes, the involvement of several other brain regions implies that surface-recorded theta represents comprehensive functional brain states rather than specific processes in the brain. The results provide further evidence for the concept that emergent theta band oscillations represent dynamic functional binding of widely distributed cortical assemblies, essential for cognitive processing. This binding process may form the source of surface-recorded EEG theta.

Validity and Power in Hemodynamic Response Modeling: A Comparison Study and a New Approach

Abstract: One of the advantages of event-related functional MRI (fMRI) is that it permits estimation of the shape of the hemodynamic response function (HRF) elicited by cognitive events. Although studies to date have focused almost exclusively on the magnitude of evoked HRFs across different tasks, there is growing interest in testing other statistics, such as the time-to-peak and duration of activation as well. Although there are many ways to estimate such parameters, we suggest three criteria for optimal estimation: 1) the relationship between parameter estimates and neural activity must be as transparent as possible; 2) parameter estimates should be independent of one another, so that true differences among conditions in one parameter (e.g., hemodynamic response delay) are not confused for apparent differences in other parameters (e.g., magnitude); and 3) statistical power should be maximized. In this work, we introduce a new modeling technique, based on the superposition of three inverse logit functions (IL), designed to achieve these criteria. In simulations based on real fMRI data, we compare the IL model with several other popular methods, including smooth finite impulse response (FIR) models, the canonical HRF with derivatives, nonlinear fits using a canonical HRF, and a standard canonical model. The IL model achieves the best overall balance between parameter interpretability and power. The FIR model was the next-best choice, with gains in power at some cost to parameter independence. We provide software implementing the IL model.

Separate brain regions code for salience vs. valence during reward prediction in humans.

Abstract: Predicting rewards and avoiding aversive conditions is essential for survival. Recent studies using computational models of reward prediction implicate the ventral striatum in appetitive rewards. Whether the same system mediates an organism's response to aversive conditions is unclear. We examined the question using fMRI blood oxygen level-dependent measurements while healthy volunteers were conditioned using appetitive and aversive stimuli. The temporal difference learning algorithm was used to estimate reward prediction error. Activations in the ventral striatum were robustly correlated with prediction error, regardless of the valence of the stimuli, suggesting that the ventral striatum processes salience prediction error. In contrast, the orbitofrontal cortex and anterior insula coded for the differential valence of appetitive/aversive stimuli. Given its location at the interface of limbic and motor regions, the ventral striatum may be critical in learning about motivationally salient stimuli, regardless of valence, and using that information to bias selection of actions.

Evaluation of PCA and ICA of simulated ERPs: Promax vs. Infomax rotations.

Abstract: Independent components analysis (ICA) and principal components analysis (PCA) are methods used to analyze event-related potential (ERP) and functional imaging (fMRI) data. In the present study, ICA and PCA were directly compared by applying them to simulated ERP datasets. Specifically, PCA was used to generate a subspace of the dataset followed by the application of PCA Promax or ICA Infomax rotations. The simulated datasets were composed of real background EEG activity plus two ERP simulated components. The results suggest that Promax is most effective for temporal analysis, whereas Infomax is most effective for spatial analysis. Failed analyses were examined and used to devise potential diagnostic strategies for both rotations. Finally, the results also showed that decomposition of subject averages yield better results than of grand averages across subjects.

Single-trial analysis of oddball event-related potentials in simultaneous EEG-fMRI

Abstract: There has recently been a growing interest in the use of simultaneous electroencephalography (EEG) and functional MRI (fMRI) for evoked activity in cognitive paradigms, thereby obtaining functional datasets with both high spatial and temporal resolution. The simultaneous recording permits obtaining event-related potentials (ERPs) and MR images in the same environment, conditions of stimulation, and subject state; it also enables tracing the joint fluctuations of EEG and fMRI signals. The goal of this study was to investigate the possibility of tracking the trial-to-trial changes in event-related EEG activity, and of using this information as a parameter in fMRI analysis. We used an auditory oddball paradigm and obtained single-trial amplitude and latency features from the EEG acquired during fMRI scanning. The single-trial P300 latency presented significant correlation with parameters external to the EEG (target-to-target interval and reaction time). Moreover, we obtained significant fMRI activations for the modulation by P300 amplitude and latency, both at the single-subject and at the group level. Our results indicate that, in line with other studies, the EEG can bring a new dimension to the field of fMRI analysis by providing fine temporal information on the fluctuations in brain activity.