Qingjiu Cao

An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: Fractional ALFF

Most of the resting-state functional magnetic resonance imaging (fMRI) studies demonstrated the correlations between spatially distinct brain areas from the perspective of functional connectivity or functional integration. The functional connectivity approaches do not directly provide information of the amplitude of brain activity of each brain region within a network. Alternatively, an index named amplitude of low-frequency fluctuation (ALFF) of the resting-state fMRI signal has been suggested to reflect the intensity of regional spontaneous brain activity. However, it has been indicated that the ALFF is also sensitive to the physiological noise. The current study proposed a fractional ALFF (fALFF) approach, i.e., the ratio of power spectrum of low-frequency (0.01-0.08 Hz) to that of the entire frequency range and this approach was tested in two groups of resting-state fMRI data. The results showed that the brain areas within the default mode network including posterior cingulate cortex, precuneus, medial prefrontal cortex and bilateral inferior parietal lobule had significantly higher fALFF than the other brain areas. This pattern was consistent with previous neuroimaging results. The non-specific signal components in the cistern areas in resting-state fMRI were significantly suppressed, indicating that the fALFF approach improved the sensitivity and specificity in detecting spontaneous brain activities. Its mechanism and sensitivity to abnormal brain activity should be evaluated in the future studies.

Altered resting-state functional connectivity patterns of anterior cingulate cortex in adolescents with attention deficit hyperactivity disorder

Dorsal anterior cingulate cortex (dACC) has been found to function abnormally in attention deficit hyperactivity disorder (ADHD) patients in several former functional MRI (fMRI) studies. Resting-state low-frequency fluctuations (LFFs) of blood oxygen level-dependent (BOLD) fMRI signals have been proved to be quite informative. This study used resting-state LFFs to investigate the resting-state functional connectivity pattern differences of dACC in adolescents with and without ADHD. As compared to the controls, the ADHD patients exhibited more significant resting-state functional connectivities with the dACC in bilateral dACC, bilateral thalamus, bilateral cerebellum, bilateral insula and bilateral brainstem (pons). No brain region in the controls was found to exhibit more significant resting-state functional connectivity with the dACC. We suggest these abnormally more significant functional connectivities in the ADHD patients may indicate the abnormality of autonomic control functions in them.

Altered small-world brain functional networks in children with attention-deficit/hyperactivity disorder.

In this study, we investigated the changes in topological architectures of brain functional networks in attention‐deficit/hyperactivity disorder (ADHD). Functional magnetic resonance images (fMRI) were obtained from 19 children with ADHD and 20 healthy controls during resting state. Brain functional networks were constructed by thresholding the correlation matrix between 90 cortical and subcortical regions and further analyzed by applying graph theoretical approaches. Experimental results showed that, although brain networks of both groups exhibited economical small‐world topology, altered functional networks were demonstrated in the brain of ADHD when compared with the normal controls. In particular, increased local efficiencies combined with a decreasing tendency in global efficiencies found in ADHD suggested a disorder‐related shift of the topology toward regular networks. Additionally, significant alterations in nodal efficiency were also found in ADHD, involving prefrontal, temporal, and occipital cortex regions, which were compatible with previous ADHD studies. The present study provided the first evidence for brain dysfunction in ADHD from the viewpoint of global organization of brain functional networks by using resting‐state fMRI. Hum Brain Mapp, 2009.

Fisher discriminative analysis of resting-state brain function for attention-deficit/hyperactivity disorder.

In this study, a resting-state fMRI based classifier, for the first time, was proposed and applied to discriminate children with attention-deficit/hyperactivity disorder (ADHD) from normal controls. On the basis of regional homogeneity (ReHo), a mapping of brain function at resting state, PCA-based Fisher discriminative analysis (PC-FDA) was trained to build a linear classifier. Permutation test was then conducted to identify the brain areas with the most significant contribution to the final discrimination. Experimental results showed a correct classification rate of 85% using a leave-one-out cross-validation. Moreover, some highly discriminative brain regions, like the prefrontal cortex and anterior cingulate cortex, well confirmed the previous findings on ADHD. Interestingly, some important but less reported regions such as the thalamus were also identified. We conclude that the classifier, using resting-state brain function as classification feature, has potential ability to improve current diagnosis and treatment evaluation of ADHD.

