Aging influence on functional connectivity of the motor network in the resting state

We used functional MRI (fMRI) to study the aging influence on functional connectivity of the motor network in the resting state. A network model based on graph theory was used to measure functional connectivity. The total connectivity degree of each region within the motor network was calculated and compared between aged and young groups. We found that the pattern of functional connectivity was changed in aged subjects, including a significant decrease in the functional connectivity degree of the right cingulate motor area and left premotor area compared to young subjects. Our study demonstrates that normal aging modulates the functional connectivity of motor network in the resting state. We postulate that this abnormal functional connectivity of motor network in the baseline state is an important reason contributing to the deteriorated motor ability in aged subjects.     

Regional homogeneity abnormalities in patients with interictal migraine without aura: a resting-state study

Previous studies have provided evidence of structural and task-related functional changes in the brains of patients with migraine without aura. Resting-state brain activity in patients with migraine provides clues to the pathophysiology of the disease. However, few studies have focused on the resting-state abnormalities in patients with migraine without aura. In the current study, we employed a data-driven method, regional homogeneity (ReHo), to analyze the local features of spontaneous brain activity in patients with migraine without aura during the resting state. Twenty-six patients with migraine without aura and 26 age-, education- and gender-matched healthy volunteers participated in this study. Compared with healthy controls, patients with migraine without aura showed a significant decrease in ReHo values in the right rostral anterior cingulate cortex (rACC), the prefrontal cortex (PFC), the orbitofrontal cortex (OFC) and the supplementary motor area (SMA). In addition, we found that ReHo values were negatively correlated with the duration of disease in the right rACC and PFC. Our results suggest that the resting-state abnormalities of these regions may be associated with functional impairments in pain processing in patients with migraine without aura. We hope that our results will improve the understanding of migraine.     

Age-Related Changes in the Thickness of Cortical Zones in Humans

Structural neuroimaging studies have demonstrated that all regions of the cortex are not affected equally by aging, with frontal regions appearing especially susceptible to atrophy. The "last in, first out" hypothesis posits that aging is, in a sense, the inverse of development: late-maturing regions of the brain are preferentially vulnerable to age-related loss of structural integrity. We tested this hypothesis by analyzing age-related changes in regional cortical thickness via three methods: (1) an exploratory linear regression of cortical thickness and age across the entire cortical mantle (2) an analysis of age-related differences in the thickness of zones of cortex defined by functional/cytoarchitectural affiliation (including primary sensory/motor, unimodal association, heteromodal association, and paralimbic zones), and (3) an analysis of age-related differences in the thickness of regions of cortex defined by surface area expansion in the period between birth and early adulthood. Subjects were grouped as young (aged 18-29, n?=?138), middle-aged (aged 30-59, n?=?80), young-old (aged 60-79, n?=?60), and old-old (aged 80+, n?=?38). Thinning of the cortex between young and middle-aged adults was greatest in heteromodal association cortex and regions of high postnatal surface area expansion. In contrast, thinning in old-old age was greatest in primary sensory/motor cortices and regions of low postnatal surface area expansion. In sum, these results lead us to propose a sequential "developmental-sensory" model of aging, in which developmental factors influence cortical vulnerability relatively early in the aging process, whereas later-in more advanced stages of aging-factors specific to primary sensory and motor cortices confer vulnerability. This model offers explicitly testable hypotheses and suggests the possibility that normal aging may potentially allow for multiple opportunities for intervention to promote the structural integrity of the cerebral cortex.     

Activation of the dorsal premotor cortex and pre-supplementary motor area of humans during an auditory conditional motor task

Using functional magnetic resonance imaging (fMRI), we measured regional blood flow to examine which motor areas of the human cerebral cortex are preferentially involved in an auditory conditional motor behavior. As a conditional motor task, randomly selected 330 or 660 Hz tones were presented to the subjects every 1. 0 s. The low and high tones indicated that the subjects should initiate three successive opposition movements by tapping together the right thumb and index finger or the right thumb and little finger, respectively. As a control task, the same subjects were asked to alternate the two opposition movements, in response to randomly selected tones that were presented at the same frequencies. Between the two tasks, MRI images were also scanned in the resting state while the tones were presented in the same way. Comparing the images during each of the two tasks with images during the resting state, it was observed that several frontal motor areas, including the primary motor cortex, dorsal premotor cortex (PMd), supplementary motor area (SMA), and pre-SMA, were activated. However, preferential activation during the conditional motor task was observed only in the PMd and pre-SMA of the subjects' left (contralateral) frontal cortex. The PMd has been thought to play an important role in transforming conditional as well as spatial visual cues into corresponding motor responses, but our results suggest that the PMd along with the pre-SMA are the sites where more general and extensive sensorimotor integration takes place.     

