Resting state fMRI in Alzheimer's disease: beyond the default mode network

Using resting state (RS) functional magnetic resonance imaging (fMRI), the connectivity patterns of the default mode (DMN), frontoparietal, executive, and salience networks were explored in 13 Alzheimer's disease (AD) patients, 12 amnestic mild cognitive impairment (aMCI) patients, and 13 healthy controls. Compared with controls and aMCI, AD was associated with opposing connectivity effects in the DMN (decreased) and frontal networks (enhanced). The only RS abnormality found in aMCI patients compared with controls was a precuneus connectivity reduction in the DMN. RS fMRI group differences were only partly related to gray matter atrophy. In AD patients, the mean executive network connectivity was positively associated with frontal-executive and language neuropsychological scores. These results suggest that AD is associated with an alteration of large-scale functional brain networks, which extends well beyond the DMN. In AD, the limited resources of the DMN may be paralleled, in an attempt to maintain cognitive efficiency, by an increased prefrontal connectivity. A medial parietal RS fMRI signal change seems to be present since the early phase of AD.     

Resting state functional connectivity alterations in primary lateral sclerosis

Resting state functional connectivity of the sensorimotor and extramotor brain networks was studied in 24 patients with primary lateral sclerosis (PLS) relative to 26 healthy controls. The relationships of RS functional connectivity with patient clinical and cognitive status and white matter tract damage (i.e., corticospinal tracts, corpus callosum, and superior longitudinal fasciculus) were investigated. Compared with controls, PLS patients showed an increased functional connectivity within the sensorimotor, frontal, and left frontoparietal networks spanning the pre- and postcentral, medial and dorsal frontal, insular, and superior temporal regions. Patients with more severe physical disability and a more rapid rate of disease progression had increased sensorimotor connectivity values. The increased functional connectivity within the frontal network was associated with executive dysfunction. In addition, higher functional connectivity correlated with greater structural damage to network-specific white matter tracts. This study shows clinically meaningful increased resting state functional connectivity in PLS.     

Ventromedial prefrontal cortex connectivity during and after psychological stress in women

The ventromedial prefrontal cortex (vmPFC) integrates sensory, affective, memory‐related, and social information from diverse brain systems to coordinate behavioral and peripheral physiological responses according to contextual demands that are appraised as stressful. However, the functionality of the vmPFC during stressful experiences is not fully understood. Among 40 female participants, the present study evaluated (a) functional connectivity of the vmPFC during exposure to and recovery following an acute psychological stressor, (b) associations among vmPFC functional connectivity, heart rate, and subjective reports of stress across individuals, and (c) whether patterns of vmPFC functional connectivity were associated with distributed brain networks. Results showed that psychological stress increased vmPFC functional connectivity with individual brain areas implicated in stressor processing (e.g., insula, amygdala, anterior cingulate cortex) and decreased connectivity with the posterior cingulate cortex and thalamus. There were no statistical differences in vmPFC connectivity to individual brain areas during recovery, as compared with baseline. Spatial similarity analyses revealed stressor‐evoked increased connectivity of the vmPFC with the so‐called dorsal attention, ventral attention, and frontoparietal networks, as well as decreased connectivity with the default mode network. During recovery, vmPFC connectivity increased with the frontoparietal network. Finally, individual differences in heart rate and perceived stress were associated with vmPFC connectivity to the ventral attention, frontoparietal, and default mode networks. Psychological stress appears to alter network‐level functional connectivity of the vmPFC in a manner that further relates to individual differences in stressor‐evoked cardiovascular and affective reactivity.     

