Principal components of functional connectivity: A new approach to study dynamic brain connectivity during rest.

Functional connectivity (FC) as measured by correlation between fMRI BOLD time courses of distinct brain regions has revealed meaningful organization of spontaneous fluctuations in the resting brain. However, an increasing amount of evidence points to non-stationarity of FC; i.e., FC dynamically changes over time reflecting additional and rich information about brain organization, but representing new challenges for analysis and interpretation. Here, we propose a data-driven approach based on principal component analysis (PCA) to reveal hidden patterns of coherent FC dynamics across multiple subjects. We demonstrate the feasibility and relevance of this new approach by examining the differences in dynamic FC between 13 healthy control subjects and 15 minimally disabled relapse-remitting multiple sclerosis patients. We estimated whole-brain dynamic FC of regionally-averaged BOLD activity using sliding time windows. We then used PCA to identify FC patterns, termed "eigenconnectivities", that reflect meaningful patterns in FC fluctuations. We then assessed the contributions of these patterns to the dynamic FC at any given time point and identified a network of connections centered on the default-mode network with altered contribution in patients. Our results complement traditional stationary analyses, and reveal novel insights into brain connectivity dynamics and their modulation in a neurodegenerative disease.

Asymmetry of Functional Connectivity in Schizophrenia at Different Spatial Scales

Introduction: The interhemispheric asymmetries that originate from connectivity-related structuring of the cerebral cortex are compromised in schizophrenia (SZ). Recently, we have revealed the whole-head topography of EEG synchronization in SZ (Jalili et al. 2007; Knyazeva et al. 2008). Here we extended the analysis to assess the abnormality in the asymmetry of synchronization, which is further motivated by the evidence that the interhemispheric asymmetries suspected to be abnormal in SZ originate from the connectivity-related structuring of the cortex. Methods: Thirteen right-handed SZ patients and thirteen matched controls, participated in this study and the multichannel (128) EEGs were recorded for 3-5 minutes at rest. Then, Laplacian EEG (LEEG) were calculated using a 2-D spline. The LEEGs were analysis through calculating the power spectral density using Welch's average periodogram method. Furthermore, using a state-space based multivariate synchronization measure, S-estimator, we analyzed the correlate of the functional cortico-cortical connectivity in SZ patients compared to the controls. The values of S-estimator were obtained at three different special scales: first-order neighbors for each sensor location, second-order neighbors, and the whole hemisphere. The synchronization measures based on LEEG of alpha and beta bands were applied and tuned to various spatial scales including local, intraregional, and long-distance levels. To assess the between-group differences, we used a permutation version of Hotelling's T2 test. For correlation analysis, Spearman Rank Correlation was calculated. Results: Compared to the controls, who had rightward asymmetry at a local level (LEEG power), rightward anterior and leftward posterior asymmetries at an intraregional level (first- and second-order S-estimator), and rightward global asymmetry (hemispheric S-estimator), SZ patients showed generally attenuated asymmetry, the effect being strongest for intraregional synchronization. This deviation in asymmetry across the anterior-to-posterior axis is consistent with the cerebral form of the so-called Yakovlevian or anticlockwise cerebral torque. Moreover, the negative occipital and positive frontal asymmetry values suggest higher regional synchronization among the left occipital and the right frontal locations relative to their symmetrical counterparts. Correlation analysis linked the posterior intraregional and hemispheric abnormalities to the negative SZ symptoms, whereas the asymmetry of LEEG power appeared to be weakly coupled to clinical ratings. The posterior intraregional abnormalities of asymmetry were shown to increase with the duration of the disease. The tentative links between these findings and gross anatomical asymmetries, including the cerebral torque and gyrification pattern in normal subjects and SZ patients, are discussed. Conclusions: Overall, our findings reveal the abnormalities in the synchronization asymmetry in SZ patients and heavy involvement of the right hemisphere in these abnormalities. These results indicate that anomalous asymmetry of cortico-cortical connections in schizophrenia is amenable to electrophysiological analysis.

