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.     

Task-dependent posterior cingulate activation in mild cognitive impairment

Neuroimaging research has demonstrated that the posterior cingulate cortex (PCC) is functionally compromised in individuals diagnosed with amnestic mild cognitive impairment (MCI), a major risk factor for the development of Alzheimer's disease (AD). In functional MRI studies with healthy participants, this same region is active during self-appraisal (requiring retrieval of semantic knowledge about the self) as well as episodic recognition of previously learned information. Administering both types of tasks to people with MCI may reveal important information on the role of the PCC in recollection. This study investigated fMRI activation in the PCC in individuals with MCI and matched controls across two tasks. The first task was a visual episodic recognition task. The second task was an autobiographical self-appraisal task in which subjects rated themselves on a set of trait adjectives. Results of a conjunction analysis revealed the PCC as the sole region commonly active during both tasks in the healthy older adults. Furthermore, additional analysis revealed an interaction in the PCC, indicating a task-dependent response in the MCI group. MCI participants showed PCC activation during self-appraisal, but not episodic retrieval. This result suggests in MCI that the PCC shows functional degradation during episodic retrieval; however, the PCC's role in retrieval and evaluation of highly elaborated information regarding the self is more well-preserved.     

Effect of CACNA1C rs1006737 on neural correlates of verbal fluency in healthy individuals

BackgroundRecent genetic studies found the A allele of the variant rs1006737 in the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene to be overrepresented in patients suffering from bipolar disorder, schizophrenia or major depression. While the functions underlying the pathophysiology of these psychiatric disorders are yet unknown, impaired performance in verbal fluency tasks is an often replicated finding. We investigated the influence of the rs1006737 single nucleotide polymorphism (SNP) on verbal fluency and its neural correlates.MethodsBrain activation was measured with functional magnetic resonance imaging (fMRI) during a semantic verbal fluency task in 63 healthy male individuals. They additionally performed more demanding verbal fluency tasks outside the scanner. All subjects were genotyped for CACNA1C rs1006737.ResultsFor the behavioral measures outside the scanner, rs1006737genotype had an effect on semantic but not on lexical verbal fluency with decreased performance in risk-allele carriers. In the fMRI experiment, while there were no differences in behavioural performance, increased activation in the left inferior frontal gyrus as well as the left precuneus was found in risk-allele carriers in the semantic verbal fluency task.ConclusionsThe rs1006737 variant does influence language production on a semantic level in conjunction with the underlying neural systems. These findings are in line with results of studies in bipolar disorder, schizophrenia and major depression and may explain some of the cognitive and brain activation variation found in these disorders.     

Interindividual differences of medial temporal lobe activation during encoding in an elderly population studied by fMRI

Functional MRI (fMRI) is used to study medial temporal lobe (MTL) activation during encoding of new information into memory. In most studies, fMRI data of different subjects are averaged in standard coordinate space. However, interindividual differences in activation can be extensive, reflecting functional heterogeneity. Further, anatomical differences in brain structure cause additional variance and loss of registration accuracy. Such differences in structural and functional MTL characteristics may interfere with the efficiency of averaging data across subjects, and may become more significant with aging and dementia. The current study concerns the analysis of individual differences in MTL activation associated with episodic encoding.Twenty-nine healthy elderly men between 60 and 70 years old performed a simple face encoding task during fMRI scanning. Individual data were analyzed in native space, and compared to the group average in standard space (Talairach and Tournoux).MTL volumes between subjects varied between 6.34 and 11.27 cm(3), and had considerable variation when mapped to standard space. Eighteen of the 29 subjects showed MTL activity and activation patterns varied both in location and size (ranging from 0.11 to 1.78 cm(3)), with the strongest activation in the left posterior part of the MTL. In standard space, no region was significantly activated on a group level at a comparable alpha level. We conclude that while the majority of elderly subjects show MTL activation during episodic encoding of faces, there is considerable structural and functional variability between subjects. Group analysis in standard space may not be appropriate for studies of a complex structure such as the MTL, particularly not in aging and dementia.     

Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects

Two limiting factors of dopamine activity are the catechol-o-methyltransferase (COMT) and the dopamine transporter (DAT), which terminate dopamine activity by degradation and uptake, respectively. Genetic variants of COMT and DAT have been related to the enzymatic activity and protein availability, respectively. The Met allele of the COMT Val108/158 Met polymorphism has been associated to lower enzymatic activity and the 9-repeat allele of the DAT 40 base-pair (bp) variable number of tandem repeat (VNTR) polymorphism has been related to lower protein availability. Genotypes for COMT and DAT were determined in a sample of 75 healthy subjects, who underwent functional magnetic resonance imaging (fMRI) while performing an N-back task. To further assess the effects of the genotypes on cognition, subjects were administered the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test (CPT). Analysis of fMRI data revealed an additive effect of these two genes on brain activation in an N-back task, with subjects homozygous for the Val and the 9-repeat alleles showing the highest activation for the same level of performance. Moreover, the Val allele was related to higher number of perseverative errors on the WCST and with a higher number of commission errors on the CPT. The 10-repeat allele was associated with faster reaction times but also with a higher number of commission errors. Our results support a role of the COMT Val108/158 Met and the DAT 40 bp VNTR in both brain activation and cognition.     

Activation of the amygdala and anterior cingulate during nonconscious processing of sad versus happy faces

Previous functional neuroimaging studies have demonstrated that the amygdala activates in response to fearful faces presented below the threshold of conscious visual perception. Using a backward masking procedure similar to that of previous studies, we used functional magnetic resonance imaging (fMRI) to study the amygdala and anterior cingulate gyrus during preattentive presentations of sad and happy facial affect. Twelve healthy adult females underwent blood oxygen level dependent (BOLD) fMRI while viewing sad and happy faces, each presented for 20 ms and "masked" immediately by a neutral face for 100 ms. Masked happy faces were associated with significant bilateral activation within the anterior cingulate gyrus and amygdala, whereas masked sadness yielded only limited activation within the left anterior cingulate gyrus. In a direct comparison, masked happy faces yielded significantly greater activation in the anterior cingulate and amygdala relative to identically masked sad faces. Conjunction analysis showed that masked affect perception, regardless of emotional valence, was associated with greater activation within the left amygdala and left anterior cingulate. Findings suggest that the amygdala and anterior cingulate are important components of a network involved in detecting and discriminating affective information presented below the normal threshold of conscious visual perception.     

熟练蒙汉双语者语义加工脑机制的fMRI分析

目的探讨熟练蒙汉双语者在蒙语和汉语语义信息加工的脑机制。方法对15右利手、蒙汉双语熟练的健康志愿者(男8名,女7名)进行fMRI测试,分析采用蒙语及汉语词语的语义判断任务。应用AFNI软件分析两种语言任务的脑功能激活情况及其差异。结果在汉语及蒙语语义信息加工过程中,语义加工的经典脑区均被激活,包括左侧颞中回、左侧后顶叶、左侧前额叶等区域。比较加工蒙语及汉语的语义信息过程,蒙语任务下左侧楔回及右侧梭状回的激活显著增加,汉语任务下在左侧颞中回后部、左侧额中回及额下回三角部、左侧顶上小叶的脑激活比蒙语显著增加。结论熟练蒙汉双语者在加工蒙语及汉语时,存在功能加工脑区的分离。fMRI研究能为双语者的语言加工脑机制提供影像学依据。     

Subjective feeling of appetite modulates brain activity: an fMRI study

Obesity and overweight are important risk factors for the development of diabetes mellitus type 2 and associated chronic diseases, and therefore, they have become serious global problems in the western and developed countries. But little is known about the neuroanatomical correlates of eating behavior and its influences on the central nervous processing in humans. We used functional magnetic resonance imaging (fMRI) to measure the cortical activation in 12 lean healthy humans during visual stimulation with food-related and nonfood pictures after a fasting period of at least 5 h. Compared to the nonfood pictures, the food stimuli elicited a significantly greater activity in the left orbitofrontal cortex and the insular/opercular cortex bilaterally with a stronger focus on the left side. Subjective ratings of appetite during the presentation of food-related stimuli modulated the activity in the insula bilaterally, the left operculum and the right putamen. These results provide further insights in the central nervous processing of food relevant stimuli in humans, specifically with respect to the subjective experience of appetite.     