Changes of functional connectivity of the motor network in the resting state in Parkinson's disease

We used functional MRI (fMRI) and a network model based on graph theory to measure functional connectivity of brain motor network in the resting state in patients with Parkinson's disease (PD). FMRIs were acquired in 22 PD patients before and after levodopa administration, and in age- and sex-matched normal controls. The total connectivity degree of each region within the motor network was calculated and compared between patients and controls. We found that PD patients at off state had significantly decreased functional connectivity in the supplementary motor area, left dorsal lateral prefrontal cortex and left putamen, and had increased functional connectivity in the left cerebellum, left primary motor cortex, and left parietal cortex compared to normal subjects. Administration of levodopa relatively normalized the pattern of functional connectivity in PD patients. The functional connectivity in most of regions in the motor network correlated with the Unified Parkinson's Disease Rating Scale motor score in the patients. Our findings demonstrate that the pattern of functional connectivity of the motor network in the resting state is disrupted in PD. This change is secondary to dopamine deficiency, and related to the severity of the disease. We postulate that this abnormal functional connectivity of motor network in the baseline state is possibly an important factor contributing to some motor deficits in PD, e.g. akinesia.     

大尺度脑网络交互支持内外部指向认知的研究进展

大量神经成像研究表明,人脑的高级认知功能不是由单个脑区负责的,而是通过多个与认知活动相关的脑区构成的特异性脑网络的协同活动实现。其中,额顶控制网络动态调控默认网络和背侧注意网络之间的信息交互,在高级认知加工中发挥重要作用。从几个方面综述这一领域的研究进展,包括默认网络、背侧注意网络和额顶控制网络的神经解剖,以及各个脑网络和网络间交互在内外部注意指向任务中的功能角色。未来研究需要对3个脑网络进行更精确的功能定义,进一步探索网络内部各个亚网络的功能角色,同时借助效应连接的手段,考察网络内部和网络间信息传递的方向性和动态性,从而更深入理解默认网络、背侧注意网络和额顶控制网络在内外部注意指向的认知活动中信息交互的神经机制。     

Evidence for a frontoparietal control system revealed by intrinsic functional connectivity

Two functionally distinct, and potentially competing, brain networks have been recently identified that can be broadly distinguished by their contrasting roles in attention to the external world versus internally directed mentation involving long-term memory. At the core of these two networks are the dorsal attention system and the hippocampal-cortical memory system, a component of the brain's default network. Here spontaneous blood-oxygenation-level-dependent (BOLD) signal correlations were used in three separate functional magnetic resonance imaging data sets (n = 105) to define a third system, the frontoparietal control system, which is spatially interposed between these two previously defined systems. The frontoparietal control system includes many regions identified as supporting cognitive control and decision-making processes including lateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule. Detailed analysis of frontal and parietal cortex, including use of high-resolution data, revealed clear evidence for contiguous but distinct regions: in general, the regions associated with the frontoparietal control system are situated between components of the dorsal attention and hippocampal-cortical memory systems. The frontoparietal control system is therefore anatomically positioned to integrate information from these two opposing brain systems.     

Gray matter deficits and resting-state abnormalities in abstinent heroin-dependent individuals

Previous neuroimaging studies have demonstrated both structural and functional damages in heroin-dependent individuals. However, few studies investigated gray matter deficits and abnormal resting-state networks together in heroin-dependent individuals. In the present study, voxel-based morphometry (VBM) was used to identify brain regions with gray matter density reduction. Resting-state fMRI connectivity analysis was employed to assess potential functional abnormalities during resting-state. All clinical significances were investigated by examining their association with duration of heroin use. Compared with healthy subjects, heroin-dependent individuals showed significant reduction in gray matter density in the right dorsolateral prefrontal cortex (DLPFC) and a decrease in resting-state functional connectivity between the right DLPFC and left inferior parietal lobe (IPL). The gray matter density of the right DLPFC and its resting-state functional connectivity with the left IPL both showed significantly negative correlation with duration of heroin use, which were likely to be related to the functional impairments in decision-making and cognitive control exhibited by heroin-dependent individuals. Our findings demonstrated that long heroin dependence impairs the right DLPFC in heroin-dependent individuals, including structural deficits and resting-state functional impairments.     

