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 Alzheimer's 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 Alzheimer's 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.     

Prefrontal and premotor cortices are involved in adapting walking and running speed on the treadmill: an optical imaging study

We investigated changes of regional activation in the frontal cortices as assessed by changes of hemoglobin oxygenation during walking at 3 and 5 km/h and running at 9 km/h on a treadmill using a near-infrared spectroscopic (NIRS) imaging technique. During the acceleration periods immediately preceded reaching the steady walking or running speed, the levels of oxygenated hemoglobin (oxyHb) increased, but those of deoxygenated hemoglobin (deoxyHb) did not in the frontal cortices. The changes were greater at the higher locomotor speed in the bilateral prefrontal cortex and the premotor cortex, but there were less speed-associated changes in the sensorimotor cortices. The medial prefrontal activation was most prominent during the running task. These results indicate that the prefrontal and premotor cortices are involved in adapting to locomotor speed on the treadmill. These areas might predominantly participate in the control of running rather than walking.     

Gender Difference in Premotor Activity during Active Tactile Discrimination

To investigate possible gender differences in tactile discrimination tasks, we measured cerebral blood flow of seven men and seven women using positron emission tomography and ¹⁵O water during tactile tasks performed with the right index finger. A nondiscrimination, somatosensory control task activated the left primary sensorimotor cortex and the left parietal operculum extending to the posterior insula without any gender difference. Compared with the control task, discrimination tasks activated the superior and inferior parietal lobules bilaterally, right dorsal premotor cortex, and dorsolateral prefrontal cortex in both genders, consistent with the notion of right hemisphere involvement during exploratory attentional movements. In both genders, symmetric activation of the superior and inferior parietal lobules and asymmetric activation of the right dorsolateral prefrontal cortex were confirmed. The former is consistent with the spatial representation of the tactile input and the latter with the spatial working memory. However, activation of the dorsal premotor cortex was asymmetric in men, whereas it was symmetric in women, the gender difference being statistically significant. This may suggest gender differences in motor programs for exploration in manipulospatial tasks such as tactile discrimination with active touch, possibly by greater interhemispheric interaction through the dorsal premotor cortices in women than in men.     

应用基于体素的形态测量学分析工作记忆老化的脑灰质萎缩基础

目的利用基于体素的形态测量学(VBM)方法探讨老年人工作记忆能力衰退与脑灰质萎缩间的关系。方法在30名老年人(老年组)和38名青壮年人(对照组)中分别进行keep-track任务和2-back任务两种工作记忆任务检测。对所有受试者进行高分辨力MR扫描,并使用统计参数图(SPM)8软件进行VBM分析,比较老年组与对照组的脑灰质体积差异,并在老年组内利用多元回归分析寻找与工作记忆任务能力下降相关的责任萎缩脑区。结果与对照组相比,老年组工作记忆能力显著衰退,且出现广泛的脑灰质萎缩。老年组中,与keep-track任务能力相关的萎缩脑区主要位于双侧前额叶中下部、运动前区、顶叶后下部和小脑;与2-back任务相关的萎缩脑区主要位于左侧的前额叶下部、运动前区和颞叶。左腹侧运动前区(BA6)皮层的灰质体积与两个任务的行为学数据均存在显著相关性。结论老年人工作记忆能力下降与工作记忆神经网络的灰质萎缩有关。     

Impaired effective cortical connectivity in vegetative state: preliminary investigation using PET

Vegetative state (VS) is a condition of abolished awareness with persistence of arousal. Awareness is part of consciousness, which itself is thought to represent an emergent property of cerebral neural networks. Our hypothesis was that part of the neural correlate underlying VS is an altered connectivity, especially between the associative cortices. We assessed regional cerebral glucose metabolism (rCMRGlu) and effective cortical connectivity in four patients in VS by means of statistical parametric mapping and [18F]fluorodeoxyglucose-positron emission tomography. Our data showed a common pattern of impaired rCMRGlu in the prefrontal, premotor, and parietotemporal association areas and posterior cingulate cortex/precuneus in VS. In a next step, we demonstrated that in VS patients various prefrontal and premotor areas have in common that they are less tightly connected with the posterior cingulate cortex than in normal controls. These results provide a strong argument for an alteration of cortical connectivity in VS patients.     

