Role of hippocampal CA1 atrophy in memory encoding deficits in amnestic Mild Cognitive Impairment

Identifying the specific substrates of memory deficits in early Alzheimer's disease would help to develop clinically-relevant therapies. The present study assesses the relationships between encoding versus retrieval deficits in patients with amnestic Mild Cognitive Impairment (aMCI) and atrophy specifically within the hippocampus and throughout the white matter. Twenty-two aMCI patients underwent T1-weighted MRI scans and neuropsychological testing. Grey matter and white matter segments obtained from the MRI images were each entered in correlation analyses, assessed only in the hippocampus for grey matter segments, with encoding and retrieval memory performances. For the grey matter segments, the resulting spmT correlation maps were then superimposed onto a 3D surface view of the hippocampus to identify the relative involvement of the different subfields, a method already used and validated elsewhere. Memory encoding deficits specifically correlated with CA1 subfield atrophy, while no relationship was found with white matter atrophy. In contrast, retrieval deficits were weakly related to hippocampal atrophy and did not involve a particular subfield, while they strongly correlated with loss of white matter, specifically in medial parietal and frontal areas. In aMCI patients, encoding impairment appears specifically related to atrophy of the CA1 hippocampal subfield, consistent with the predominance of encoding deficits and CA1 atrophy in aMCI. In contrast, episodic retrieval deficits seem to be underlain by more distributed tissue losses, consistent with a disruption of a hippocampo-parieto-frontal network.     

Accuracy of spatial normalization of the hippocampus: implications for fMRI research in memory disorders

Functional magnetic resonance imaging (fMRI) studies in memory impairment have detected functional alterations in medial temporal lobe (MTL) structures, notably the hippocampus. Many of these studies employ spatial normalization to place subjects in a standardized template space prior to analysis; however, little is known about the effects of local atrophy on the normalization process in structures such as the hippocampus. The purpose of this study was to compare the accuracy of spatial normalization of the hippocampus between memory-impaired patients and controls. Twenty clinically-defined mild cognitive impairment (MCI) subjects and twenty elderly controls were studied at 4T with structural and functional MRI during a memory encoding-retrieval task. Bilateral hippocampal regions-of-interest (ROIs) were manually drawn for all subjects and further divided into anterior/posterior subregions. To assess normalization accuracy to the Montreal Neurological Institute template, the percentage of each template-defined hippocampal ROI originating from true hippocampal tissue was determined for all subjects. To assess the ability of spatial normalization to equalize group differences in hippocampal volume, pre- and post-normalization hippocampal volumes were compared. Finally, fMRI measures from template and non-template analyses were compared. Poorer normalization accuracy of the bilateral hippocampi, particularly the posterior portions, was found for MCI subjects. Significant group differences were found in left hippocampal and bilateral posterior hippocampal volumes, and these differences were not corrected with normalization. Hippocampal volumes were significantly correlated with normalization accuracy across MCI and control groups, but some significant differences in normalization accuracy persisted independent of these volume differences. Template and non-template fMRI analyses were significantly correlated in controls, but not MCI subjects, during memory retrieval. These findings suggest decreased normalization accuracy in memory-impaired subjects is a potentially important confounder of template-based fMRI analyses in the hippocampus and MTL.     

Hippocampal activations during encoding and retrieval in a verbal working memory paradigm

Though the hippocampus has been associated with encoding and retrieval processes in episodic memory, the precise nature of its involvement in working memory has yet to be determined. This functional magnetic resonance imaging (fMRI) study employed a verbal working memory paradigm that allows for the within-subject comparison of functional activations during encoding, maintenance, and retrieval. In each trial, participants were shown 5 target words and, after an 8 s delay, a series of probe words. Probe words consisted of target matches, phonetically or semantically related foils, or foils unrelated to the target words. Both the left and right hippocampi showed higher mean activation amplitudes during encoding than maintenance. In contrast, the right dorsolateral prefrontal cortex (DLPFC) showed greater activation during maintenance than encoding. Both hippocampal and DLPFC regions were more active during retrieval than maintenance. Furthermore, an analysis of retrieval activation separated by probe type showed a trend toward greater bilateral hippocampal activation for probes related (both semantically and phonetically) to the target than for unrelated probes and still greater activation for target matches. This pattern suggests that there may be roles for the hippocampus and DLPFC in working memory that change as function of information processing stage. Additionally, the trend towards increased involvement of the hippocampus with the increase in relatedness of the probe stimuli to the information maintained is interpreted to be consistent with the role of the hippocampus in recollection-based retrieval in long-term memory and may indicate that this role extends to working memory processes.     