A positron emission tomography study of self-paced finger movements at different frequencies.

Regional cerebral blood flow was measured in six right-handed volunteers using positron emission tomography during tasks involving repetitive self-paced finger tapping at five different frequencies. The contralateral primary sensorimotor cortex, the pre-supplementary motor area and the cingulate motor area showed significant activation during self-paced finger tapping tasks, compared with the resting state. A positive correlation between the regional cerebral blood flow and the movement frequency was found only in the primary sensorimotor cortex. In the pre-supplementary motor area and the cingulate motor area, however, activity increased when the subject employed movement frequencies faster or slower than his own pace. The same tendency was noted with respect to the relative variability of the inter-tapping interval. The results therefore indicate that the activity of the pre-supplementary motor area and the cingulate motor area may well be related to the increased difficulty in motor control rather than to the execution of the movement itself.     

基于独立成分分析和时间相关分析的脑功能连通研究方法

目的：利用静息状态功能磁共振成像（functional magnetic resonance imaging，fMRI）技术，提出联合独立成分分析（independent component analysis，ICA）和时间相关分析的人脑功能连通性研究方法。方法：首先采用空间ICA定位任务激活的脑区；然后选择一个激活区作为感兴趣区域（region of interest，ROI），采用时间相关分析方法检测静息状态大脑特定皮层的功能连通性，并通过检测人脑运动皮层的功能连通性验证方法的有效性。结果：大脑运动皮层功能连通网络包括初级运动区、辅助运动区、初级感觉皮层、背侧前运动区和后顶骨体觉区。实验结果表明，静息状态下。时间相关分析检测到的运动皮层的功能连通网络与已知的解剖连通相一致。结论：利用静息fMRI。结合空间ICA和时间相关分析方法。检测了静息时人脑运动皮层的功能连通网络。为脑区间功能连通的研究提供了一种简便的、无损的、有效的研究方法。     

基于独立成分分析和时间相关分析的脑功能连通研究方法[英文]

目的:利用静息状态功能磁共振成像(functional magnetic resonance imaging,fMRI)技术,提出联合独立成分分析(independent component analysis,ICA)和时间相关分析的人脑功能连通性研究方法。方法:首先采用空间ICA定位任务激活的脑区;然后选择一个激活区作为感兴趣区域(region of interest,ROI),采用时间相关分析方法检测静息状态大脑特定皮层的功能连通性,并通过检测人脑运动皮层的功能连通性验证方法的有效性。结果:大脑运动皮层功能连通网络包括初级运动区、辅助运动区、初级感觉皮层、背侧前运动区和后顶骨体觉区。实验结果表明,静息状态下,时间相关分析检测到的运动皮层的功能连通网络与已知的解剖连通相一致。结论:利用静息fMRI,结合空间ICA和时间相关分析方法,检测了静息时人脑运动皮层的功能连通网络,为脑区间功能连通的研究提供了一种简便的、无损的、有效的研究方法。     

The Influence of Apolipoprotein E Epsilon4 Polymorphism on qEEG Profiles in Healthy Young Females: A Resting EEG Study

The epsilon4 allele of the Apolipoprotein E (ApoE) gene has been linked to various neurological conditions and the aging process in the elderly. However, evidence has suggested that the influence of ApoE epsilon4 may commence in early life. This study examined the modulatory effects of ApoE epsilon4 on regional neural activity as well as inter-regional neural interactions in a young population aged 19-21. Blood samples and resting state eyes-closed EEG signals were collected from 265 healthy females, and stratified into two groups: epsilon4 carriers and non-carriers. The values of the log-transformed mean power of 18 electrodes and the mutual information of 20 channel pairs across delta, theta, alpha and beta frequencies were analyzed. Our connectivity analysis was based on information theory, which combined Morlet wavelet transform and mutual information calculation. Between-group statistics were performed by independent t-test. We notice a consistent trend across the brain, in which ApoE epsilon4 carriers possess lower regional power at the alpha band. The epsilon4 allele is also associated with lower regional power at the theta frequency in the left frontal and posterior brain regions. Functional connectivity analyses reveal a right-lateralized network that differentiates epsilon4 carriers and non-carriers, with lower connectivity strengths for the former. Our tonic EEG analyses complement those of previous reports in that the ApoE epsilon4 allele has a negative impact on regional neural synchronization and inter-regional neural interaction.     