Functional and Structural Alterations in Temporal Lobe Tumor Patients: Evidence of Functional Compensation in the Human Brain

Patients with temporal lobe tumor are frequently accompanied by cognitive impairments. This study aims to combine diffusion tensor imaging(DTI) with resting-state functional magnetic resonance image(fMRI) to explore the underlying cognitive alternation and functional reorganization in patients with temporal lobe tumor.Twenty patients with right temporal lobe tumor and seventeen healthy volunteers were recruited in this study. Independent component analysis(ICA) was utilized to divide the whole brain into six sub functional networks, and DTI combined with graph-based topological analysis was used to calculate the structural properties of whole-brain and sub functional networks. Besides, the rich hubs in both patients and healthy controls(HCs)were identified and a further analysis of their internal functional and structural connectivity was also conducted. The E_(global) in self-referential network(SRN) of patients is higher than HCs, while decreased E_(global) of dorsal attention network(DAN) and default mode network(DMN) were found in patients. For the patients, brain regions with increased nodal efficiency(E_(nodal)) were located in the frontal lobe(corresponding to SRN). Six identical hubs were found in two groups. Compared patients with HCs, significant between-group differences in both functional and structural connectivity were observed between right insula(INS.R) and right lenticular nucleus, putamen(PUT.R). The findings provide evidence that impaired cognition are closely related to functional and structural abnormalities and the compensatory roles of frontal lobe were also identified in patients.The proposed combination of DTI and f MRI promises a widespread utilization in clinical research on the mechanisms of neurological diseases.     

Altered structural networks and executive deficits in traumatic brain injury patients

Recent research on traumatic brain injury (TBI) has shown that impairments in cognitive and executive control functions are accompanied by a disrupted neural connectivity characterized by white matter damage. We constructed binary and weighted brain structural networks in 21 patients with chronic TBI and 17 healthy young adults utilizing diffusion tensor tractography and calculated topological properties of the networks using a graph theoretical method. Executive function was assessed with the local global task and the trail making task, requiring inhibition, updating, and switching. The results revealed that TBI patients were less successful than controls on the executive tasks, as shown by the higher reaction times, higher switch costs, and lower accuracy rates. Moreover, both TBI patients and controls exhibited a small world topology in their white matter networks. More importantly, the TBI patients demonstrated increased shortest path length and decreased global efficiency of the structural network. These findings suggest that TBI patients have a weaker globally integrated structural brain network, resulting in a limited capacity to integrate information across brain regions. Furthermore, we showed that the white matter networks of both groups contained highly connected hub regions that were predominately located in the parietal cortex, frontal cortex, and basal ganglia. Finally, we showed significant correlations between switching performance and network property metrics within the TBI group. Specifically, lower scores on the switching tasks corresponded to a lower global efficiency. We conclude that analyzing the structural brain network connectivity provides new insights into understanding cognitive control changes following brain injury.     

Optical Mapping of Brain Activation and Connectivity in Occipitotemporal Cortex During Chinese Character Recognition

In this study, functional near-infrared spectroscopy (fNIRS) was used to examine the brain activation and connectivity in occipitotemporal cortex during Chinese character recognition (CCR). Eighteen healthy participants were recruited to perform a well-designed task with three categories of stimuli (real characters, pseudo characters, and checkerboards). By inspecting the brain activation difference and its relationship with behavioral data, the left laterality during CCR was clearly identified in the Brodmann area (BA) 18 and 19. In addition, our novel findings also demonstrated that the bilateral superior temporal gyrus (STG), bilateral BA 19, and left fusiform gyrus were also involved in high-level lexical information processing such as semantic and phonological ones. Meanwhile, by examining functional brain networks, we discovered that the right BA 19 exhibited enhanced brain connectivity. In particular, the connectivity in the right fusiform gyrus, right BA 19, and left STG showed significant correlation with the performance of CCR. Consequently, the combination of fNIRS technique with functional network analysis paves a new avenue for improved understanding of the cognitive mechanism underlying CCR.     