Dysbindin modulates brain function during visual processing in children

Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain function is poorly understood. It has been proposed that DTNBP1 may be associated with differences in visual processing. To test this, we examined the impact on visual processing in 61 healthy children aged 10–12 years of a genetic variant in DTNBP1 (rs2619538) that was common to all schizophrenia associated haplotypes in an earlier UK-Irish study. We tested the hypothesis that carriers of the risk allele would show altered occipital cortical function relative to noncarriers. Functional Magnetic Resonance Imaging (fMRI) was used to measure brain responses during a visual matching task. The data were analysed using statistical parametric mapping and statistical inferences were made at p < 0.05 (corrected for multiple comparisons). Relative to noncarriers, carriers of the risk allele had greater activation in the lingual, fusiform gyrus and inferior occipital gyri. In these regions DTNBP1 genotype accounted for 19%, 20% and 14% of the inter-individual variance, respectively. Our results suggest that that genetic variation in DTNBP1 is associated with differences in the function of brain areas that mediate visual processing, and that these effects are evident in young children. These findings are consistent with the notion that the DTNBP1 gene influences brain development and can thereby modulate vulnerability to schizophrenia.     

Functional imaging of visuospatial processing in Alzheimer's disease

Alzheimer's disease (AD) is known to cause a variety of disturbances of higher visual functions that are closely related to the neuropathological changes. Visual association areas are more affected than primary visual cortex. Additionally, there is evidence from neuropsychological and imaging studies during rest or passive visual stimulation that the occipitotemporal pathway is less affected than the parietal pathway. Our goal was to investigate functional activation patterns during active visuospatial processing in AD patients and the impact of local cerebral atrophy on the strength of functional activation. Fourteen AD patients and fourteen age-matched controls were measured with functional magnetic resonance imaging (fMRI) while they performed an angle discrimination task. Both groups revealed overlapping networks engaged in angle discrimination including the superior parietal lobule (SPL), frontal and occipitotemporal (OTC) cortical regions, primary visual cortex, basal ganglia, and thalamus. The most pronounced differences between the two groups were found in the SPL (more activity in controls) and OTC (more activity in patients). The differences in functional activation between the AD patients and controls were partly explained by the differences in individual SPL atrophy. These results indicate that parietal dysfunction in mild to moderate AD is compensated by recruitment of the ventral visual pathway. We furthermore suggest that local cerebral atrophy should be considered as a covariate in functional imaging studies of neurodegenerative disorders.     

Activation of central sympathetic networks during innocuous and noxious somatosensory stimulation

Although pain is accompanied by autonomic nervous system responses, the cerebral circuits involved in the autonomic pain dimension remain elusive. Therefore, we used functional magnetic resonance imaging (fMRI) and investigated brain processing associated with cutaneous sympathetic vasoconstrictor reflexes during noxious stimulation. When a classical fMRI analysis based on the applied block design was performed, we were able to detect activations well known to be engaged in the central processing of touch and pain. A parametric fMRI analysis in which cutaneous vasoconstrictor activity was correlated with MRI signals revealed two distinct patterns of brain activity. During (i) noxious stimulation itself, brain activity correlated with sympathetic activity in the anterior insula, ventrolateral prefrontal cortex (VLPFC), anterior cingulate cortex (ACC), and secondary somatosensory cortex (S2). During (ii) baseline, brain activity correlated with sympathetic activity in the VMPFC, dorsolateral prefrontal cortex (DLPFC), OFC, PCC, cuneus, precuneus, occipital areas, and hypothalamus. Conjunction analysis revealed significant similar responses during periods of noxious stimulation and periods of sympathetic activation in the anterior insula, ACC and VLPFC (activation) and VMPFC, OFC, PCC, cuneus and precuneus (deactivation). Therefore, we here describe a cerebral network which may be engaged in the processing of the autonomic subdimension of the human pain experience.     

Memory for motion and spatial location is mediated by contralateral and ipsilateral motion processing cortex

Memory and perception have been associated with common sensory cortical activity. However, previous studies have only investigated memory and perception effects associated with a single feature (i.e., spatial location or color). The aim of the present functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) study was to assess whether memory for multiple (two) features would produce sensory cortical activity that mirrored perceptual processing of the same features. During encoding, moving or stationary abstract shapes were presented to the right or left of fixation. During retrieval, shapes were presented at fixation and participants classified each item as previously in motion or stationary within the right or left visual field. Memory for items in motion, regardless of spatial location, produced fMRI activity in perceptual motion processing region MT+. Memory for motion and spatial location produced contralateral and ipsilateral fMRI activity in perceptual motion processing sub-region MT. Following TMS to MT, memory for motion was impaired, but performance did not differ between the contralateral and ipsilateral visual fields. The present results are consistent with previous findings in that memory for motion produced fMRI activity in MT+ and was impaired following TMS to MT. However, memory for motion and spatial location produced contralateral and ipsilateral fMRI and TMS effects, deviating from the primarily contralateral perceptual processing organization of MT. The present evidence suggests that during memory for motion and spatial location only motion information is coded in motion processing cortex, while previous findings suggest spatial location information is coded in earlier extrastriate cortex.     