Age-related decrease of functional connectivity additional to gray matter atrophy in a network for movement initiation

Healthy aging is accompanied by a decrease in cognitive and motor capacities. In a network associated with movement initiation, we investigated age-related changes of functional connectivity (FC) as well as regional atrophy in a sample of 232 healthy subjects (age range 18–85 years). To this end, voxel-based morphometry and whole-brain resting-state FC were analyzed for the supplementary motor area (SMA), anterior midcingulate cortex (aMCC) and bilateral striatum (Str). To assess the specificity of age-related effects, bilateral primary sensorimotor cortex (S1/M1) closely associated with motor execution was used as control seeds. All regions showed strong reduction of gray matter volume with age. Corrected for this regional atrophy, the FC analysis revealed an age × seed interaction for each of the bilateral Str nodes against S1/M1 with consistent age-related decrease in FC with bilateral caudate nucleus and anterior putamen. Specific age-dependent FC decline of SMA was found in bilateral central insula and the adjacent frontal operculum. aMCC showed exclusive age-related decoupling from the anterior cingulate motor area. The present study demonstrates network as well as node-specific age-dependent FC decline of the SMA and aMCC to highly integrative cortical areas involved in cognitive motor control. FC decrease in addition to gray matter atrophy within the Str may provide a substrate for the declining motor control in elderly. Finally, age-related FC changes in both the network for movement initiation as well as the network for motor execution are not explained by regional atrophy in the healthy aging brain.     

Caffeine alters resting‐state functional connectivity measured by blood oxygenation level‐dependent MRI

This study aimed to investigate the pharmacological effect of caffeine on functional connectivity measured by resting‐state blood oxygenation level‐dependent (BOLD) MRI in the motor cortex, visual cortex and default mode network (DMN). The protocols and procedures of the study were reviewed and approved by the Institutional Review Board of our institution. On a 3‐T clinical MR system, 20 healthy volunteers underwent imaging before and after oral ingestion of a 200‐mg over‐the‐counter caffeine pill (data from three individuals were excluded from further analysis because of excessive motion). The demographics of the remaining participants were as follows: female/male, 8/9; age, 21–35 years; non‐habitual caffeine consumers over the past 6 months. Functional connectivity was calculated using the general linear model, assessed in terms of connected area (voxels) and statistical significance (Student t‐values), and correlated with changes in regional cerebral blood flow as measured by arterial spin labeling MRI. Per‐subject data analysis showed that caffeine decreased functional connectivity in the motor/visual cortices, but its effects on DMN varied among subjects. Correlation analysis of the changes in functional connectivity and regional blood flow suggested that the effect of caffeine on BOLD functional connectivity was predominantly neural (motor/visual cortices) and partly vascular (DMN). Group analysis showed that, after caffeine ingestion, DMN involved more attentional networks, and more extrastriate areas were integrated into the functional connectivity of the visual cortex, which may be associated with the known pharmacological effect of caffeine in elevating alertness. Caffeine consumption should thus be considered in the experimental design and data interpretation of functional connectivity studies using resting‐state BOLD MRI. © 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.     

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.     

Age-dependent changes in the activity and isoenzymatic pattern of the phosphofructokinase in different areas of the central nervous systems.

Regional activity of phosphofructokinase enzyme and the amount of the isoenzyme C in 7 areas of young, adult and aged rats brain have been studied. The phosphofructokinase activity in substantia nigra decreased in adult and aged rats, but the maximum decrease was found in the septum of aged rats. There is a regional distribution of the isoenzyme C in the different areas studied. There was a general decrease in the amount of this isoenzyme in the areas studied with the exception of the hippocampus and the amygdala. The highest decrease was found in the septal area and in the diagonal band of Broca. These results are discussed in relation to the aging in different regions.     

Effects of age and dopamine D2L receptor-deficiency on motor and learning functions

Decreases in the activity or density of dopamine D2 receptor (D2R) have been associated with age-related changes and neurodegenerative diseases such as Parkinson's disease. There are two isoforms of the D2R, termed the D2 long receptor (D2LR) and D2 short receptor (D2SR). To study the function of these two isoforms and their role in aging, we generated mice selectively lacking D2LR (D2L-/-). Here, we showed that middle-aged (12 months) to aged wild-type (WT) mice (22-24 months) displayed significantly lower levels of motor and learning functions than young WT mice (3 months). Interestingly, young D2L-/- mice (which still express D2SR) showed behavioral deficits similar to aged WT mice. It is possible that deletion of the D2LR might facilitate the aging process in mice. Our results also suggest that a deterioration of the D2LR (but not D2SR) system during aging may account, at least in part, for the motor and learning deficits exhibited in aged WT mice. We also showed that the critical age at which significant reduction in behavior occurred varied among different behaviors. Defining the age-related critical periods and understanding the role of the two D2R isoforms in aging may facilitate the development of new strategies for delaying or ameliorating age-related motor and learning impairments.     