Regional activation of the human medial temporal lobe during intentional encoding of objects and positions

The medial temporal lobe (MTL) consists of several regions thought to be involved in learning and memory. However, the degree of functional specialization among these regions remains unclear. Previous studies have demonstrated effects of both content and processing stage, but findings have been inconsistent. In particular, studies have suggested that the perirhinal cortex is more involved in object processing than spatial processing, while other regions such as the parahippocampal cortex have been implicated in spatial processing. In this study, functional magnetic resonance imaging (fMRI) optimized for the MTL region was used to probe MTL activation during intentional encoding of object identities or positions. A region of interest analysis showed that object encoding evoked stronger activation than position encoding in bilateral perirhinal cortex, temporopolar cortex, parahippocampal cortex, hippocampus and amygdala. Results also indicate an unexpected significant correlation in activation level between anterior and posterior portions in both the left parahippocampal cortex and left hippocampus. Exploratory analysis did not show any regional content effects during preparation and rehearsal stages. These results provide additional evidence for functional specialization within the MTL, but were less clear regarding the specific nature of content specificity in these regions.     

复发缓解型多发性硬化患者深部灰质核团体积和灌注改变与临床评分的相关性

目的 采用基于体素的形态学（VBM）方法及3D伪连续动脉自旋标记（3D pCASL）技术探讨复发-缓解型多发性硬化（RRMS）患者深部灰质体积和灌注改变,及其与临床扩展残疾状态量表（EDSS）和神经心理学量表评分间的相关性。方法 对30例RRMS患者（RRMS组）和24名健康志愿者（对照组）行EDSS量表和神经心理学量表测试,评估其记忆功能。行3D T1WI及3D pCASL扫描,并应用Matlab平台的SPM 8及VBM 8软件对图像进行预处理。采用SPM统计软件,分析RRMS患者深部灰质体积、灌注改变,进一步提取深部灰质体积、灌注显著改变脑区的参数值与EDSS和神经心理学量表评分进行相关性分析。结果 与对照组比较,RRMS组双侧丘脑、左侧海马、左侧壳核、右侧苍白球体积显著下降（P均<0.05,FDR校正）,双侧丘脑、双侧尾状核脑血流量（CBF）显著下降（P<0.05,FDR校正）。RRMS组左右侧丘脑体积、右侧苍白球体积、左侧丘脑CBF与符号数字转换测验评分呈正相关（r_s=0.757、0.709、0.463、0.454,P均<0.05）,左右侧丘脑体积、左侧丘脑CBF与Rey听觉词语学习测试-即刻记忆评分呈正相关（r_s=0.565、0.503、0.492,P均<0.05）,与EDSS评分均无明显相关性（P均>0.05）。结论 RRMS患者深部灰质体积和灌注均发生改变,深部灰质体积和灌注下降均与记忆功能受损有关。     

Dissociating intentional learning from relative novelty responses in the medial temporal lobe

The establishment of a role for medial temporal lobe (MTL) structures in episodic memory has led to an investigative focus on the specific contributions and interactions between constituent MTL regions, including the hippocampus and surrounding medial temporal cortices. By dissociating an intentional stimulus-category learning condition from a passive viewing condition, we demonstrate, using fMRI, that novelty- and familiarity-driven responses in human anterior and posterior hippocampus, respectively, only occur during intentional learning. With increasing familiarity of stimulus-category associations, there is a shift in neuronal responses from anterior to posterior hippocampal regions. This anterior/posterior response gradient may reflect a weighting of functional hippocampal architecture related to encoding of novel and retrieval of familiar information. By contrast, perirhinal cortex is engaged by novel stimuli irrespective of task, highlighting this region as a component of a generic familiarity discrimination system. By introducing distinct stimulus types, we further demonstrate that these MTL responses are independent of stimulus complexity. Different patterns of activity for intentional learning vs. passive viewing indicate that intentional encoding/retrieval of stimulus-category associations and automatic novelty/familiarity assessment of stimuli are processed in anatomically dissociable neuronal ensembles within the MTL memory system.     

Multiple white matter tract abnormalities underlie cognitive impairment in RRMS

Diffusion tensor imaging (DTI) is a sensitive tool for detecting microstructural tissue damage in vivo. In this study, we investigated DTI abnormalities in individuals with relapsing remitting multiple sclerosis (RRMS) and examined the relations between imaging-based measures of white matter injury and cognitive impairment. DTI-derived metrics using tract-based spatial statistics (TBSS) were compared between 37 individuals with RRMS and 20 healthy controls. Cognitive impairment was assessed with three standard tests: the Symbol Digit Modalities Test (SDMT), which measures cognitive processing speed and visual working memory, the Rey Auditory Verbal Learning Test (RAVLT), which examines verbal memory, and the Paced Auditory Serial Addition Test (PASAT), which assesses sustained attention and working memory. Correlations between DTI-metrics and cognition were explored in regions demonstrating significant differences between the RRMS patients and the control group. Lower fractional anisotropy (FA) was found in RRMS participants compared to controls across the tract skeleton (0.40 ± 0.03 vs. 0.43 ± 0.01, p < 0.01). In areas of reduced FA, mean diffusivity was increased and was dominated by increased radial diffusivity with no significant change in axial diffusivity, an indication of the role of damage to CNS myelin in MS pathology. In the RRMS group, voxelwise correlations were found between FA reduction and cognitive impairment in cognitively-relevant tracts, predominantly in the posterior thalamic radiation, the sagittal stratum, and the corpus callosum; the strongest correlations were with SDMT measures, with contributions to these associations from both lesion and normal-appearing white matter. Moreover, results using threshold-free cluster enhancement (TFCE) showed more widespread white matter involvement compared to cluster-based thresholding. These findings indicate the important role for DTI in delineating mechanisms underlying MS-associated cognitive impairment and suggest that DTI could play a critical role in monitoring the clinical and cognitive effects of the disease.     