Attention to action: specific modulation of corticocortical interactions in humans

The prefrontal cortex may exert cognitive control by a general mechanism of attentional selection of neuronal representations. We used functional magnetic resonance imaging to test this hypothesis in the motor system. Normal volunteers were scanned during performance of a simple motor task, with their attention either directed towards their actions, or diverted towards a visual search task, or neither. Attention to action increased activity in prefrontal, premotor and parietal cortex, compared with unattended performance of the same movements. Analysis of cortical activity by structural equation modelling of regional fMRI time series was used to measure effective connectivity among prefrontal, premotor and parietal cortices. Attention to action enhanced effective connectivity between dorsal prefrontal cortex and premotor cortex, whereas non-motor attention diminished it. These effects were not attributable to common inputs from parietal cortex to the prefrontal and premotor cortex. The results suggest a supra-modal role for the dorsal prefrontal cortex in attentional selection, operating within the motor system as well as sensory and mnemonic domains.     

Cortical processing of noxious somatosensory stimuli in the persistent vegetative state

The persistent vegetative state (PVS) is a devastating medical condition characterized by preserved wakefulness contrasting with absent voluntary interaction with the environment. We used positron emission tomography to assess the central processing of noxious somatosensory stimuli in the PVS. Changes in regional cerebral blood flow were measured during high-intensity electrical stimulation of the median nerve compared with rest in 15 nonsedated patients and in 15 healthy controls. Evoked potentials were recorded simultaneously. The stimuli were experienced as highly unpleasant to painful in controls. Brain glucose metabolism was also studied with [(18)F]fluorodeoxyglucose in resting conditions. In PVS patients, overall cerebral metabolism was 40% of normal values. Nevertheless, noxious somatosensory stimulation-activated midbrain, contralateral thalamus, and primary somatosensory cortex in each and every PVS patient, even in the absence of detectable cortical evoked potentials. Secondary somatosensory, bilateral insular, posterior parietal, and anterior cingulate cortices did not show activation in any patient. Moreover, in PVS patients, the activated primary somatosensory cortex was functionally disconnected from secondary somatosensory, bilateral posterior parietal, premotor, polysensory superior temporal, and prefrontal cortices. In conclusion, somatosensory stimulation of PVS patients, at intensities that elicited pain in controls, resulted in increased neuronal activity in primary somatosensory cortex, even if resting brain metabolism was severely impaired. However, this activation of primary cortex seems to be isolated and dissociated from higher-order associative cortices.     

Changes in hippocampal connectivity in the early stages of Alzheimer's disease: evidence from resting state fMRI

A selective distribution of Alzheimer's disease (AD) pathological lesions in specific cortical layers isolates the hippocampus from the rest of the brain. However, functional connectivity between the hippocampus and other brain regions remains unclear in AD. Here, we employ a resting state functional MRI (fMRI) to examine changes in hippocampal connectivity comparing 13 patients with mild AD versus 13 healthy age-matched controls. Hippocampal connectivity was investigated by examination of the correlation between low frequency fMRI signal fluctuations in the hippocampus and those in all other brain regions. We found that functional connectivity between the right hippocampus and a set of regions was disrupted in AD; these regions are: medial prefrontal cortex (MPFC), ventral anterior cingulate cortex (vACC), right inferotemporal cortex, right cuneus extending into precuneus, left cuneus, right superior and middle temporal gyrus and posterior cingulate cortex (PCC). We also found increased functional connectivity between the left hippocampus and the right lateral prefrontal cortex in AD. In addition, rightward asymmetry of hippocampal connectivity observed in elderly controls was diminished in AD patients. The disrupted hippocampal connectivity to the MPFC, vACC and PCC provides further support for decreased activity in "default mode network" previously shown in AD. The decreased connectivity between the hippocampus and the visual cortices might indicate reduced integrity of hippocampus-related cortical networks in AD. Moreover, these findings suggest that resting-state fMRI might be an appropriate approach for studying pathophysiological changes in early AD.     

The human prefrontal and parietal association cortices are involved in NO-GO performances: an event-related fMRI study

One of the important roles of the prefrontal cortex is inhibition of movement. We applied an event-related functional magnetic resonance imaging (fMRI) technique to observe changes in fMRI signals of the entire brain during a GO/NO-GO task to identify the functional fields activated in relation to the NO-GO decision. Eleven normal subjects participated in the study, which consisted of a random series of 30 GO and 30 NO-GO trials. The subjects were instructed to press a mouse button immediately after the GO signal was presented. However, they were instructed not to move when the NO-GO signal was presented. We detected significant changes in MR signals in relation to the preparation phases, GO responses, and NO-GO responses. The activation fields related to the NO-GO responses were located in the bilateral middle frontal cortices, left dorsal premotor area, left posterior intraparietal cortices, and right occipitotemporal area. The fields of activation in relation to the GO responses were found in the left primary sensorimotor, right cerebellar anterior lobule, bilateral thalamus, and the area from the anterior cingulate to the supplementary motor area (SMA). Brain activations related to the preparation phases were identified in the left dorsal premotor, left lateral occipital, right ventral premotor, right fusiform, and the area from the anterior cingulate to the SMA. The results indicate that brain networks consisting of the bilateral prefrontal, intraparietal, and occipitotemporal cortices may play an important role in executing a NO-GO response.     

