One of the grand challenges faced by neuroscience is to delineate the determinants of interindivi... more One of the grand challenges faced by neuroscience is to delineate the determinants of interindividual variation in the comprehensive structural and functional connection matrices that comprise the human connectome. At present, this endeavor appears most tractable at the macroanatomic scale, where intrinsic brain activity exhibits robust patterns of synchrony that recapitulate core functional circuits at the individual level. Here, we use a classical twin study design to examine the heritability of intrinsic functional network properties in 101 twin pairs, including network activity (i.e., variance of a network's specific temporal fluctuations) and internetwork coherence (i.e., correlation between networks' specific temporal fluctuations). Five of 7 networks exhibited significantly heritable (23.3-65.2%) network activity, 6 of the 21 internetwork coherences were significantly heritable (25.6-42.0%), and 11 of the 21 internetwork coherences were significantly influenced by common environmental factors (18.0-47.1%). These results suggest that the source of interindividual variation in functional connectome has a modular architecture: individual modules represented by intrinsic connectivity networks are genetic controlled, while environmental factors influence the interplays between the modules. This work further provides network-specific hypotheses for discovery of the specific genetic and environmental factors influencing functional specialization and integration of the human brain.
The relationships between structural and functional measures of the human brain remain largely un... more The relationships between structural and functional measures of the human brain remain largely unknown. A majority of our limited knowledge regarding structure-function associations has been obtained through comparisons between specific groups of patients and healthy controls. Unfortunately, a direct and complete view of the associations across multiple structural and functional metrics in normal population is missing. We filled this gap by learning cross-individual co-variance among structural and functional measures using large-scale neuroimaging datasets. A discover-confirm scheme was applied to two independent samples (N = 184 and N = 340) of multimodal neuroimaging datasets. A data mining tool, gRAI-CAR, was employed in the discover stage to generate quantitative and unbiased hypotheses of the co-variance among six functional and six structural imaging metrics. These hypotheses were validated using an independent dataset in the confirm stage. Fifteen multi-metric co-variance units, representing different co-variance relationships among the 12 metrics, were reliable across the two sets of neuroimaging datasets. The reliable co-variance units were summarized into a database, where users can select any location on the cortical map of any metric to examine the co-varying maps with the other 11 metrics. This database characterized the six functional metrics based on their covariance with structural metrics, and provided a detailed reference to connect previous findings using different metrics and to predict maps of unexamined metrics. Gender, age, and handedness were associated to the co-variance units, and a sub-study of schizophrenia demonstrated the usefulness of the co-variance database.
While researchers have extensively characterized functional connectivity between brain regions, t... more While researchers have extensively characterized functional connectivity between brain regions, the characterization of functional homogeneity within a region of the brain connectome is in early stages of development. Several functional homogeneity measures were proposed previously, among which regional homogeneity (ReHo) was most widely used as a measure to characterize functional homogeneity of resting state fMRI (R-fMRI) signals within a small region . Despite a burgeoning literature on ReHo in the field of neuroimaging brain disorders, its test-retest (TRT) reliability remains unestablished. Using two sets of public R-fMRI TRT data, we systematically evaluated the ReHo's TRT reliability and further investigated the various factors influencing its reliability and found: 1) nuisance (head motion, white matter, and cerebrospinal fluid) correction of R-fMRI time series can significantly improve the TRT reliability of ReHo while additional removal of global brain signal reduces its reliability, 2) spatial smoothing of R-fMRI time series artificially enhances ReHo intensity and influences its reliability, 3) surface-based R-fMRI computation largely improves the TRT reliability of ReHo, 4) a scan duration of 5 min can achieve reliable estimates of ReHo, and 5) fast sampling rates of R-fMRI dramatically increase the reliability of ReHo. Inspired by these findings and seeking a highly reliable approach to exploratory analysis of the human functional connectome, we established an R-fMRI pipeline to conduct ReHo computations in both 3-dimensions (volume) and 2-dimensions (surface).