Abnormal resting-state functional connectivity patterns of the putamen in medication-naïve children with attention deficit hyperactivity disorder

Structural and functional alterations of the putamen have been reported in patients with attention deficit hyperactivity disorder (ADHD), but the functional relationships between this area and other brain regions are seldom explored. In the present study, seed-based correlation analyses were performed in the resting-state functional magnetic resonance imaging (fMRI) data to examine the differences in functional connectivity of the putamen between medication-naïve children with ADHD and normal children. Positive functional connectivity with the putamen-ROIs was seen in bilateral sensorimotor area, prefrontal cortex, insula, superior temporal gyrus and subcortical regions and negative functional connectivity was located in bilateral parietal and occipital cortex as well as clusters in the frontal, middle temporal cortex and cerebellum. Group comparison showed that decreases in functional connectivity with the putamen-ROIs were observed in ADHD relative to the controls, except for the right globus pallidus/thalamus, which showed increased positive connectivity with left putamen-ROI. For children with ADHD, areas exhibiting decreased positive functional connectivity with left putamen-ROI were seen in right frontal and limbic regions, and regions showing decreased negative connectivity with the putamen-ROIs were observed in areas belonging to the default mode network (for left putamen-ROI, including right cerebellum and right temporal lobe; for right putamen-ROI, including left cerebellum and right precuneus). The above results suggest that abnormal functional relationships between the putamen and the cortical-striatal-thalamic circuits as well as the default mode network may underlie the pathological basis of ADHD.

Abnormal functional connectivity between the anterior cingulate and the default mode network in drug-naïve boys with attention deficit hyperactivity disorder.

A previous study indicated that adults with attention deficit hyperactivity disorder (ADHD) had a decreased anti-correlation between the dorsal anterior cingulate cortex (dACC) and the default mode network (DMN). In this study, we investigated whether children with ADHD also show a decreased anti-correlation between the dACC and the DMN. We also explored the developmental characteristics of the resting-state functional connectivity (RSFC) of the dACC with the DMN in children with ADHD. Resting-state functional magnetic resonance imaging scans were obtained from a 3T scanner in 19 drug-naïve boys with ADHD and 23 controls. Compared with normal controls, the dACC in boys with ADHD showed a significantly decreased negative RSFC with the DMN, including the dorsomedial prefrontal cortex and the posterior cingulate cortex. The RSFC strength between the dACC and the posterior cingulate cortex showed a significantly negative correlation with age in normal controls, but not in boys with ADHD. This decreased anti-correlation may suggest an abnormal balance or interaction between attentional and intrinsic thoughts. Our age-related analysis suggested an abnormal development pattern of the dACC-DMN interaction in ADHD.

Probabilistic Diffusion Tractography and Graph Theory Analysis Reveal Abnormal White Matter Structural Connectivity Networks in Drug-Naive Boys with Attention Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD), which is characterized by core symptoms of inattention and hyperactivity/impulsivity, is one of the most common neurodevelopmental disorders of childhood. Neuroimaging studies have suggested that these behavioral disturbances are associated with abnormal functional connectivity among brain regions. However, the alterations in the structural connections that underlie these behavioral and functional deficits remain poorly understood. Here, we used diffusion magnetic resonance imaging and probabilistic tractography method to examine whole-brain white matter (WM) structural connectivity in 30 drug-naive boys with ADHD and 30 healthy controls. The WM networks of the human brain were constructed by estimating inter-regional connectivity probability. The topological properties of the resultant networks (e.g., small-world and network efficiency) were then analyzed using graph theoretical approaches. Nonparametric permutation tests were applied for between-group comparisons of these graphic metrics. We found that both the ADHD and control groups showed an efficient small-world organization in the whole-brain WM networks, suggesting a balance between structurally segregated and integrated connectivity patterns. However, relative to controls, patients with ADHD exhibited decreased global efficiency and increased shortest path length, with the most pronounced efficiency decreases in the left parietal, frontal, and occipital cortices. Intriguingly, the ADHD group showed decreased structural connectivity in the prefrontal-dominant circuitry and increased connectivity in the orbitofrontal-striatal circuitry, and these changes significantly correlated with the inattention and hyperactivity/impulsivity symptoms, respectively. The present study shows disrupted topological organization of large-scale WM networks in ADHD, extending our understanding of how structural disruptions of neuronal circuits underlie behavioral disturbances in patients with ADHD.

