The neural basis of episodic memory: evidence from functional neuroimaging

We review some of our recent research using functional neuroimaging to investigate neural activity supporting the encoding and retrieval of episodic memories, that is, memories for unique events. Findings from studies of encoding indicate that, at the cortical level, the regions responsible for the effective encoding of a stimulus event as an episodic memory include some of the regions that are also engaged to process the event 'online'. Thus, it appears that there is no single cortical site or circuit responsible for episodic encoding. The results of retrieval studies indicate that successful recollection of episodic information is associated with activation of lateral parietal cortex, along with more variable patterns of activity in dorsolateral and anterior prefrontal cortex. Whereas parietal regions may play a part in the representation of retrieved information, prefrontal areas appear to support processes that act on the products of retrieval to align behaviour with the demands of the retrieval task.     

Functional imaging of memory processes in humans: positron emission tomography and functional magnetic resonance imaging

Human memory is not a unitary function; it consists of multiple memory systems, with different characteristics and specialisations that are implemented in the brain. The cognitive neuroscience of human memory tries to comprehend how we encode, store, and retrieve memory items within and across those systems. The emergence of functional neuroimaging techniques offered the unprecedented opportunity to directly observe the brain regions engaged in memory functions. Brain imaging techniques can roughly be divided into those measuring the electric or magnetic fields generated by neuronal activity (EEG, magnetencephalography [MEG]) and those measuring the haemodynamic or metabolic sequelae of neuronal activity (positron emission tomography [PET], functional magnetic resonance imaging [fMRI]). Out of these techniques, the following two will be discussed in detail: fMRI and PET. Although functional neuroimaging is able to acquire images of the brain engaged in consolidating or retrieving memories, these processes are not clearly visible in the data. Statistical techniques are needed to reduce the complexity of the data and to extract the processes of interest. This article outlines the experimental and analytical procedures of neuroimaging studies with PET and fMRI. We will use a PET-study on episodic memory in human volunteers to illustrate design, analysis, and interpretation of functional imaging studies on memory.     

Statistical epistasis and functional brain imaging support a role of voltage-gated potassium channels in human memory

Despite the current progress in high-throughput, dense genome scans, a major portion of complex traits' heritability still remains unexplained, a phenomenon commonly termed "missing heritability." The negligence of analytical approaches accounting for gene-gene interaction effects, such as statistical epistasis, is probably central to this phenomenon. Here we performed a comprehensive two-way SNP interaction analysis of human episodic memory, which is a heritable complex trait, and focused on 120 genes known to show differential, memory-related expression patterns in rat hippocampus. Functional magnetic resonance imaging was also used to capture genotype-dependent differences in memory-related brain activity. A significant, episodic memory-related interaction between two markers located in potassium channel genes (KCNB2 and KCNH5) was observed (P(nominal combined)=0.000001). The epistatic interaction was robust, as it was significant in a screening (P(nominal)=0.0000012) and in a replication sample (P(nominal)=0.01). Finally, we found genotype-dependent activity differences in the parahippocampal gyrus (P(nominal)=0.001) supporting the behavioral genetics finding. Our results demonstrate the importance of analytical approaches that go beyond single marker statistics of complex traits.     

Concept of functional imaging of memory decline in Alzheimer's disease

Functional imaging methods such as Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) have contributed inestimably to the understanding of physiological cognitive processes in the brain in the recent decades. These techniques for the first time allowed the in vivo assessment of different features of brain function in the living human subject. It was therefore obvious to apply these methods to evaluate pathomechanisms of cognitive dysfunction in disorders such as Alzheimer's disease (AD) as well. One of the most dominant symptoms of AD is the impairment of memory. In this context, the term "memory" represents a simplification and summarizes a set of complex cognitive functions associated with encoding and retrieval of different types of information. A number of imaging studies assessed the functional changes of neuronal activity in the brain at rest and also during performance of cognitive work, with regard to specific characteristics of memory decline in AD. In the current article, basic principles of common functional imaging procedures will be explained and it will be discussed how they can be reasonably applied for the assessment of memory decline in AD. Furthermore, it will be illustrated how these imaging procedures have been employed to improve early and specific diagnosis of the disease, to understand specific pathomechanisms of memory dysfunction and associated compensatory mechanisms, and to draw reverse conclusions on physiological function of memory.     

Embodied semantics for actions: findings from functional brain imaging.