Predicting clinical scores from magnetic resonance scans in Alzheimer's disease.

Machine learning and pattern recognition methods have been used to diagnose Alzheimer's disease (AD) and mild cognitive impairment (MCI) from individual MRI scans. Another application of such methods is to predict clinical scores from individual scans. Using relevance vector regression (RVR), we predicted individuals' performances on established tests from their MRI T1 weighted image in two independent data sets. From Mayo Clinic, 73 probable AD patients and 91 cognitively normal (CN) controls completed the Mini-Mental State Examination (MMSE), Dementia Rating Scale (DRS), and Auditory Verbal Learning Test (AVLT) within 3months of their scan. Baseline MRI's from the Alzheimer's disease Neuroimaging Initiative (ADNI) comprised the other data set; 113 AD, 351 MCI, and 122 CN subjects completed the MMSE and Alzheimer's Disease Assessment Scale-Cognitive subtest (ADAS-cog) and 39 AD, 92 MCI, and 32 CN ADNI subjects completed MMSE, ADAS-cog, and AVLT. Predicted and actual clinical scores were highly correlated for the MMSE, DRS, and ADAS-cog tests (P<0.0001). Training with one data set and testing with another demonstrated stability between data sets. DRS, MMSE, and ADAS-Cog correlated better than AVLT with whole brain grey matter changes associated with AD. This result underscores their utility for screening and tracking disease. RVR offers a novel way to measure interactions between structural changes and neuropsychological tests beyond that of univariate methods. In clinical practice, we envision using RVR to aid in diagnosis and predict clinical outcome.

The history and role of long duration stimulation in fMRI.

During the past 20 years, BOLD fMRI has developed towards a central and fundamental tool in neuroscience. It has been shown that the BOLD response provides an indicator of neuronal activity in the brain. Consequently, for an accurate interpretation of findings in BOLD MRI experiments and to draw meaningful conclusions about the temporal evolution of neural events, a deep understanding of the nature of the BOLD contrast has become of essential importance. Since the dynamics of the major direct determinants of the BOLD signal (CBF, CBV and CMRO(2)) range between seconds and minutes, long duration stimulation was an early key strategy needed to study and understand the BOLD characteristics. This paper summarizes and discusses the thoughts and rationales of the long duration stimulation studies.

On the origin of the MR image phase contrast: an in vivo MR microscopy study of the rat brain at 14.1 T.

Recent studies at high magnetic fields using the phase of gradient-echo MR images have shown the ability to unveil cortical substructure in the human brain. To investigate the contrast mechanisms in phase imaging, this study extends, for the first time, phase imaging to the rodent brain. Using a 14.1 T horizontal bore animal MRI scanner for in vivo micro-imaging, images with an in-plane resolution of 33 microm were acquired. Phase images revealed, often more clearly than the corresponding magnitude images, hippocampal fields, cortical layers (e.g. layer 4), cerebellar layers (molecular and granule cell layers) and small white matter structures present in the striatum and septal nucleus. The contrast of the phase images depended in part on the orientation of anatomical structures relative to the magnetic field, consistent with bulk susceptibility variations between tissues. This was found not only for vessels, but also for white matter structures, such as the anterior commissure, and cortical layers in the cerebellum. Such susceptibility changes could result from variable blood volume. However, when the deoxyhemoglobin content was reduced by increasing cerebral blood flow (CBF) with a carbogen breathing challenge, contrast between white and gray matter and cortical layers was not affected, suggesting that tissue cerebral blood volume (and therefore deoxyhemoglobin) is not a major source of the tissue phase contrast. We conclude that phase variations in gradient-echo images are likely due to susceptibility shifts of non-vascular origin.

Electrical neuroimaging of memory discrimination based on single-trial multisensory learning.