Anatomic dissociation of selective and suppressive processes in visual attention

Visual spatial attention is associated with activation in parietal regions as well as with modulation of visual activity in ventral occipital cortex. Within the parietal lobe, localisation of activity has been hampered by variation in individual anatomy. Using fMRI within regions of interest derived from individual functional maps, we examined the response of superior parietal lobule, intraparietal sulcus, and ventral occipital cortex in 11 normal adults as attention was directed to the left and right visual hemifields during bilateral visual stimulation. Activation in ventral occipital cortex was augmented contralateral to the attended hemifield (P < 0.006), while intraparietal activation was augmented ipsilaterally (P < 0.009), and superior parietal lobule showed no modulation of activity as a function of attended hemifield. These findings suggest that spatial enhancement of relevant stimuli in ventral occipital cortex is complemented by an intraparietal response associated with suppression of, or preparation of a reflexive shift of attention toward, irrelevant stimuli. The spatial attention system in superior parietal cortex, in contrast, may be driven to equal degrees by currently attended stimuli and by stimuli that are potential targets of attention.     

Task demand modulations of visuospatial processing measured with functional magnetic resonance imaging

Brain imaging based on functional magnetic resonance imaging (fMRI) provides a useful tool to examine neural networks and cerebral structures subserving visuospatial function. It allows not only the qualitative determination of which areas are active during task processing, but also estimates the quantitative contribution of involved brain regions to different aspects of spatial processing. In this study, we investigated in 10 healthy subjects how the amount of task (computational) demand in an angle discrimination task was related to neural activity as measured with event-related fMRI. Task demand, indicated by behavioral performance, was modulated by presenting clocks with different angular disparity and length of hands. Significant activations were found in the cortical network subserving the visual and visuospatial processing, including the right and left superior parietal lobules (SPL), striate visual areas, and sensorimotor areas. Both blood oxygenation level-dependent (BOLD) signal strength and spatial extent of activation in right as well as left SPL increased with task demand. By contrast, no significant correlation or a very weak correlation was found between the task demand and the BOLD signal as well as between task demand and spatial extent of activations in the striate visual areas and in the sensorimotor areas. These results support the hypothesis that increased computational demand requires more brain resources. The brain regions that are most specialized for the execution of the visuospatial task can be assessed by relating the imposed task demand to the functional activation measured.     

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。     

Symbol processing in the left angular gyrus: evidence from passive perception of digits

Arabic digits are one of the most ubiquitous symbol sets in the world. While there have been many investigations into the neural processing of the semantic information digits represent (e.g. through numerical comparison tasks), little is known about the neural mechanisms which support the processing of digits as visual symbols. To characterise the component neurocognitive mechanisms which underlie numerical cognition, it is essential to understand the processing of digits as a visual category, independent of numerical magnitude processing. The 'Triple Code Model' (Dehaene, 1992; Dehaene and Cohen, 1995) posits an asemantic visual code for processing Arabic digits in the ventral visual stream, yet there is currently little empirical evidence in support of this code. This outstanding question was addressed in the current functional Magnetic Resonance (fMRI) study by contrasting brain responses during the passive viewing of digits versus letters and novel symbols at short (50 ms) and long (500 ms) presentation times. The results of this study reveal increased activation for familiar symbols (digits and letters) relative to unfamiliar symbols (scrambled digits and letters) at long presentation durations in the left dorsal Angular gyrus (dAG). Furthermore, increased activation for Arabic digits was observed in the left ventral Angular gyrus (vAG) in comparison to letters, scrambled digits and scrambled letters at long presentation durations, but no digit specific activation in any region at short presentation durations. These results suggest an absence of a digit specific 'Visual Number Form Area' (VNFA) in the ventral visual cortex, and provide evidence for the role of the left ventral AG during the processing of digits in the absence of any explicit processing demands. We conclude that Arabic digit processing depends specifically on the left AG rather than a ventral visual stream VNFA.     