The theory of embodied semantics for actions specifies that the sensory-motor areas used for producing an action are also used for the conceptual representation of the same action. Here we review the functional imaging literature that has explored this theory and consider both supporting as well as challenging fMRI findings. In particular we address the representation of actions and concepts as well as literal and metaphorical phrases in the premotor cortex.     

Working memory and executive function: evidence from neuroimaging

Traditional theories of working memory and executive function, when mapped in straightforward ways into the neural domain, yield predictions that are only partly supported by the recent neuroimaging studies. Neuroimaging studies suggest that some constituent functions, such as maintaining information in active form and manipulating it, are not discretely localized in prefrontal regions. Some hypothesized executive processes, such as goal management, have effects in several cortical regions, including posterior regions. Such results suggest a more dynamic and distributed view of the cortical organization of working memory and executive functions.     

IL-10 is excluded from the functional cytokine memory of human CD4+ memory T lymphocytes

Epigenetic modifications, including DNA methylation, profoundly influence gene expression of CD4(+) Th-specific cells thereby shaping memory Th cell function. We demonstrate here a correlation between a lacking fixed potential of human memory Th cells to re-express the immunoregulatory cytokine gene IL10 and its DNA methylation status. Memory Th cells secreting IL-10 or IFN-gamma were directly isolated ex vivo from peripheral blood of healthy volunteers, and the DNA methylation status of IL10 and IFNG was assessed. Limited difference in methylation was found for the IL10 gene locus in IL-10-secreting Th cells, as compared with Th cells not secreting IL-10 isolated directly ex vivo or from in vitro-established human Th1 and Th2 clones. In contrast, in IFN-gamma(+) memory Th cells the promoter of the IFNG gene was hypomethylated, as compared with IFN-gamma-nonsecreting memory Th cells. In accordance with the lack of epigenetic memory, almost 90% of ex vivo-isolated IL-10-secreting Th cells lacked a functional memory for IL-10 re-expression after restimulation. Our data indicate that IL10 does not become epigenetically marked in human memory Th cells unlike effector cytokine genes such as IFNG. The exclusion of IL-10, but not effector cytokines, from the functional memory of human CD4(+) T lymphocytes ex vivo may reflect the need for appropriate regulation of IL-10 secretion, due to its potent immunoregulatory potential.     

RNA polymerase. Direct evidence for a unique topographical site for initiation

The compound 9-(3'-azido-3'-deoxy-beta-D-xylofuranosyl)adenine 5'-monophosphate is an inhibitor (Ki = 330 microM) of the initiation binding site of the DNA-dependent RNA polymerase derived from Escherichia coli. The alpha-32P derivative of this photo-labile compound is used to derivatize a site on the sigma subunit of the holoenzyme (E sigma) using either T7 delta D111 or poly[d(A-T)] as a DNA template. The incorporation of the 32P label into the sigma subunit could be prevented by the addition of either 5'-AMP or 5'-ATP. The results are suggested to support the existence of a unique initiation binding site, topographically distinct from the sites employed during the elongation phase.     

Structural evidence of functional divergence in human alkaline phosphatases

The evolution of the alkaline phosphatase (AP) gene family has lead to the existence in humans of one tissue-nonspecific (TNAP) and three tissue-specific isozymes, i.e. intestinal (IAP), germ cell (GCAP), and placental AP (PLAP). To define the structural differences between these isozymes, we have built models of the TNAP, IAP, and GCAP molecules based on the 1.8-structure of PLAP(1) and have performed a comparative structural analysis. We have examined the monomer-monomer interface as this area is crucial for protein stability and enzymatic activity. We found that the interface allows the formation of heterodimers among IAP, GCAP, and PLAP but not between TNAP with any of the three tissue-specific isozymes. Secondly, the active site cleft was mapped into three regions, i.e. the active site itself, the roof of the cleft, and the floor of the cleft. This analysis led to a structural fingerprint of the active site of each AP isozyme that suggests a diversification in substrate specificity for this isozyme family.     