Hyperactive external awareness against hypoactive internal awareness in disorders of consciousness using resting‐state functional MRI: highlighting the involvement of visuo‐motor modulation

Resting‐state functional MRI (fMRI) has emerged as a valuable tool to characterize the complex states encompassing disorders of consciousness (DOC). Awareness appears to comprise two coexistent, anticorrelated components named the external and internal awareness networks. The present study hypothesizes that DOC interrupts the balance between the internal and external awareness networks. To gain more understanding of this phenomenon, the present study analyzed resting‐state fMRI data from 12 patients with DOC versus 12 healthy age‐matched controls. The data were explored using independent component analysis and amplitude of low‐frequency fluctuation (ALFF) analysis. The results indicated that DOC deactivated midline areas associated with internal awareness. In addition, external awareness was strengthened in DOC because of increased activation in the insula, lingual gyrus, paracentral and supplementary motor area. The activity patterns suggested strengthened external awareness against weakened internal awareness in DOC. In particular, increased activity found in the insula, lingual gyrus, paracentral and supplementary motor area of patients with DOC implied possible involvement of augmented visuo‐motor modulation in these patients. DOC is probably related to hyperactive external awareness opposing hypoactive internal awareness. This unique pattern of brain activity may potentially be a prognostic marker for DOC. Copyright © 2014 John Wiley & Sons, Ltd.     

5 Hz repetitive TMS increases anticipatory motor activity in the human cortex

In the present study, we analyzed how high-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor hand area (M1-Hand) shapes anticipatory motor activity in frontal areas as indexed by the contingent negative variation (CNV). Eight right-handed volunteers received real or sham 5Hz rTMS at an intensity of 90% resting motor threshold (1,500 stimuli per session). Real but not sham rTMS to left M1-Hand induced a site-specific increase in amplitude of the late component of the CNV at the electrode C3 overlaying the site of stimulation. The increase in pre-movement activity in the stimulated cortex may reflect an increase in facilitatory drive from connected motor areas, enhanced responsiveness of the stimulated cortex to these inputs or both.     

Resting State fMRI Demonstrates a Disturbance of the Cerebello-Cortical Circuit in Essential Tremor

Individuals with essential tremor (ET) have postural and active movement abnormalities. Disturbances in the cerebello-thalamo-cortical circuit may contribute to the several motor symptoms of ET. Resting state fMRI provides a valuable, noninvasive tool to study intrinsic activation in the human brain, particularly in the brains of individuals with neuropsychiatric diseases. To investigate the low frequency oscillation features of intrinsic activation in ET in this study, we performed a resting state fMRI analysis in 24 patients with ET and 23 healthy controls. The amplitudes of low frequency fluctuation (ALFF) were analyzed. When compared with healthy controls, patients showed significantly enhanced ALFF in the bilateral cerebral cortex, which is related to motor function, including the pre- and post-central gyrus, supplementary motor area and paracentral lobule. The larger ALFF value in the right precentral gyrus is related to a longer duration of tremor. The decreased ALFF in the bilateral cerebellum was also observed in patients. In addition, aberrant ALFF in the right cerebellar tonsil was negatively associated with the duration of tremor. Our findings suggest that abnormalities exist in the intrinsic activation of brain regions in patients with ET. These findings provide noninvasive evidence that supports the hypothesis that the abnormality of intrinsic activity in the cerebello-cerebral cortex pathway could be associated with the motor-related symptoms of ET. Furthermore, the duration of a tremor might relate to the severity of the alterations to the motor system of ET.     