Introduction: Interpersonal hypersensitivity is often observed in schizophrenia and has been asso... more Introduction: Interpersonal hypersensitivity is often observed in schizophrenia and has been associated with psychopathological deficits in schizophrenia. Here, we investigated dysfunctions of interpersonal information processing in schizophrenia at both conscious and subconscious levels. Methods: The experiment included 143 schizophrenia patients and 59 healthy controls. A continuous flashing suppression approach based on binocular rivalry was employed, which included two modes: invisible (subconscious) and visible (conscious). The accuracy and reaction time of a Gabor patch direction-detection task were assessed under three types of stimuli in both modes: images with no person (type 1), images with two to three noncommunicating persons (type 2), and images with more than three communicating individuals (type 3). Results: In the visible mode, the accuracy of the Gabor patch directiondetection task in the case group was significantly lower than in the control group for the third type of stimuli (P = 0.015). In the invisible mode, however, the accuracy was higher in the case group than in the control group (P = 0.037). The response time difference of the Gabor patch direction-detection task for the third type of images in the invisible mode was negatively correlated with the duration of the illness (P = 0.008). Discussion: These findings suggest that schizophrenia patients exhibit attentional bias to interpersonal interaction behaviors at both conscious and subliminal levels but toward opposite directions. Our findings shed light on the subconscious deficits under the paranoid symptom in schizophrenia.
Early-onset schizophrenia (EOS) offers a unique opportunity to study pathophysiological mechanism... more Early-onset schizophrenia (EOS) offers a unique opportunity to study pathophysiological mechanisms and development of schizophrenia. Using 26 drug-naïve, first-episode EOS patients and 25 age-and gender-matched control subjects, we examined intrinsic connectivity network (ICN) deficits underlying EOS. Due to the emerging inconsistency between behavior-based psychiatric disease classification system and the underlying brain dysfunctions, we applied a fully data-driven approach to investigate whether the subjects can be grouped into highly homogeneous communities according to the characteristics of their ICNs. The resultant subject communities and the representative characteristics of ICNs were then associated with the clinical diagnosis and multivariate symptom patterns. A default mode ICN was statistically absent in EOS patients. Another frontotemporal ICN further distinguished EOS patients with predominantly negative symptoms. Connectivity patterns of this second network for the EOS patients with predominantly positive symptom were highly similar to typically developing controls. Our post-hoc functional connectivity modeling confirmed that connectivity strength in this frontotemporal circuit was significantly modulated by relative severity of positive and negative syndromes in EOS. This study presents a novel subtype discovery approach based on brain networks and proposes complex links between brain networks and symptom patterns in EOS. E arly-onset schizophrenia (EOS) is a rare and severe form of schizophrenia characterized by psychotic symptoms before the age of 18, worse prognosis than adult-onset counterparts 1-3 , and greater genetic liability 4 . EOS opens a unique opportunity to study the pathophysiological development and mechanisms of schizophrenia 5 . Neuroimaging studies have reported widespread brain structure abnormalities in EOS 6-8 , suggesting that the functional impairments are distributed across brain networks.
Multi-variate pattern analysis (MVPA) applied to BOLD-fMRI has proven successful at decoding comp... more Multi-variate pattern analysis (MVPA) applied to BOLD-fMRI has proven successful at decoding complicated fMRI signal patterns associated with a variety of cognitive processes. One cognitive process, not yet investigated, is the mental representation of "Yes/No" thoughts that precede the actual overt response to a binary "Yes/No" question. In this study, we focus on examining: (1) whether spatial patterns of the hemodynamic response carry sufficient information to allow reliable decoding of "Yes/No" thoughts; and (2) whether decoding of "Yes/No" thoughts is independent of the intention to respond honestly or dishonestly. To achieve this goal, we conducted two separate experiments. Experiment 1, collected on a 3T scanner, examined the whole brain to identify regions that carry sufficient information to permit significantly above-chance prediction of "Yes/No" thoughts at the group level. In Experiment 2, collected on a 7T scanner, we focused on the regions identified in Experiment 1 to examine the capability of achieving high decoding accuracy at the single subject level. A set of regionsnamely right superior temporal gyrus, left supra-marginal gyrus, and left middle frontal gyrusexhibited high decoding power. Decoding accuracy for these regions increased with trial averaging. When 18 trials were averaged, the median accuracies were 82.5%, 77.5%, and 79.5%, respectively. When trials were separated according to deceptive intentions (set via experimental cues), and classifiers were trained on honest trials, but tested on trials where subjects were asked to deceive, the median accuracies of these regions still reached 66%, 75%, and 78.5%. These results provide evidence that concealed "Yes/No" thoughts are encoded in the BOLD signal, retaining some level of independence from the subject's intentions to answer honestly or dishonestly. These findings also suggest the theoretical possibility for more efficient brain-computer interfaces where subjects only need to think their answers to communicate.