Four subgroups of Alzheimer's disease based on patterns of atrophy using VBM and a unique pattern for early onset disease

To clarify the involvement of the posterior cingulate cortex (PCC) in Alzheimer's disease (AD), we analyzed brain volume loss by voxel-based morphometry. Forty patients with non-familial AD and 20 patients with mild cognitive impairment (MCI) were recruited and compared to 88 elderly volunteers and 40 young volunteers. Local atrophy with aging was observed bilaterally in the perisylvian opercula, anterior cingulate cortex, caudate head, dorsomedial thalamus and parahippocampal cortex. In addition to those, atrophy in AD patients was observed in the amygdala, hippocampus, subcallosal region, posterior-associated cortices and PCC. We classified AD into four subgroups according to the atrophy pattern; atrophy in the amygdala/hippocampal formations (Hipp), in the Hipp and posterior cortices, in the Hipp and PCC and in the PCC and posterior cortices (PCC/-TOPa). As a result, the probability of PCC/-TOPa was 90% for ages <65 years, whereas that of the Hipp was 100% for disease duration >36 months. PCC atrophy was found in 16 of 40 AD patients and eight of 20 MCI patients. There seemed to be two subgroups with atrophy of the PCC, the one with disease progression and the other without. The latter had characteristic features of early onset and no significant atrophy in the amygdala/anterior hippocampus. There are at least four atrophy patterns that raise doubts about a single disease entity or progression in AD. This may reflect a different hierarchical pattern of progression in patients who have atrophy in PCC and posterior cortices when compared to the Braak staging scheme.     

Frontostriatal system in planning complexity: a parametric functional magnetic resonance version of Tower of London task

In the present study, we sought to investigate which brain structures are recruited in planning tasks of increasing complexity. For this purpose, a parametric self-paced pseudo-randomized event-related functional MRI version of the Tower of London task was designed. We tested 22 healthy subjects, enabling assessment of imaging results at a second (random effects) level of analysis. Compared with baseline, planning activity was correlated with increased blood oxygenation level-dependent (BOLD) signal in the dorsolateral prefrontal cortex, striatum, premotor cortex, supplementary motor area, and visuospatial system (precuneus and inferior parietal cortex). Task load was associated with increased activity in these same regions. In addition, increasing task complexity was correlated with activity in the left anterior prefrontal cortex, a region supposed to be specifically involved in third-order higher cognitive functioning.     

深部脑电刺激治疗帕金森病的FDGPET研究

目的研究双侧丘脑底核慢性电刺激术对晚期帕金森病患者脑局部糖代谢的影响及作用机制.方法对7例进行双侧STN DBS的晚期帕金森病患者,在术前和术后1个月电刺激条件下,分别进行18F-脱氧葡萄糖(18F-FDG)PET显像和UPDRS评分,通过SPM进行数据分析.结果 7例患者临床症状明显改善,同时FDG PET显像提示双侧豆状核、脑干、顶枕部、运动前区(BA6)及扣带回的脑代谢增加,而前额叶底部及海马的脑代谢减少(P<0.05).结论双侧STN DBS可使PD患者临床症状改善.FDG PET可作为PD进行STN治疗适应证选择的方法之一.     

广泛性焦虑障碍发病机制的静息态功能磁共振成像

目的 应用静息态功能磁共振成像(rs-fMRI)观察广泛性焦虑障碍(GAD)患者全脑活动及网络连接的变化,探索其与临床焦虑症状的相关性。方法 对28例GAD患者(GAD组)、28名健康对照(HC)组进行fMRI扫描。逐体素对比分析两组低频振幅(ALFF)和种子点静息态功能连接(FC)的差异,采用Pearson相关分析研究其与焦虑自评量表、汉密尔顿焦虑量表(HAM-A)、GAD-7项量表和汉密尔顿抑郁量表等评分的相关性。结果 GAD组双侧背内侧前额叶、左楔前叶/后扣带回和双侧背外侧前额叶ALFF值明显高于HC组(P均<0.05)。GAD组右侧眶额叶/岛叶-背内侧前额叶、左侧眶额叶/岛叶-背内侧前额叶、左侧背外侧前额叶皮层-右侧海马的功能连接与HAM-A评分和GAD-7评分均有相关性。结论 背侧前额叶皮层及楔前叶/后扣带回脑活动、前额叶-边缘组织回路异常可能是GAD重要的发病机制。     

Comparison of impaired subcortico-frontal metabolic networks in normal aging, subcortico-frontal dementia, and cortical frontal dementia.