CBF changes during brain activation: fMRI vs. PET

The changes in regional cerebral blood flow (rCBF) associated with the changes in neuronal activity are routinely measured both by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) techniques. However, direct comparison has not been performed to determine similarities and differences of PET and fMRI techniques in determining the rCBF response to brain activation. In the present study, a quantitative comparison of the functional rCBF maps obtained by PET and fMRI are made by performing an activation study in a single group of subjects under precisely controlled conditions and using identical visual stimuli. Twelve healthy volunteers participated in the activation study using the visual checkerboard stimulation with flip frequency at 8 Hz. By selecting the conjunctive pixels which activated on both PET and fMRI maps, the change in rCBF measured by fMRI was 36.95 +/- 2.54%, whereas the value measured by PET was 38.79 +/- 2.63%. Our results have demonstrated that there is no statistically significant difference (P = 0.22) in the measurements of rCBF change between MRI and PET methods.     

Combination of event-related fMRI and diffusion tensor imaging in an infant with perinatal stroke

Focal ischemic brain injury, or stroke, is an important cause of later handicap in children. Early assessment of structure-function relationships after such injury will provide insight into clinico-anatomic correlation and potentially guide early intervention strategies. We used combined functional MRI (fMRI) with diffusion tensor imaging (DTI) in a 3-month-old infant to explore the structure-function relationship after unilateral perinatal stroke that involved the visual pathways. With visual stimuli, fMRI showed a negative BOLD activation in the visual cortex of the intact right hemisphere, principally in the anterior part, and no activation in the injured hemisphere. The functional activation in the intact hemisphere correlated clearly with the fiber tract of the optic radiation visualized with DTI. DTI confirmed the absence of the optic radiation in the damaged left hemisphere. In addition, event-related fMRI (ER-fMRI) experiments were performed to define the characteristics of the BOLD response. The shape is that of an inverted gamma function (similar to a negative mirror image of the known positive adult BOLD response). The maximum decrease was reached at 5-7 s with signal changes of -1.7 +/- 0.4%.Thus, this report describes for the first time the combined use of DTI and event-related fMRI in an infant and provides insight into the localization of the fMRI visual response in the young infant and the characteristics of the BOLD response.     

不同相干水平视觉运动刺激皮层反应特征的fMRI研究

目的探讨随机点动态运动图作为刺激源是否能够对参与视觉运动觉处理的大脑皮层区域进行准确的功能定位,并在此基础上进一步观测在不同运动相干水平情况下,相关大脑皮层的血氧水平依赖反应特点。方法12名受试者在功能磁共振扫描过程中接受三种不同相干水平的视觉运动刺激(5%,20%,80%),刺激呈现采用组块设计模式。数据经预处理和统计分析得到激活图,并进一步进行兴趣区分析。结果随机点动态运动图作为刺激源能够有效的激活视觉运动觉处理相关视觉皮层区域;以hMT 作兴趣区分析得到三种不同相干水平运动刺激下该区域的激活体积。结论随机点动态运动图刺激能对参与视觉运动觉处理的大脑皮层区域进行准确的功能定位;hMT 的激活体积随着相干水平的提高而减小。     

生理性进食之后静息态fMRI脑功能连接的变化

目的探讨生理性进食之后静息态脑功能连接的变化。材料与方法 42名健康被试按照人口统计学特征平衡分为三组。为了增加胃肠活动的差异,三组分别服用多潘立酮、奥替溴铵、安慰剂。所有被试均给予标准实验早餐,于空腹、早餐后、餐后2h及午餐前行静息态功能磁共振(functional MRI,fMRI)检查。数据分析采用扣带回后部-楔前叶作为种子点,计算全脑功能连接,并采用重复测量ANOVA分析在时间与药物因素上具有显著差异的脑区,并提取其功能连接Z值,进行事后检验。结果时间主效应:右侧眶额回/壳核/丘脑、右侧缘上回和右侧岛盖的功能连接在时间因素上有显著差异(P0.05)。药物主效应:右侧楔前叶、左侧颞中回、左侧舌回、右侧颞中回、右侧额上回、双侧眶额回、左侧额中回的功能连接在药物因素上有显著差异(P0.05)。结论静息态fMRI健康被试生理性进食前后,奖赏系统、右侧丘脑和躯体感觉区的功能连接会发生变化,并且呈现右侧偏侧化优势;胃动力药物对上述脑区的变化无影响。为常规fMRI实验中被试进食状态对实验结果的潜在影响提供了分析依据。