Numerous studies have shown cerebellar involvement in item-speci¯c association, a form of explici... more Numerous studies have shown cerebellar involvement in item-speci¯c association, a form of explicit learning. However, very few have demonstrated cerebellar participation in automation of non-motor cognitive tasks. Applying fMRI to a repeated verb-generation task, we sought to distinguish cerebellar involvement in learning of item-speci¯c noun-verb association and automation of verb generation skill. The same set of nouns was repeated in six verb-generation blocks so that subjects practiced generating verbs for the nouns. The practice was followed by a novel block with a di®erent set of nouns. The cerebellar vermis (IV/V) and the right cerebellar lobule VI showed decreased activation following practice; activation in the right cerebellar Crus I was signi¯cantly lower in the novel challenge than in the initial verb-generation task. Furthermore, activation in this region during well-practiced blocks strongly correlated with improvement of behavioral performance in both the well-practiced and the novel blocks, suggesting its role in the learning of general mental skills not speci¯c to the practiced noun-verb pairs. Therefore, the cerebellum processes both explicit verbal associative learning and automation of cognitive tasks. Di®erent cerebellar regions predominate in this processing: lobule VI during the acquisition of item-speci¯c association, and Crus I during automation of verb-generation skills through practice.
Objective: Major depressive disorder (MDD) has been characterized by abnormalities in emotional p... more Objective: Major depressive disorder (MDD) has been characterized by abnormalities in emotional processing. However, what remains unclear is whether MDD also shows deficits in the unconscious processing of either positive or negative emotions. We conducted a psychological study in healthy and MDD subjects to investigate unconscious emotion processing and its valence-specific alterations in MDD patients.
Multivariate pattern analysis (MVPA) is a recently-developed approach for functional magnetic res... more Multivariate pattern analysis (MVPA) is a recently-developed approach for functional magnetic resonance imaging (fMRI) data analyses. Compared with the traditional univariate methods, MVPA is more sensitive to subtle changes in multivariate patterns in fMRI data. In this review, we introduce several significant advances in MVPA applications and summarize various combinations of algorithms and parameters in different problem settings. The limitations of MVPA and some critical questions that need to be addressed in future research are also discussed.
Independent component analysis (ICA) is a data-driven approach that has exhibited great utility f... more Independent component analysis (ICA) is a data-driven approach that has exhibited great utility for functional magnetic resonance imaging (fMRI). Standard ICA implementations, however, do not provide the number and relative importance of the resulting components. In addition, ICA algorithms utilizing gradient-based optimization give decompositions that are dependent on initialization values, which can lead to dramatically different results. In this work, a new method, RAICAR (Ranking and Averaging Independent Component Analysis by Reproducibility), is introduced to address these issues for spatial ICA applied to fMRI. RAICAR utilizes repeated ICA realizations and relies on the reproducibility between them to rank and select components. Different realizations are aligned based on correlations, leading to aligned components. Each component is ranked and thresholded based on between-realization correlations. Furthermore, different realizations of each aligned component are selectively averaged to generate the final estimate of the given component. Reliability and accuracy of this method are demonstrated with both simulated and experimental fMRI data. Hum Brain Mapp 29:711-725, 2008. V V C 2007 Wiley-Liss, Inc.