Dysfunctions within limbic–motor networks in amyotrophic lateral sclerosis

Previous studies have shown that affective symptoms are part of the clinical picture in amyotrophic lateral sclerosis (ALS), the most common motor neuron disorder in elderly people. Diffuse neurodegeneration of limbic regions (e.g., prefrontal cortex [PFC], amygdala) was demonstrated in ALS post-mortem, although the mechanisms of emotional dysregulation in ALS in vivo remain unclear. Using functional imaging, we assessed the brain responses to emotional faces in 11 cognitively unimpaired ALS patients and 12 healthy controls (HCs). We tested whether regional activities and connectivity patterns in the limbic system differed between ALS patients and HCs and whether the variability in clinical measures modulated the neuroimaging data. Relative to HCs, ALS patients displayed greater activation in a series of PFC areas and altered left amygdala–PFC connectivity. Anxiety modulated the right amygdala–PFC connectivity in HCs but not in ALS patients. Reduced right premotor cortex activity and altered left amygdala–supplementary motor area connectivity were associated with longer disease duration and greater disease severity, respectively. Our findings demonstrate dysfunctions of the limbic system in ALS patients at early stages of the disease, and extend our knowledge about the interplay between emotional brain areas and the regions traditionally implicated in motor control.     

Cortico-striatal-thalamic network functional connectivity in hemiparkinsonism

Cortico-striatal-thalamic network functional connectivity (FC) and its relationship with levodopa (L-dopa) were investigated in 69 patients with hemiparkinsonism (25 drug-naïve [n-PD] and 44 under stable/optimized dopaminergic treatment [t-PD]) and 27 controls. Relative to controls, n-PD patients showed an increased FC between the left and the right basal ganglia, and a decreased connectivity of the affected caudate nucleus and thalamus with the ipsilateral frontal and insular cortices. Compared with both controls and n-PD patients, t-PD patients showed a decreased FC among the striatal and thalamic regions, and an increased FC between the striatum and temporal cortex, and between the thalamus and several sensorimotor, parietal, temporal, and occipital regions. In both n-PD and t-PD, patients with more severe motor disability had an increased striatal and/or thalamic FC with temporal, parietal, occipital, and cerebellar regions. Cortico-striatal-thalamic functional abnormalities occur in patients with hemiparkinsonism, antecede the onset of the motor symptoms on the opposite body side and are modulated by L-dopa. In patients with hemiparkinsonism, L-dopa is likely to facilitate a compensation of functional abnormalities possibly through an increased thalamic FC.     

Pain enhances functional connectivity of a brain network evoked by performance of a cognitive task

Experimental and clinical evidence indicates that pain can affect cognitive processes, but the cortical networks involved in pain-cognition interactions are unclear. In this study, we determined the effect of pain on the activity of cortical areas involved in cognition acting as a whole (i.e., a network). Subjects underwent functional magnetic resonance imaging (fMRI) while engaged in an attention-demanding cognitive task (multisource interference task) of varying difficulty and simultaneously receiving painful stimuli at varying intensities. The control (baseline) condition was simple finger tapping that had minimal cognitive demands and without pain. Functional connectivity analysis revealed a cortical network consisting of two anti-correlated parts: a task-negative part (precuneus/posterior cingulate cortex, medial frontal and inferior parietal/temporal) the activity of which correlated negatively with the cognitive task and positively with the control baseline, and a task-positive part (inferior frontal, superior parietal, premotor, and anterior insula cortices) the activity of which correlated positively with the cognitive task and negatively with the baseline. Independent components analysis revealed these opposing networks were operating at a low frequency (0.03-0.08 Hz). The functional connectivity of the task-positive network was increased by cognitive demand and by pain. We suggest this attention-specific network balances the needs of general self-referential and environmental awareness versus focused attention to salient information. We postulate that pain affects cognitive ability by its reliance on this common attention-specific network. These data provide evidence that pain can modulate a network presumed to be involved in focused attention, suggesting a mechanism for the interference of pain on cognitive ability by the consumption of attentional resources.     