The cerebral oscillatory network of voluntary tremor

It has recently been shown that resting tremor in Parkinson's disease is associated with oscillatory neural coupling in an extensive cerebral network comprising a cerebello–diencephalic–cortical loop and cortical motor, somatosensory and posterior parietal areas contralateral to the tremor hand. The aim of the present study was to investigate whether this oscillatory brain network exclusively reflects a pathophysiological state in parkinsonian resting tremor or whether it constitutes a fundamental feature of physiological motor control. We investigated cerebro-muscular and cerebro-cerebral coupling in 11 healthy subjects imitating typical antagonistic parkinsonian tremor. We recorded brain activity with a 122-channel whole-head neuromagnetometer and surface EMGs of the forearm extensor. Analysis of cerebro-muscular and cerebro-cerebral coherence revealed oscillatory coupling in the same brain structures that comprise the oscillatory network of parkinsonian resting tremor. Interestingly, similar to parkinsonian resting tremor, cerebro-cerebral coherences often showed a significant peak at twice the simulated tremor frequency. The most striking differences between parkinsonian patients, as investigated in a previous study and healthy subjects imitating the antagonistic resting tremor were a reduction of the coupling between primary sensorimotor cortex and a diencephalic structure – most likely the thalamus – and an enhancement of the coupling between premotor and primary sensorimotor cortex. Our results indicate that the coupling of oscillatory activity within a cerebello–diencephalic–cortical loop constitutes a basic feature of physiological motor control. Thus, our data are consistent with the hypothesis that parkinsonian resting tremor involves oscillatory cerebro-cerebral coupling in a physiologically pre-existing network.     

Parkinson's disease involves autophagy and abnormal distribution of cathepsin L

Intrinsic brain activity in a resting state incorporates components of the task negative network called default mode network (DMN) and task-positive networks called attentional networks. In the present study, the reciprocal neuronal networks in the elder group were compared with the young group to investigate the differences of the intrinsic brain activity using a method of temporal correlation analysis based on seed regions of posterior cingulate cortex (PCC) and ventromedial prefrontal cortex (vmPFC). We found significant decreased positive correlations and negative correlations with the seeds of PCC and vmPFC in the old group. The decreased coactivations in the DMN network components and their negative networks in the old group may reflect age-related alterations in various brain functions such as attention, motor control and inhibition modulation in cognitive processing. These alterations in the resting state anti-correlative networks could provide neuronal substrates for the aging brain.     

Brain regional angiogenic potential at the neurovascular unit during normal aging

Given strong regional specialization of the brain, cerebral angiogenesis may be regionally modified during normal aging. To test this hypothesis, expression of a broad cadre of angiogenesis-associated genes was assayed at the neurovascular unit (NVU) in discrete brain regions of young versus aged mice by laser capture microdissection coupled to quantitative real-time polymerase chain reaction (PCR). Complementary quantitative capillary density/branching studies were performed as well. Effects of physical exercise were also assayed to determine if age-related trends could be reversed. Additionally, gene response to hypoxia was probed to highlight age-associated weaknesses in adapting to this angiogenic stress. Aging impacted resting expression of angiogenesis-associated genes at the NVU in a region-dependent manner. Physical exercise reversed some of these age-associated gene trends, as well as positively influenced cerebral capillary density/branching in a region-dependent way. Lastly, hypoxia revealed a weaker angiogenic response in aged brain. These results suggest heterogeneous changes in angiogenic capacity of the brain during normal aging, and imply a therapeutic benefit of physical exercise that acts at the level of the NVU.     

Comparative study of regional homogeneity in schizophrenia and major depressive disorder

Compelling evidence suggests that there is a considerable overlap in structural and functional alternation in the brain between different neuropsychiatric disorders. However, whether these overlaps are specific for schizophrenia has yet to be investigated. A total of 36 patients with paranoid schizophrenia, 43 patients with major depressive disorder (MDD), and 44 healthy controls were recruited to undergo resting‐state functional magnetic resonance imaging (rs‐fMRI) for analysis of regional homogeneity (ReHo). Twelve regions of interest (ROIs) in the frontal and temporal lobes were generated and one‐way ANOVA was performed to test the ReHo differences within these ROIs between the above three groups. The ReHo values within ROIs were extracted to investigate whether a left‐right asymmetry existed in a mental disorder. One‐way ANOVA showed significant differences in ReHo in the right superior frontal gyrus and left superior temporal gyrus; post hoc analysis revealed that schizophrenic patients had lower ReHo in the left superior temporal gyrus than either control subjects or patients with MDD. Increased ReHo was observed in the right superior frontal gyrus in schizophrenic patients compared with control subjects, and a left‐less‐than‐right asymmetry was also found in this region in schizophrenic patients. The above alterations in ReHo were not affected by age and genders. Our study suggests that the altered ReHo in the superior frontal and temporal gyrus may be specific for schizophrenia rather than MDD. A left‐less‐than‐right asymmetry activation pattern may exist in the resting‐state superior frontal gyrus in schizophrenia. This finding would be helpful for better understanding the pathological mechanisms of schizophrenia. © 2012 Wiley Periodicals, Inc.