Although research has provided abundant evidence for Taichi-induced improvements in psychological... more Although research has provided abundant evidence for Taichi-induced improvements in psychological and physiological well-being, little is known about possible links to brain structure of Taichi practice. Using high-resolution MRI of 22 Tai Chi Chuan (TCC) practitioners and 18 controls matched for age, sex and education, we set out to examine the underlying anatomical correlates of long-term Taichi practice at two different levels of regional specificity. For this purpose, parcel-wise and vertex-wise analyses were employed to quantify the difference between TCC practitioners and the controls based on cortical surface reconstruction. We also adopted the Attention Network Test (ANT) to explore the effect of TCC on executive control. TCC practitioners, compared with controls, showed significantly thicker cortex in precentral gyrus, insula sulcus and middle frontal sulcus in the right hemisphere and superior temporal gyrus and medial occipito-temporal sulcus and lingual sulcus in the left hemisphere. Moreover, we found that thicker cortex in left medial occipito-temporal sulcus and lingual sulcus was associated with greater intensity of TCC practice. These findings indicate that long-term TCC practice could induce regional structural change and also suggest TCC might share similar patterns of neural correlates with meditation and aerobic exercise.
Objective: Bipolar disorder patients experiencing a depressive episode (BD-dep) without an observ... more Objective: Bipolar disorder patients experiencing a depressive episode (BD-dep) without an observed history of mania are often misdiagnosed and are consequently treated as having unipolar depression (UD), leading to inadequate treatment and poor outcomes. An essential solution to this problem is to identify objective biological markers that distinguish BD-dep and UD patients at an early stage. However, studies directly comparing the brain dysfunctions associated with BD-dep and UD are rare. More importantly, the specificity of the differences in brain activity between these mental disorders has not been examined. With whole-brain regional homogeneity analysis and region-of-interest (ROI) based receiver operating characteristic (ROC) analysis, we aimed to compare the resting-state brain activity of BD-dep and UD patients. Furthermore, we examined the specific differences and whether these differences were attributed to the brain abnormality caused by BD-dep, UD, or both. Methods: Twenty-one bipolar and 21 unipolar depressed patients, as well as 26 healthy subjects matched for gender, age, and educational levels, participated in the study. We compared the differences in the regional homogeneity (ReHo) of the BD-dep and UD groups and further identified their pathophysiological abnormality. In the brain regions showing a difference between the BD-dep and UD groups, we further conducted receptive operation characteristic (ROC) analyses to confirm the effectiveness of the identified difference in classifying the patients. Results: We observed ReHo differences between the BD-dep and UD groups in the right ventrolateral middle frontal gyrus, right dorsal anterior insular, right ventral anterior insular, right cerebellum posterior gyrus, right posterior cingulate cortex, right parahippocampal gyrus, and left cerebellum anterior gyrus. Further ROI comparisons and ROC analysis on these ROIs showed that the right parahippocampal gyrus reflected abnormality specific to the BD-dep group, while the right middle frontal gyrus, the right dorsal anterior insular, the right cerebellum posterior gyrus, and the right posterior cingulate cortex showed abnormality specific to the UD group. Conclusions: We found brain regions showing resting state ReHo differences and examined their sensitivity and specificity, suggesting a potential neuroimaging biomarker to distinguish between BD-dep and UD patients. We further clarified the pathophysiological abnormality of these regions for each of the two patient populations.