Multisensory experiences influence subsequent memory performance and brain responses. Studies have thus far concentrated on semantically congruent pairings, leaving unresolved the influence of stimulus pairing and memory sub-types. Here, we paired images with unique, meaningless sounds during a continuous recognition task to determine if purely episodic, single-trial multisensory experiences can incidentally impact subsequent visual object discrimination. Psychophysics and electrical neuroimaging analyses of visual evoked potentials (VEPs) compared responses to repeated images either paired or not with a meaningless sound during initial encounters. Recognition accuracy was significantly impaired for images initially presented as multisensory pairs and could not be explained in terms of differential attention or transfer of effects from encoding to retrieval. VEP modulations occurred at 100-130ms and 270-310ms and stemmed from topographic differences indicative of network configuration changes within the brain. Distributed source estimations localized the earlier effect to regions of the right posterior temporal gyrus (STG) and the later effect to regions of the middle temporal gyrus (MTG). Responses in these regions were stronger for images previously encountered as multisensory pairs. Only the later effect correlated with performance such that greater MTG activity in response to repeated visual stimuli was linked with greater performance decrements. The present findings suggest that brain networks involved in this discrimination may critically depend on whether multisensory events facilitate or impair later visual memory performance. More generally, the data support models whereby effects of multisensory interactions persist to incidentally affect subsequent behavior as well as visual processing during its initial stages.

MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field.

The large spatial inhomogeneity in transmit B(1) field (B(1)(+)) observable in human MR images at high static magnetic fields (B(0)) severely impairs image quality. To overcome this effect in brain T(1)-weighted images, the MPRAGE sequence was modified to generate two different images at different inversion times, MP2RAGE. By combining the two images in a novel fashion, it was possible to create T(1)-weighted images where the result image was free of proton density contrast, T(2) contrast, reception bias field, and, to first order, transmit field inhomogeneity. MP2RAGE sequence parameters were optimized using Bloch equations to maximize contrast-to-noise ratio per unit of time between brain tissues and minimize the effect of B(1)(+) variations through space. Images of high anatomical quality and excellent brain tissue differentiation suitable for applications such as segmentation and voxel-based morphometry were obtained at 3 and 7 T. From such T(1)-weighted images, acquired within 12 min, high-resolution 3D T(1) maps were routinely calculated at 7 T with sub-millimeter voxel resolution (0.65-0.85 mm isotropic). T(1) maps were validated in phantom experiments. In humans, the T(1) values obtained at 7 T were 1.15+/-0.06 s for white matter (WM) and 1.92+/-0.16 s for grey matter (GM), in good agreement with literature values obtained at lower spatial resolution. At 3 T, where whole-brain acquisitions with 1 mm isotropic voxels were acquired in 8 min, the T(1) values obtained (0.81+/-0.03 s for WM and 1.35+/-0.05 for GM) were once again found to be in very good agreement with values in the literature.

Topographic organization of V1 projections through the corpus callosum in humans.

The visual cortex in each hemisphere is linked to the opposite hemisphere by axonal projections that pass through the splenium of the corpus callosum. Visual-callosal connections in humans and macaques are found along the V1/V2 border where the vertical meridian is represented. Here we identify the topography of V1 vertical midline projections through the splenium within six human subjects with normal vision using diffusion-weighted MR imaging and probabilistic diffusion tractography. Tractography seed points within the splenium were classified according to their estimated connectivity profiles to topographic subregions of V1, as defined by functional retinotopic mapping. First, we report a ventral-dorsal mapping within the splenium with fibers from ventral V1 (representing the upper visual field) projecting to the inferior-anterior corner of the splenium and fibers from dorsal V1 (representing the lower visual field) projecting to the superior-posterior end. Second, we also report an eccentricity gradient of projections from foveal-to-peripheral V1 subregions running in the anterior-superior to posterior-inferior direction, orthogonal to the dorsal-ventral mapping. These results confirm and add to a previous diffusion MRI study (Dougherty et al., 2005) which identified a dorsal/ventral mapping of human splenial fibers. These findings yield a more detailed view of the structural organization of the splenium than previously reported and offer new opportunities to study structural plasticity in the visual system.