Age-related functional reorganization,structural changes,and preserved cognition

Although healthy aging is associated with general cognitive decline, there is considerable variability in the extent to which cognitive functions decline or are preserved. Preserved cognitive function in the context of age-related neuroanatomical and functional changes, has been attributed to compensatory mechanisms. However, the existing sparse evidence is largely focused on functions associated with the frontal cortex, leaving open the question of how wider age-related brain changes relate to compensation. We evaluated relationships between age-related neural and functional changes in the context of preserved cognitive function by combining measures of structure, function, and cognitive performance during spoken language comprehension using a paradigm that does not involve an explicit task. We used a graph theoretical approach to derive cognitive activation-related functional magnetic resonance imaging networks. Correlating network properties with age, neuroanatomical variations, and behavioral data, we found that decreased gray matter integrity was associated with decreased connectivity within key language regions but increased overall functional connectivity. However, this network reorganization was less efficient, suggesting that engagement of a more distributed network in aging might be triggered by reduced connectivity within specialized networks.     

Functional anatomy of cortical areas characterized by Von Economo neurons

Von Economo’s neurons (VENs) are large, bipolar or corkscrew-shaped neurons located in layers III and V of the frontoinsular and the anterior cingulate cortices. VENs are reported to be altered in pathologies such as frontotemporal dementia and autism, in which the individual’s self control is seriously compromised. To investigate the role of VENs in the active human brain, we have explored the functional connectivity of brain areas containing VENs by analyzing resting state functional connectivity (rsFC) in 20 healthy volunteers. Our results show that cortical areas containing VENs form a network of frontoparietal functional connectivity. With the use of fuzzy clustering techniques, we find that this network comprises four sub-networks: the first network cluster resembles a “saliency detection” attentional network, which includes superior frontal cortex (Brodmann’s Area, BA 10), inferior parietal lobe, anterior insula, and dorsal anterior cingulate cortex; the second cluster, part of a “sensory-motor network”, comprises the superior temporal, precentral and postcentral areas; the third cluster consists of frontal ventromedial and ventrodorsal areas constituted by parts of the “anterior default mode network”; and the fourth cluster encompasses dorsal anterior cingulate cortex, dorsomedial prefrontal, and superior frontal (BA 10) areas, resembling the anterior part of the “dorsal attentional network”. Thus, the network that emerges from analyzing functional connectivity among areas that are known to contain VENs is primarily involved in functions of saliency detection and self-regulation. In addition, parts of this network constitute sub-networks that partially overlap with the default mode, the sensory-motor and the dorsal attentional networks.     

Associations between insomnia symptoms and functional connectivity in the UK Biobank cohort (n = 29,423)

An increasing number of studies harness resting-state fMRI functional connectivity analysis to investigate the neurobiological mechanisms of insomnia. The results to date are inconsistent and the detection of minor and widely distributed alterations in functional connectivity requires large sample sizes. The present study investigated associations between insomnia symptoms and resting-state functional connectivity at the whole-brain level in the largest sample to date. This cross-sectional analysis used resting-state imaging data from the UK Biobank, a large scale, population-based biomedical database. The analysis included 29,423 participants (age: 63.1 ± 7.5 years, 54.3% female), comprising 9210 with frequent insomnia symptoms and 20,213 controls without. Linear models were adjusted for relevant clinical, imaging, and socio-demographic variables. The Akaike information criterion was used for model selection. Multiple comparisons were corrected using the false discovery rate with a significance level of q < 0.05. Frequent insomnia symptoms were associated with increased connectivity within the default mode network and frontoparietal network, increased negative connectivity between the default mode network and the frontoparietal network, and decreased connectivity between the salience network and a node of the default mode network. Furthermore, frequent insomnia symptoms were associated with altered functional connectivity between nodes comprising sensory areas and the cerebellum. These functional alterations of brain networks may underlie dysfunctional affective and cognitive processing in insomnia and contribute to subjectively and objectively impaired sleep. However, it must be noted that the item that was used to assess frequent insomnia symptoms in this study did not assess all the characteristics of clinically diagnosed insomnia.     