Bipolar depression (BD) is a common psychiatric illness characterized by deficits in emotional an... more Bipolar depression (BD) is a common psychiatric illness characterized by deficits in emotional and cognitive processing. Abnormalities in the subregions of the insula are common findings in neuroanatomical studies of patients with bipolar disorder. However, the specific relationships between morphometric changes in specific insular subregions and the pathogenesis of BD are not clear. In this study, structural magnetic resonance imaging (MRI) was used to investigate gray matter volume abnormalities in the insular subregion in 27 patients with BD and in 27 age and sex-matched controls. Using DARTEL (diffeomorphic anatomical registration through exponentiated lie algebra) for voxel-based morphometry (VBM), we examined changes in regional gray matter volumes of the insula in patients with BD. As compared with healthy controls, the BD patients showed decreased gray matter volumes in the right posterior insula and left ventral anterior insula and increased gray matter volumes in the left dorsal anterior insula. Consistent with the emerging theory of insular interference as a contributor to emotional-cognitive dysregulation, the current findings suggest that the insular cortex may be involved in the neural substrates of BD.
WhetherTai Chi Chuan (TCC) can influence the intrinsic functional architecture of the human brain... more WhetherTai Chi Chuan (TCC) can influence the intrinsic functional architecture of the human brain remains unclear. To examine TCC-associated changes in functional connectomes, resting-state functional magnetic resonance images were acquired from 40 older individuals including 22 experienced TCC practitioners (experts) and 18 demographically matched TCC-naïve healthy controls, and their local functional homogeneities across the cortical mantle were compared. Compared to the controls, theTCC experts had significantly greater and more experience-dependent functional homogeneity in the right post-central gyrus (PosCG) and less functional homogeneity in the left anterior cingulate cortex (ACC) and the right dorsal lateral prefrontal cortex. Increased functional homogeneity in the PosCG was correlated with TCC experience. Intriguingly, decreases in functional homogeneity (improved functional specialization) in the left ACC and increases in functional homogeneity (improved functional integration) in the right PosCG both predicted performance gains on attention network behavior tests. These findings provide evidence for the functional plasticity of the brain's intrinsic architecture toward optimizing locally functional organization, with great implications for understanding the effects of TCC on cognition, behavior and health in aging population.
We examined resting state brain activity in the depressive phase of bipolar disorder (BD) by meas... more We examined resting state brain activity in the depressive phase of bipolar disorder (BD) by measuring the amplitude of low-frequency fluctuations (ALFF) in the functional magnetic resonance imaging (fMRI) signal. Unlike functional connectivity, the ALFF approach reflects local properties in specific regions and provides direct information about impaired foci. Groups of 26 patients with BD depression and 26 gender-, age-, and educationmatched healthy subjects participated in fMRI scans. We examined group differences in ALFF findings as well as correlations between clinical measurements and ALFF in the regions showing significant group differences. Our results showed that patients with BD depression had significantly increased ALFF in the left insula, the right caudate nucleus, the temporal gyrus, the bilateral inferior frontal gyrus, and the posterior lobe of the cerebellum. They also had decreased ALFF in the left postcentral gyrus, the left parahippocampal gyrus, and the cerebellum. Moderate negative correlations were found between the Hamilton Depression Rating Scale score and ALFF in the left insular cortex in the patient group. These results support a model of BD that involves dysfunction in the prefrontal-limbic networks and associated striatal systems. We also demonstrated the feasibility of ALFF as a technique to investigate persistent cerebral dysfunction in BD.
Schizophrenia is increasingly thought of as a brain network or connectome disorder and is associa... more Schizophrenia is increasingly thought of as a brain network or connectome disorder and is associated with neurodevelopmental processes. Previous studies have suggested the important role of anatomical distance in developing a connectome with optimized performance regarding both the cost and efficiency of information processing. Distance-related disturbances during development have not been investigated in schizophrenia. To test the distance-related miswiring profiles of connectomes in schizophrenia, we acquired resting-state images from 20 adulthood-onset (AOS) and 26 early-onset schizophrenia (EOS) patients, as well as agematched healthy controls. All patients were drug naive and had experienced their first psychotic episode. A novel threshold-free surface-based analytic framework was developed to examine local-to-remote functional connectivity profiles in both AOS and EOS patients. We observed consistent increases of local connectivity across both EOS and AOS patients in the right superior frontal gyrus, where the connectivity strength was correlated with a positive syndrome score in AOS patients. In contrast, EOS but not AOS patients exhibited reduced local connectivity within the right postcentral gyrus and the left middle occipital cortex. These regions' remote connectivity with their interhemispheric areas and brain network hubs was altered. Diagnosis-age interactions were detectable for both local and remote connectivity profiles. The functional covariance between local and remote homotopic connectivity was present in typically developing controls, but was absent in EOS patients. These findings suggest that a distance-dependent miswiring pattern may be one of the key neurodevelopmental features of the abnormal connectome organization in schizophrenia.