Multiparametric brainstem segmentation using a modified multivariate mixture of Gaussians

The human brainstem is a densely packed, complex but highly organised structure. It not only serves as a conduit for long projecting axons conveying motor and sensory information, but also is the location of multiple primary nuclei that control or modulate a vast array of functions, including homeostasis, consciousness, locomotion, and reflexive and emotive behaviours. Despite its importance, both in understanding normal brain function as well as neurodegenerative processes, it remains a sparsely studied structure in the neuroimaging literature. In part, this is due to the difficulties in imaging the internal architecture of the brainstem in vivo in a reliable and repeatable fashion. A modified multivariate mixture of Gaussians (mmMoG) was applied to the problem of multichannel tissue segmentation. By using quantitative magnetisation transfer and proton density maps acquired at 3 T with 0.8 mm isotropic resolution, tissue probability maps for four distinct tissue classes within the human brainstem were created. These were compared against an ex vivo fixated human brain, imaged at 0.5 mm, with excellent anatomical correspondence. These probability maps were used within SPM8 to create accurate individual subject segmentations, which were then used for further quantitative analysis. As an example, brainstem asymmetries were assessed across 34 right-handed individuals using voxel based morphometry (VBM) and tensor based morphometry (TBM), demonstrating highly significant differences within localised regions that corresponded to motor and vocalisation networks. This method may have important implications for future research into MRI biomarkers of pre-clinical neurodegenerative diseases such as Parkinson's disease.

Bilateral dorsal and ventral fiber pathways for the processing of affective prosody identified by probabilistic fiber tracking.

Dorsal and ventral pathways for syntacto-semantic speech processing in the left hemisphere are represented in the dual-stream model of auditory processing. Here we report new findings for the right dorsal and ventral temporo-frontal pathway during processing of affectively intonated speech (i.e. affective prosody) in humans, together with several left hemispheric structural connections, partly resembling those for syntacto-semantic speech processing. We investigated white matter fiber connectivity between regions responding to affective prosody in several subregions of the bilateral superior temporal cortex (secondary and higher-level auditory cortex) and of the inferior frontal cortex (anterior and posterior inferior frontal gyrus). The fiber connectivity was investigated by using probabilistic diffusion tensor based tractography. The results underscore several so far underestimated auditory pathway connections, especially for the processing of affective prosody, such as a right ventral auditory pathway. The results also suggest the existence of a dual-stream processing in the right hemisphere, and a general predominance of the dorsal pathways in both hemispheres underlying the neural processing of affective prosody in an extended temporo-frontal network.

The brain uses single-trial multisensory memories to discriminate without awareness.

Multisensory experiences enhance perceptions and facilitate memory retrieval processes, even when only unisensory information is available for accessing such memories. Using fMRI, we identified human brain regions involved in discriminating visual stimuli according to past multisensory vs. unisensory experiences. Subjects performed a completely orthogonal task, discriminating repeated from initial image presentations intermixed within a continuous recognition task. Half of initial presentations were multisensory, and all repetitions were exclusively visual. Despite only single-trial exposures to initial image presentations, accuracy in indicating image repetitions was significantly improved by past auditory-visual multisensory experiences over images only encountered visually. Similarly, regions within the lateral-occipital complex-areas typically associated with visual object recognition processes-were more active to visual stimuli with multisensory than unisensory pasts. Additional differential responses were observed in the anterior cingulate and frontal cortices. Multisensory experiences are registered by the brain even when of no immediate behavioral relevance and can be used to categorize memories. These data reveal the functional efficacy of multisensory processing.

Plastic brain mechanisms for attaining auditory temporal order judgment proficiency.

