Chunming Xie

Classification of Alzheimer Disease, Mild Cognitive Impairment, and Normal Cognitive Status with Large-Scale Network Analysis Based on Resting-State Functional MR Imaging

PURPOSE To use large-scale network (LSN) analysis to classify subjects with Alzheimer disease (AD), those with amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) subjects. MATERIALS AND METHODS The study was conducted with institutional review board approval and was in compliance with HIPAA regulations. Written informed consent was obtained from each participant. Resting-state functional magnetic resonance (MR) imaging was used to acquire the voxelwise time series in 55 subjects with clinically diagnosed AD (n = 20), aMCI (n =15), and normal cognitive function (n = 20). The brains were divided into 116 regions of interest (ROIs). The Pearson product moment correlation coefficients of pairwise ROIs were used to classify these subjects. Error estimation of the classifications was performed with the leave-one-out cross-validation method. Linear regression analysis was performed to analyze the relationship between changes in network connectivity strengths and behavioral scores. RESULTS The area under the receiver operating characteristic curve (AUC) yielded 87% classification power, 85% sensitivity, and 80% specificity between the AD group and the non-AD group (subjects with aMCI and CN subjects) in the first-step classification. For differentiation between subjects with aMCI and CN subjects, AUC was 95%; sensitivity, 93%; and specificity, 90%. The decreased network indexes were significantly correlated with the Mini-Mental State Examination score in all tested subjects. Similarly, changes in network indexes significantly correlated with Rey Auditory Verbal Leaning Test delayed recall scores in subjects with aMCI and CN subjects. CONCLUSION LSN analysis revealed that interconnectivity patterns of brain regions can be used to classify subjects with AD, those with aMCI, and CN subjects. In addition, the altered connectivity networks were significantly correlated with the results of cognitive tests.

Abnormal insula functional network is associated with episodic memory decline in amnestic mild cognitive impairment

Abnormalities of functional connectivity in the default mode network (DMN) recently have been reported in patients with amnestic mild cognitive impairment (aMCI), Alzheimers disease (AD) or other psychiatric diseases. As such, these abnormalities may be epiphenomena instead of playing a causal role in AD progression. To date, few studies have investigated specific brain networks, which extend beyond the DMN involved in the early AD stages, especially in aMCI. The insula is one site affected by early pathological changes in AD and is a crucial hub of the human brain networks. Currently, we explored the contribution of the insula networks to cognitive performance in aMCI patients. Thirty aMCI and 26 cognitively normal (CN) subjects participated in this study. Intrinsic connectivity of the insula networks was measured, using the resting-state functional connectivity fMRI approach. We examined the differential connectivity of insula networks between groups, and the neural correlation between the altered insula networks connectivity and the cognitive performance in aMCI patients and CN subjects, respectively. Insula subregional volumes were also investigated. AMCI subjects, when compared to CN subjects, showed significantly reduced right posterior insula volumes, cognitive deficits and disrupted intrinsic connectivity of the insula networks. Specifically, decreased intrinsic connectivity was primarily located in the frontal-parietal network and the cingulo-opercular network, including the anterior prefrontal cortex (aPFC), anterior cingulate cortex, operculum, inferior parietal cortex and precuneus. Increased intrinsic connectivity was primarily situated in the visual-auditory pathway, which included the posterior superior temporal gyrus and middle occipital gyrus. Conjunction analysis was performed; and significantly decreased intrinsic connectivity in the overlapping regions of the anterior and posterior insula networks, including the bilateral aPFC, left dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, and anterior temporal pole was found. Furthermore, the disrupted intrinsic connectivity was associated with episodic memory (EM) deficits in the aMCI patients and not in the CN subjects. These findings demonstrated that the functional integration of the insula networks plays an important role in the EM process. They provided new insight into the neural mechanism underlying the memory deficits in aMCI patients.

Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment.