The macrostructural and microstructural abnormalities of corpus callosum in children with attention deficit/hyperactivity disorder: a combined morphometric and diffusion tensor MRI study.

The corpus callosum (CC) is one of focused target areas which may play an important role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Conventional structural magnetic resonance imaging (MRI) studies have revealed the macrostructural abnormalities of CC and its subdivisions in ADHD compared with controls. However, no study has examined the macrostructural and microstructural characteristics of the CC in the same ADHD group. In this study, MRI morphometric and diffusion tensor imaging (DTI) techniques were combined to explore the area and measure fractional anisotropy (FA) abnormality of CC and its seven subdivisions in children with ADHD. Twenty-eight boys with ADHD (13.3+/-1.5 years) and 27 age- and gender- matched controls (13.2+/-0.9 years) were included. We co-registered individual structural MRI and DTI images manually and subdivided the midsagittal CC into seven subdivisions. The area and FA of the CC and its subdivisions were then compared between the patients and the matched controls. Results showed that ADHD had decreased area of entire CC, anterior middle-body, and isthmus. Meanwhile, reduced FA value of the isthmus was found in the ADHD group compared with the controls. Our study indicated that not only macrostructural abnormalities but also microstructural alterations in CC, especially in isthmus occurred in ADHD. The abnormality of the isthmus, the subdivision that contains the fibers connecting posterior regions of brain, may play an important role in the pathophysiology of ADHD and may be implicated in the disorders of attention.

Alerting deficits in children with attention deficit/hyperactivity disorder: Event-related fMRI evidence

Attention deficit/hyperactivity disorder (ADHD) is one of the most common but poorly understood developmental disorders in childhood. Although neuropsychological studies demonstrate that children with ADHD have attentional alerting deficits, the neurobiological bases of such deficits have not been examined extensively. In this study, by using functional magnetic resonance imaging (fMRI), we explored the neural correlates of intrinsic alertness and phasic alertness deficits in ADHD by comparing twelve boys with ADHD (13.4+/-1.7 years) with 13 age-matched normal controls (13.2+/-1.2 years) in a cued target detection task. Behaviorally, compared with the controls, the ADHD group showed a higher overall error rate and a larger reaction time variability in performing the task. At the neural level, children with ADHD showed less activation than the controls in frontal (middle and superior frontal gyrus), parietal (inferior parietal lobe, precuneus) and putamen regions. These results demonstrate that children with ADHD have deficits in alerting functions and these deficits are related to the abnormal activities in frontal and parietal regions subserving top-down attention control processes.

Imaging functional and structural brain connectomics in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopment disorders in childhood. Clinically, the core symptoms of this disorder include inattention, hyperactivity, and impulsivity. Previous studies have documented that these behavior deficits in ADHD children are associated with not only regional brain abnormalities but also changes in functional and structural connectivity among regions. In the past several years, our understanding of how ADHD affects the brain’s connectivity has been greatly advanced by mapping topological alterations of large-scale brain networks (i.e., connectomes) using noninvasive neurophysiological and neuroimaging techniques (e.g., electroencephalograph, functional MRI, and diffusion MRI) in combination with graph theoretical approaches. In this review, we summarize the recent progresses of functional and structural brain connectomics in ADHD, focusing on graphic analysis of large-scale brain systems. Convergent evidence suggests that children with ADHD had abnormal small-world properties in both functional and structural brain networks characterized by higher local clustering and lower global integrity, suggesting a disorder-related shift of network topology toward regular configurations. Moreover, ADHD children showed the redistribution of regional nodes and connectivity involving the default-mode, attention, and sensorimotor systems. Importantly, these ADHD-associated alterations significantly correlated with behavior disturbances (e.g., inattention and hyperactivity/impulsivity symptoms) and exhibited differential patterns between clinical subtypes. Together, these connectome-based studies highlight brain network dysfunction in ADHD, thus opening up a new window into our understanding of the pathophysiological mechanisms of this disorder. These works might also have important implications on the development of imaging-based biomarkers for clinical diagnosis and treatment evaluation in ADHD.