Normal aging, progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD) are characterized by different degrees of decline in frontal lobe functions. We used (18)FDG-PET and statistical parametric mapping (SPM96) to compare relative subcorticofrontal metabolic impairment at rest in 21 healthy elderly subjects (HES), 20 PSP patients, and 6 FTD patients. When HES were compared to 22 healthy young subjects, widespread decrease in metabolism was observed in bilateral medial prefrontal areas including anterior cingulate cortices, in dorsolateral prefrontal areas, in left lateral premotor area, in Broca's area, and in left insula. In PSP compared to the 43 healthy subjects (HS), we observed subcorticofrontal metabolic impairment including both motor and cognitive neural networks. Impairment of functional connections between midbrain tegmentum and cerebellar, temporal and pallidal regions was demonstrated in PSP as compared to HS. When comparing FTD to HS, glucose uptake was primarily reduced in dorsolateral and ventrolateral prefrontal cortices and in frontopolar and anterior cingulate regions. There was also bilateral anterior temporal, right inferior parietal, and bilateral striatal hypometabolism. Finally, FTD showed more severe striatofrontal metabolic impairment than PSP, while mesencephalothalamic involvement was only observed in PSP. Our data suggest that subcorticofrontal metabolic impairment is distributed in distinct subcorticocortical networks in normal aging, PSP, and FTD. Subcorticofrontal dementia in PSP is related to hypometabolism in discrete frontal areas, which are probably disconnected from certain subcortical structures. The concept of subcortical dementia is reinforced by our data, which show disrupted functional connections between mesencephalon and cerebellar cortex, inferior and medial temporal regions, and pallidum.     

A fronto-parietal circuit for tactile object discrimination: an event-related fMRI study

Previous studies of somatosensory object discrimination have been focused on the primary and secondary sensorimotor cortices. However, we expected the prefrontal cortex to also become involved in sequential tactile discrimination on the basis of its role in working memory and stimulus discrimination as established in other domains. To investigate the contributions of the different cerebral structures to tactile discrimination of sequentially presented objects, we obtained event-related functional magnetic resonance images from seven healthy volunteers. Our results show that right hand object exploration involved left sensorimotor cortices, bilateral premotor, parietal and temporal cortex, putamen, thalamus, and cerebellum. Tactile exploration of parallelepipeds for subsequent object discrimination activated further areas in the dorsal and ventral portions of the premotor cortex, as well as parietal, midtemporal, and occipital areas of both cerebral hemispheres. Discriminating a parallelepiped from the preceding one involved a bilateral prefrontal-anterior cingulate-superior temporal-posterior parietal circuit. While the prefrontal cortex was active with right hemisphere dominance during discrimination, there was left hemispheric prefrontal activation during the delay period between object presentations. Delay related activity was further seen in the anterior intraparietal area and the fusiform gyrus. The results reveal a prominent role of the human prefrontal cortex for somatosensory object discrimination in correspondence with recent models on stimulus discrimination and working memory.     

Evidence of enhancement of spatial attention during inhibition of a visuo-motor response

A visuo-motor task was used as the setting for a study into inhibition in six healthy volunteers using fMRI. The task involved responding to colored stimuli, which appeared at random positions in the left and right visual field, with the corresponding hand. The volunteers were asked to respond to green colored stimuli ("go" response) and to inhibit responses to red stimuli ("no-go" response). The task was presented in a block design with blocks of three types; only "go" trials, a pseudo-random mixture of "go" and "no-go" tasks ("go/no-go" block), and "visual control." ANCOVA analysis of the fMRI data was performed within the framework of SPM99. Increased activation in the go vs visual control comparison was found in the bilateral motor and medial premotor cortices associated with the action of the button press response, as well as parietal regions attending to the task of identifying the visual field. The go/no-go vs visual control comparison showed a similar pattern, plus additional prefrontal areas that have previously been shown to be associated with inhibition. The direct comparison of the go and go/no-go blocks highlighted large differences not only in the prefrontal cortices, associated with inhibition, but also particularly in the right parietal cortex. We interpret the increased parietal activation, during inhibition, as representing a heightened spatial attention required for the correct execution of the inhibition task.     