Increasing neuroimaging evidence suggests that autism patients exhibit abnormal brain structure a... more Increasing neuroimaging evidence suggests that autism patients exhibit abnormal brain structure and function. We used the Autism Brain Imaging Data Exchange (ABIDE) sample to analyze locally focal (∼8 mm) functional connectivity of 223 autism patients and 285 normal controls from 15 international sites using a recently developed surface-based approach. We observed enhanced local connectivity in the middle frontal cortex, left precuneus, and right superior temporal sulcus, and reduced local connectivity in the right insular cortex. The local connectivity in the right middle frontal gyrus was positively correlated with the total score of the autism diagnostic observation schedule whereas the local connectivity within the right superior temporal sulcus was positively correlated with total subscores of both the communication and the stereotyped behaviors and restricted interests of the schedule. Finally, significant interactions between age and clinical diagnosis were detected in the left precuneus. These findings replicated previous observations that used a volume-based approach and suggested possible neuropathological impairments of local information processing in the frontal, temporal, parietal, and insular cortices. Novel site-variability analysis demonstrated high reproducibility of our findings across the 15 international sites. The age-disease interaction provides a potential target region for future studies to further elucidate the neurodevelopmental mechanisms of autism.
Little is known about the impact of learning to read on early neural development for word process... more Little is known about the impact of learning to read on early neural development for word processing and its collateral effects on neural development in non-word domains. Here, we examined the effect of early exposure to reading on neural responses to both word and face processing in preschool children with the use of the Event Related Potential (ERP) methodology. We specifically linked children's reading experience (indexed by their sight vocabulary) to two major neural markers: the amplitude differences between the left and right N170 on the bilateral posterior scalp sites and the hemispheric spectrum power differences in the g band on the same scalp sites. The results showed that the left-lateralization of both the word N170 and the spectrum power in the g band were significantly positively related to vocabulary. In contrast, vocabulary and the word left-lateralization both had a strong negative direct effect on the face right-lateralization. Also, vocabulary negatively correlated with the right-lateralized face spectrum power in the g band even after the effects of age and the word spectrum power were partialled out. The present study provides direct evidence regarding the role of reading experience in the neural specialization of word and face processing above and beyond the effect of maturation. The present findings taken together suggest that the neural development of visual word processing competes with that of face processing before the process of neural specialization has been consolidated.
Much like genomics, brain connectomics has rapidly become a core component of most national brain... more Much like genomics, brain connectomics has rapidly become a core component of most national brain projects around the world. Beyond the ambitious aims of these projects, a fundamental challenge is the need for an efficient, robust, reliable and easy-to-use pipeline to mine such large neuroscience datasets. Here, we introduce a computational pipeline-namely the Connectome Computation System (CCS)-for discovery science of human brain connectomes at the macroscale with multimodal magnetic resonance imaging technologies. The CCS is designed with a three-level hierarchical structure that includes data cleaning and preprocessing, individual connectome mapping and connectome mining, and knowledge discovery. Several functional modules are embedded into this hierarchy to implement quality control procedures, reliability analysis and connectome visualization. We demonstrate the utility of the CCS based upon a publicly available dataset, the NKI-Rockland Sample, to delineate the normative trajectories of well-known large-scale neural networks across the natural life span (6-85 years of age). The CCS has been made freely available to the public via GitHub (https://github.com/ zuoxinian/CCS) and our laboratory's Web site (http://lfcd. psych.ac.cn/ccs.html) to facilitate progress in discovery science in the field of human brain connectomics.
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Papers by Zhi Yang