Accurate perception of the order of occurrence of sensory information is critical for the building up of coherent representations of the external world from ongoing flows of sensory inputs. While some psychophysical evidence reports that performance on temporal perception can improve, the underlying neural mechanisms remain unresolved. Using electrical neuroimaging analyses of auditory evoked potentials (AEPs), we identified the brain dynamics and mechanism supporting improvements in auditory temporal order judgment (TOJ) during the course of the first vs. latter half of the experiment. Training-induced changes in brain activity were first evident 43-76 ms post stimulus onset and followed from topographic, rather than pure strength, AEP modulations. Improvements in auditory TOJ accuracy thus followed from changes in the configuration of the underlying brain networks during the initial stages of sensory processing. Source estimations revealed an increase in the lateralization of initially bilateral posterior sylvian region (PSR) responses at the beginning of the experiment to left-hemisphere dominance at its end. Further supporting the critical role of left and right PSR in auditory TOJ proficiency, as the experiment progressed, responses in the left and right PSR went from being correlated to un-correlated. These collective findings provide insights on the neurophysiologic mechanism and plasticity of temporal processing of sounds and are consistent with models based on spike timing dependent plasticity.

Early attentional processes distinguish selective from global motor inhibitory control : An electrical neuroimaging study

The rapid stopping of specific parts of movements is frequently required in daily life. Yet, whether selective inhibitory control of movements is mediated by a specific neural pathway or by the combination between a global stopping of all ongoing motor activity followed by the re-initiation of task-relevant movements remains unclear. To address this question, we applied time-wise statistical analyses of the topography, global field power and electrical sources of the event-related potentials to the global vs selective inhibition stimuli presented during a Go/NoGo task. Participants (n = 18) had to respond as fast as possible with their two hands to Go stimuli and to withhold the response from the two hands (global inhibition condition, GNG) or from only one hand (selective inhibition condition, SNG) when specific NoGo stimuli were presented. Behaviorally, we replicated previous evidence for slower response times in the SNG than in the Go condition. Electrophysiologically, there were two distinct phases of event-related potentials modulations between the GNG and the SNG conditions. At 110âeuro"150 ms post-stimulus onset, there was a difference in the strength of the electric field without concomitant topographic modulation, indicating the differential engagement of statistically indistinguishable configurations of neural generators for selective and global inhibitory control. At 150âeuro"200 ms, there was topographic modulation, indicating the engagement of distinct brain networks. Source estimations localized these effects within bilateral temporo-parieto-occipital and within parieto-central networks, respectively. Our results suggest that while both types of motor inhibitory control depend on global stopping mechanisms, selective and global inhibition still differ quantitatively at early attention-related processing phases.

Food's visually perceived fat content affects discrimination speed in an orthogonal spatial task.

Choosing what to eat is a complex activity for humans. Determining a food's pleasantness requires us to combine information about what is available at a given time with knowledge of the food's palatability, texture, fat content, and other nutritional information. It has been suggested that humans may have an implicit knowledge of a food's fat content based on its appearance; Toepel et al. (Neuroimage 44:967-974, 2009) reported visual-evoked potential modulations after participants viewed images of high-energy, high-fat food (HF), as compared to viewing low-fat food (LF). In the present study, we investigated whether there are any immediate behavioural consequences of these modulations for human performance. HF, LF, or non-food (NF) images were used to exogenously direct participants' attention to either the left or the right. Next, participants made speeded elevation discrimination responses (up vs. down) to visual targets presented either above or below the midline (and at one of three stimulus onset asynchronies: 150, 300, or 450 ms). Participants responded significantly more rapidly following the presentation of a HF image than following the presentation of either LF or NF images, despite the fact that the identity of the images was entirely task-irrelevant. Similar results were found when comparing response speeds following images of high-carbohydrate (HC) food items to low-carbohydrate (LC) food items. These results support the view that people rapidly process (i.e. within a few hundred milliseconds) the fat/carbohydrate/energy value or, perhaps more generally, the pleasantness of food. Potentially as a result of HF/HC food items being more pleasant and thus having a higher incentive value, it seems as though seeing these foods results in a response readiness, or an overall alerting effect, in the human brain.