Common and unique components of response inhibition revealed by fMRI

The ability to inhibit inappropriate responses is central to cognitive control, but whether the same brain mechanisms mediate inhibition across different tasks is not known. We present evidence for a common set of frontal and parietal regions engaged in response inhibition across three tasks: a go/no-go task, a flanker task, and a stimulus-response compatibility task. Regions included bilateral anterior insula/frontal operculum and anterior prefrontal, right dorsolateral and premotor, and parietal cortices. Insula activity was positively correlated with interference costs in behavioral performance in each task. Principal components analysis showed a coherent pattern of individual differences in these regions that was also positively correlated with performance in all three tasks. However, correlations among tasks were low, for both brain activity and performance. We suggest that common interference detection and/or resolution mechanisms are engaged across tasks, and that inter-task correlations in behavioral performance are low because they conflate measurements of common mechanisms with measurements of individual biases unique to each task.     

The functional anatomy of parkinsonian bradykinesia

To investigate the difficulty that patients with Parkinson's disease (PD) have in performing fast movements, we used H(2)(15)O PET to study regional cerebral blood flow (rCBF) associated with performance of a simple predictive visuomanual tracking task at three different velocities. Tracking movements in PD patients (versus tracking with the eyes alone) were associated with a general underactivation of the areas normally activated by the task (sensorimotor cortex contralateral to the moving arm, bilateral dorsal premotor cortices, and ipsilateral cerebellum). Presupplementary motor cortex (pre-SMA) ipsilateral to the moving arm had greater than normal movement-related activations. Increasing movement velocity led to increased rCBF in multiple premotor and parietal cortical areas and basal ganglia in the patients as opposed to the few cerebral locations that are normally velocity-related. The functional correlates of PD bradykinesia are: (1) impaired recruitment of cortical and subcortical systems that normally regulate kinematic parameters of movement such as velocity; and (2) increased recruitment of multiple premotor areas including both regions specialized for visuomotor control (ventral premotor and parietal cortices) and some that are not (pre-SMA). The overactivation of cortical regions observed in patients may be functional correlates of compensatory mechanisms and/or impaired suppression as a facet of the primary pathophysiology of PD.     

首发精神分裂症患者威斯康星卡片分类测验中的脑功能障碍研究

目的:探讨首发未服药精神分裂症患者进行威斯康星卡片分类测验(WCST)操作时的脑功能状态特点。方法:20名健康受试者(对照组)和20名首发未服药精神分裂症患者(患者组)操作WCST和颜色卡片分类测验(CCST)时进行脑功能磁共振成像(fMRI),比较2组激活脑区的激活体积。结果:对照组WCST和CCST功能图像相减获得的脑活动功能图像显示,激活主要分布在双侧前额叶,尤其是背外侧部以及顶叶后下部皮质和前扣带回。患者组WCST操作成绩较对照组差,有显著性差异(P<0.01)。与对照组相比,患者组的左侧前额叶背外侧部、左前扣带回皮质激活低下,左顶叶后下部皮质激活增加(P<0.01或0.05)。结论:双侧前额叶,尤其是背外侧部,以及顶叶后下部皮质和前扣带回皮质参与WCST操作的高级认知过程。精神分裂症患者在未治疗前就存在执行功能缺陷,其前额叶和扣带回功能低下,可能与患者执行功能障碍相关;后顶叶皮质功能亢进,可能对前额叶功能低下有补偿作用。     

遗忘型轻度认知障碍患者默认网络改变:基于后扣带回的脑连接研究

目的 探讨遗忘型轻度认知障碍(aMCI)患者后扣带回(PCC)功能连接的变化。 方法 选取性别、年龄和教育程度相匹配的18例aMCI患者(aMCI组)和20名健康老年人(健康老年组)进行GRE-EPI序列的静息状态fMRI检查,以PCC作为种子点,与全脑其他区域进行基于体素的时间序列相关分析。 结果 aMCI组与PCC有显著连接的脑区包括双侧背外侧前额叶(DLPFC)、左侧内侧前额叶(MPFC)及左侧前扣带回(ACC)、双侧顶下小叶(IPL)、双侧颞中回和双侧楔前叶。健康老年组与PCC有显著连接的脑区包括双侧DLPFC、右侧MPFC及ACC、双侧IPL、双侧颞中回、双侧颞下回和双侧楔前叶。健康老年组较aMCI组在右侧额上回、额中回、额下回的盖部及三角部、MPFC及ACC、颞中回及左侧楔前叶连接增强;aMCI组多个脑区功能连接较健康老年组增强,主要包括左侧半球的扣带回中部、顶上小叶(SPL)、IPL、颞中回及右侧IPL。 结论 PCC是aMCI患者脑代谢最先降低的区域,aMCI的PCC与多个功能区的连接破坏是其情节记忆功能减退的生物学基础,而其连接增强提示功能代偿可能。