Acetylcholinesterase inhibitors (AChEIs), such as donepezil, have been shown to improve cognition in mild to moderate Alzheimers disease (AD) patients. In this paper, our goal is to determine the relationship between altered cerebral blood flow (CBF) and intrinsic functional network connectivity changes in mild AD patients before and after 12-week donepezil treatment. An integrative neuroimaging approach was employed by combining pseudocontinuous arterial spin labeling (pCASL) MRI and resting-state functional MRI (R-fMRI) methods to determine the changes in CBF and functional connectivity (FC) in the cholinergic pathway. Linear regression analyses determined the correlations of the regional CBF alterations and functional connectivity changes with cognitive responses. These were measured with the Mini-Mental Status Examination (MMSE) scores and Alzheimers disease Assessment Scale-Cognitive subscale (ADAS-cog) scores. Our results show that the regional CBF in mild AD subjects after donepezil treatment was significantly increased in the middle cingulate cortex (MCC) and posterior cingulate cortex (PCC), which are the neural substrates of the medial cholinergic pathway. In both brain regions, the baseline CBF and its changes after treatment were significantly correlated with the behavioral changes in ADAS-cog scores. The intrinsic FC was significantly enhanced in the medial cholinergic pathway network in the brain areas of the parahippocampal, temporal, parietal and prefrontal cortices. Finally, the FC changes in the medial prefrontal areas demonstrated an association with the CBF level in the MCC and the PCC, and also were correlated with ADAS-cog score changes. These findings indicate that regional CBF and FC network changes in the medial cholinergic pathway were associated with cognitive performance. It also is suggested that the combined pCASL-MRI and R-fMRI methods could be used to detect regional CBF and FC changes when using drug treatments in mild AD subjects.

Dynamic Neural Responses to Cue-Reactivity Paradigms in Heroin-Dependent Users : An fMRI Study

Neuroimaging methods have been employed to study cue‐reactivity‐induced neural correlates in the human brain. However, very few studies have focused on characterizing the dynamic neural responses to the factorial interactions between the cues and the subjects. Fifteen right‐handed heroin‐dependent subjects and 12 age‐matched nondrug using subjects participated in this study. Cue‐reactivity paradigms were employed, while changes in blood oxygenation level‐dependent (BOLD) signals were acquired by functional MRI (fMRI). The fMRI datasets were analyzed with AFNI software and repeated two‐way ANOVA was employed for factorial analyses. Neural correlates of factorial interactions between cue‐factor and subject‐factor were identified in the regions of the ventral tegmental area (VTA), the left and right amygdala, the left and right fusiform cortex, and the precuneus in the mesocorticolimbic system, and in the superior frontal, dorsal lateral prefrontal, and orbitofrontal cortices in the prefrontal cortex system. The neural response patterns in the prefrontal systems are dynamic: decreased response to neutral‐cues and increased response to heroin‐cues. Further, heroin‐cue‐induced neural responses within the subregions in the PFC system are significantly intercorrelated. In conclusion, the cue‐reactivity paradigms significantly activated the dynamic neural activations in the prefrontal system. It is suggested that the dynamic response patterns in the PFC system characterize the impaired brain control functions in heroin‐dependent subjects. Hum Brain Mapp, 2009.

A method to determine the necessity for global signal regression in resting‐state fMRI studies

In resting‐state functional MRI studies, the global signal (operationally defined as the global average of resting‐state functional MRI time courses) is often considered a nuisance effect and commonly removed in preprocessing. This global signal regression method can introduce artifacts, such as false anticorrelated resting‐state networks in functional connectivity analyses. Therefore, the efficacy of this technique as a correction tool remains questionable. In this article, we establish that the accuracy of the estimated global signal is determined by the level of global noise (i.e., non‐neural noise that has a global effect on the resting‐state functional MRI signal). When the global noise level is low, the global signal resembles the resting‐state functional MRI time courses of the largest cluster, but not those of the global noise. Using real data, we demonstrate that the global signal is strongly correlated with the default mode network components and has biological significance. These results call into question whether or not global signal regression should be applied. We introduce a method to quantify global noise levels. We show that a criteria for global signal regression can be found based on the method. By using the criteria, one can determine whether to include or exclude the global signal regression in minimizing errors in functional connectivity measures. Magn Reson Med, 2012.

Recovery of hippocampal network connectivity correlates with cognitive improvement in mild alzheimer's disease patients treated with donepezil assessed by resting-state fMRI

To identify the neural correlates of cognitive improvement in mild Alzheimers disease (AD) subjects following 12 weeks of donepezil treatment.

Identification of Hyperactive Intrinsic Amygdala Network Connectivity Associated with Impulsivity in Abstinent Heroin Addicts