Material-specific lateralization of memory encoding in the medial temporal lobe: blocked versus event-related design

Lesion-deficit studies have provided evidence for a functional dissociation between the left medial temporal lobe (MTL) mediating verbal memory encoding and right MTL mediating non-verbal memory encoding. While a small number of functional MRI studies have demonstrated similar findings, none has looked specifically for material-specific lateralization using subsequent memory effects. In addition, in many fMRI studies, encoding activity has been located in posterior MTL structures, at odds with lesion-deficit and positron emission tomography (PET) evidence. In this study, we used an event-related fMRI memory encoding paradigm to demonstrate a material-specific lateralization of encoding in the medial temporal lobes of ten healthy control subjects. Activation was left-lateralized for word encoding, bilateral for picture encoding, and right-lateralized for face encoding. Secondly, we demonstrated the locations of activations revealed using an event-related analysis to be more anterior than those revealed using a blocked analysis of the same data. This suggests that anterior MTL structures underlie memory encoding as judged by subsequent memory effects, and that more posterior activity detected in other fMRI studies is related to deficiencies of blocked designs in the analysis of memory encoding.     

Phasic deactivation of the medial temporal lobe enables working memory processing under stress

Demanding cognitive tasks are sometimes carried out under stressful conditions. Several studies indicate that whereas severe stress impairs performance, moderate stress can enhance cognitive performance. In this study, we investigated how moderate stress influences the neural systems supporting working memory. We embedded an N-back working memory task in a moderately stressful context, as indicated by our physiological stress measures, and probed phasic and tonic human brain activity using two fMRI-techniques: conventional blood oxygen level dependent fMRI and arterial spin labeling (ASL). The results showed that the stress induction, as compared to the neutral control condition, led to slightly faster reaction times without changes in accuracy. In general, working memory processing was associated with increased activity in a frontoparietal network and reduced activity in the medial temporal lobe (MTL). The stress induction led to enhanced reduction of phasic MTL responses, specifically the hippocampus and amygdala. In addition, ASL showed that stress increased tonic amygdala activity, while tonic hippocampal activity was unaffected. These findings suggest that the influence of stress on MTL deactivation during working memory processing is task-related rather than a general consequence of the stressful state. The temporal suspension of hippocampal processing in favor of more task relevant processes may allow subjects to maintain normal performance levels under moderate stress.     

静息态功能磁共振和纤维追踪技术在单纯脊髓受累型多发性硬化患者的临床应用

目的联合应用静息态功能磁共振成像(resting-state functional magnetic resonance imaging,RS-fMRI)和纤维追踪技术探索单纯脊髓受累的多发性硬化患者(multiple sclerosis patients with simple spinal cord involvement,MS-SSCI)脑部功能和脑白质完整性是否有改变。材料与方法利用RS-fMRI比较22例MS-SSCI及22例年龄、性别相匹配的健康对照组的基础脑活动,将组间有差异的区域作为感兴趣区,利用纤维追踪技术重建穿过这些区域的白质纤维束,比较两组之间纤维束的部分各向异性(FA)和表观弥散系数(ADC),最后将MS-SSCI组感兴趣区低频振幅(amplitude of low frequency fluctuation,ALFF)、FA、ADC分别与临床扩展残疾状态量表(expanded disability states scale,EDSS)评分进行Pearson相关分析。结果与健康对照组相比,MS-SSCI组右侧海马ALFF值明显减低,左侧额中回、左侧后扣带回、右侧枕中回ALFF值明显增高(双样本t检验,经AlphaSim校正,P＜0.01,体素大小＞40),MS-SSCI组右侧海马FA值(t右侧海马=2.099, P右侧海马=0.042)和ADC值(t右侧海马=－2.053,P右侧海马=0.047)存在明显差异;MS-SSCI左侧后扣带回ALFF值与EDSS显著相关,结构变化参数与EDSS间无明显相关性(P＞0.05)。结论 MS-SSCI脑内存在功能和结构异常,功能改变与认知障碍密切相关。