慢性失眠患者大脑蓝斑的异常静息态功能连接

目的:利用功能连接方法观察慢性失眠患者静息态下蓝斑的异常功能连接。方法:采集49例慢性失眠患者以及47例性别年龄和受教育程度相匹配的健康对照组的功能磁共振图像,以蓝斑为感兴趣区域,与全脑其他体素进行功能连接分析,得到两组之间功能连接的差异脑区,再对异常连接脑区的功能连接值与临床量表分数做相关分析。结果:与对照组相比,慢性失眠患者蓝斑与右楔前叶皮质、右后扣带回皮质、左颞中回皮质、左距状沟周围皮质、右眶部额上回皮质之间的功能连接增强（P<0.05, FDR校正）,并且蓝斑与左颞中回皮质之间功能连接值与抑郁自评量表呈正相关（P=0.021）。结论:慢性失眠患者蓝斑与多个脑区（主要是默认模式网络）出现的异常功能连接,可能有助于更好地理解慢性失眠的神经生物学机制,可能为失眠的高度唤醒假说提供新的影像学证据。     

Age-related differences of saccade induced cortical activation

Recent functional MRI (fMRI) studies have described the increased task-related brain activation in older subjects during motor, cognitive and perceptual tasks. Age affects the ability to control saccadic eye movements. To investigate the age-related changes of oculomotor control, we studied the representation of saccades in 11 young (median age 29 years) and 11 older (median age 62 years) healthy individuals using fMRI. Brain activation was measured during a visually guided prosaccade trial. Differences in activation between rest and saccades as well as between younger and older subjects were assessed with statistical parametric mapping (SPM). In both age groups, activation of a frontoparietal network was observed. Older subjects showed increased activation compared to younger subjects with overactivation in bilateral parietal eye fields, the right frontal eye field, as well as in the right extrastriate cortex. We conclude that older adults increase activation in an extended oculomotor and visual network to maintain performance during simple prosaccades. This observation also underlines the importance of using appropriate age-matched control groups in fMRI studies after brain lesions.     

Abnormal Functional Connectivity Density in Post-traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that occurs in individuals who have experienced life-threatening mental traumas. Previous neuroimaging studies have indicated that the pathology of PTSD may be associated with the abnormal functional integration among brain regions. In the current study, we used functional connectivity density (FCD) mapping, a novel voxel-wise data-driven approach based on graph theory, to explore aberrant FC through the resting-state functional magnetic resonance imaging of the PTSD. We calculated both short- and long-range FCD in PTSD patients and healthy controls (HCs). Compared with HCs, PTSD patients showed significantly increased long-range FCD in the left dorsolateral prefrontal cortex (DLPFC), but no abnormal short-range FCD was found in PTSD. Furthermore, seed-based FC analysis of the left DLPFC showed increased connectivity in the left superior parietal lobe and visual cortex of PTSD patients. The results suggested that PTSD patients experienced a disruption of intrinsic long-range functional connections in the fronto-parietal network and visual cortex, which are associated with attention control and visual information processing.     

Basal ganglia circuits changes in Parkinson's disease patients

Functional changes in basal ganglia circuitry are responsible for the major clinical features of Parkinson's disease (PD). Current models of basal ganglia circuitry can only partially explain the cardinal symptoms in PD. We used functional MRI to investigate the causal connectivity of basal ganglia networks from the substantia nigra pars compacta (SNc) in PD in the movement and resting state. In controls, SNc activity predicted increased activity in the supplementary motor area, the default mode network, and dorsolateral prefrontal cortex, but, in patients, activity predicted decreases in the same structures. The SNc had decreased connectivity with the striatum, globus pallidus, subthalamic nucleus, thalamus, supplementary motor area, dorsolateral prefrontal cortex, insula, default mode network, temporal lobe, cerebellum, and pons in patients compared to controls. Levodopa administration partially normalized the pattern of connectivity. Our findings show how the dopaminergic system exerts influences on widespread brain networks, including motor and cognitive networks. The pattern of basal ganglia network connectivity is abnormal in PD secondary to dopamine depletion, and is more deviant in more severe disease. Use of functional MRI with network analysis appears to be a useful method to demonstrate basal ganglia pathways in vivo in human subjects.