Impulsivity is a pathological hallmark of drug addiction. However, little is known about the neuropsychological underpinnings of this impaired impulsive control network on drug addiction. Twenty two abstinent heroin dependent (HD) subjects and 15 cognitively normal (CN) subjects participated in this study. Resting-state functional connectivity MRI was employed to measure abnormalities in the intrinsic amygdala functional connectivity (iAFC) network activity and the Barratt Impulsive Scale, 11th version was used to measure impulsivity. Linear regression analysis was applied to detect the neural constructs underlying impulsivity by correlating iAFC network activity with impulsive scores. In the HD group, higher impulsivity scores and significantly enhanced iAFC network activity were found, especially in bilateral thalamus, right insula, and inferior frontal gyrus. Markedly decreased anticorrelated iAFC network activity was seen in the left precuneus, and even switched to positive correlation pattern in right precuneus, relative to the CN group. The iAFC network strengths in the HD group were positively correlated with impulsivity in the right subcallosal gyrus, insula, thalamus and posterior cingulate cortex, and negatively correlated in left fusiform area. In the CN group, the left pre-somamotor area-amygdala connectivity was positively correlated, and right orbital frontal cortex-amygdala and precuneus-amygdala connectivity were negatively correlated with impulsivity scores. Our study demonstrates different constructs of the impulsive network in HD and CN subjects. Altered iAFC network connectivity in HD subjects may contribute to the loss of impulsive control. This further facilitates our understanding of the neural underpinnings of behavior dysfunction in addiction.

Effect of treatment on serum glial cell line-derived neurotrophic factor in bipolar patients

OBJECTIVE Post-mortem studies have demonstrated various glial deficits in different brain areas of patients diagnosed with bipolar disorder (BD). Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor from the transforming growth factor beta family which has been implicated in the pathophysiology of BD. This study aimed to determine whether GDNF in serum was abnormal in BD, and how it responded to drug treatment of BD. METHOD Serum GDNF concentrations were measured in BD patients before treatment, after 8 weeks of drug treatment, and in control subjects using a sandwich ELISA method. RESULTS Before treatment, serum GDNF was significantly lower in BD patients during both manic (P<0.001) and depressive (P<0.001) episodes than in control subjects. From baseline to remission after 8 weeks of treatment, the increase in serum GDNF was statistically significant (P<0.001). CONCLUSIONS The present study suggests that lower GDNF levels might be involved in the pathophysiology of BD and drug treatment increases the GDNF in BD.

Negative Functional Connectivity and Its Dependence on the Shortest Path Length of Positive Network in the Resting-State Human Brain

It is suggested that structurally segregated and functionally specialized brain regions are mediated by synchrony over large-scale networks in order to provide the formation of dynamic links and integration functions. The existence of negative synchrony, or negative functional connectivity (NFC), however, has been a subject of debate in terms of its origin, interpretation, relationship with structural connectivity, and possible neurophysiological function. The present study, which incorporated 20 cognitively healthy elderly human subjects, focused on testing the hypothesis that NFC significantly correlates with the shortest path length (SPL) in the human brain network. Our theoretical calculation, simulated data, and human study results support this hypothesis. In the human study, we find that (1) the percentage of NFC connections among all connections between brain regions significantly correlates with spatial Euclidian distance; (2) the strength of the NFC between the right amygdala and the left dorsolateral prefrontal cortex is significantly correlated with the SPL across the 20 human subjects; (3) such a significant relationship between the NFC and SPL exists in all the NFC connections in the whole brain; and (4) the correlations between the NFC and SPL also are frequency bandwidth dependent. These results suggest that an accumulated phased delay gives rise to the NFC, along the shortest path in the large-scale brain functional network. It is suggested that our study can be extended to examine a variety of neurological diseases and psychiatric disorders by measuring the changes of SPL and functional reorganization in the brain.

Neural correlates of the interactive relationship between memory deficits and depressive symptoms in nondemented elderly: Resting fMRI study

Prospective studies have shown an association between depressive symptoms and cognitive impairment among older adults. However, the neural correlates of this relationship are poorly understood. Our aim was to examine whether interactive effects of memory deficits and depressive symptoms are present in the memory-associated functional networks, in nondemented elderly subjects. Fifteen subjects with amnestic mild cognitive impairment (aMCI) and 20 age-matched normal (CN) elderly subjects participated in this cross-sectional study. Resting-state functional connectivity MRI (R-fMRI) measured the hippocampal functional connectivity (HFC) alterations between the two groups. Voxelwise linear regression analysis was performed to correlate hippocampal network strength with the Rey Auditory Verbal Learning Test delayed recall and the Geriatric Depression Scale scores, after adjusting for age and group effects. Poorer memory performance was associated with decreased positively correlated HFC connectivity in the specific frontal lobe and default mode network (DMN) structures. Poorer memory performance also was associated with decreased anticorrelated HFC connectivity in the bilateral inferior parietal and right dorsolateral prefrontal cortices. In contrast, greater depressive symptom severity was associated with increased HFC connectivity in several frontal lobes and DMN regions. Depressive symptoms and memory functions had interactive effects on the HFC, in the frontal, temporal, and PCC structures. Our findings suggest that the R-fMRI technique can be used to examine the changes in functional neural networks where memory deficits and depressive symptoms coexist in the geriatric population.