Hippocampal involvement in the pharmacologic induction of withdrawal-like behaviors

Kainic acid is an analog of glutamate. The CA3-4 field of the hippocampus is extremely sensitive to its toxic properties. Intracerebroventricular injection of of nontoxic doses of kainic acid in rats produces behaviors similar to morphine withdrawal. Lesion of CA3-4 abolishes this response to kainic acid. Destruction of CA3-4 blocks the ability of Met-enkephalin, ketocyclazocine, and 5-hydroxytryptophan, but not sodium valproate or ice water to induce withdrawal-like behaviors. The actions of kainic acid, endorphins, and ketocyclazocine are blocked by naloxone and enhanced by opiate agonists. Sodium valproate, ice water, and withdrawal itself are released by naloxone and blocked by opiate agonists. Similar discriminations by CA3-4 lesions and challenge by naloxone and morphine may indicate that two neural circuits exist through which withdrawal-like behaviors are evoked. The hippocampal circuit is not directly involved in dependence, but may modulate withdrawal. Withdrawal-like behaviors are observed in rats in situations where behavior is blocked. These withdrawal-like behaviors are reminiscent of verbal reports of anxiety. In particular, wet-dog shakes in these situations may be analogous to shuddering. In humans, monosodium glutamate intolerance is associated with shuddering.     

正常人长时数字记忆信息提取的神经基础的功能磁共振研究

本文旨在通过功能磁共振成像(functional magnetic resonance imaging,fMRI)技术研究正常人进行长时数字记忆信息提取的神经基础。选取22名右利手志愿者进行长时数字记忆任务实验,采用组块设计,记忆任务与对照任务交替进行,同时利用Siemens 1.5T超导型磁共振仪进行fMRI成像,采用SPM99软件进行数据分析,脑功能区定位在Talairach坐标中显示。结果显示被试者在进行长时数字记忆提取任务时,激活最显著的皮层是左侧额中回(Brodmann分区9区,BA9区),另外左额叶内侧回、左额下回、右额下回、扣带回、左顶下小叶、左顶上小叶、右顶上小叶、右颞中回、左枕舌回、左枕中回、右中脑、小脑、右尾状核尾部等结构也有激活,各大脑皮层的激活均呈现明显的左侧半球优势。根据上述结果推论,长时数字记忆由以左侧大脑半球为优势的各脑区共同参与完成,其中左侧额叶外侧面可能是信息提取的重要结构,而其它脑叶及其之间的广泛联系可能在数字信息的加工、处理和存储中起重要作用。     

Evidence from functional magnetic resonance imaging of crossmodal binding in the human heteromodal cortex

BACKGROUND: Integrating information from the different senses markedly enhances the detection and identification of external stimuli. Compared with unimodal inputs, semantically and/or spatially congruent multisensory cues speed discrimination and improve reaction times. Discordant inputs have the opposite effect, reducing performance and slowing responses. These behavioural features of crossmodal processing appear to have parallels in the response properties of multisensory cells in the superior colliculi and cerebral cortex of non-human mammals. Although spatially concordant multisensory inputs can produce a dramatic, often multiplicative, increase in cellular activity, spatially disparate cues tend to induce a profound response depression. RESULTS: Using functional magnetic resonance imaging (fMRI), we investigated whether similar indices of crossmodal integration are detectable in human cerebral cortex, and for the synthesis of complex inputs relating to stimulus identity. Ten human subjects were exposed to varying epochs of semantically congruent and incongruent audio-visual speech and to each modality in isolation. Brain activations to matched and mismatched audio-visual inputs were contrasted with the combined response to both unimodal conditions. This strategy identified an area of heteromodal cortex in the left superior temporal sulcus that exhibited significant supra-additive response enhancement to matched audio-visual inputs and a corresponding sub-additive response to mismatched inputs. CONCLUSIONS: The data provide fMRI evidence of crossmodal binding by convergence in the human heteromodal cortex. They further suggest that response enhancement and depression may be a general property of multisensory integration operating at different levels of the neuroaxis and irrespective of the purpose for which sensory inputs are combined.     

Concept of functional imaging of memory decline in Alzheimer’s disease

Functional imaging methods such as Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) have contributed inestimably to the understanding of physiological cognitive processes in the brain in the recent decades. These techniques for the first time allowed the in vivo assessment of different features of brain function in the living human subject. It was therefore obvious to apply these methods to evaluate pathomechanisms of cognitive dysfunction in disorders such as Alzheimer’s disease (AD) as well. One of the most dominant symptoms of AD is the impairment of memory. In this context, the term “memory” represents a simplification and summarizes a set of complex cognitive functions associated with encoding and retrieval of different types of information. A number of imaging studies assessed the functional changes of neuronal activity in the brain at rest and also during performance of cognitive work, with regard to specific characteristics of memory decline in AD. In the current article, basic principles of common functional imaging procedures will be explained and it will be discussed how they can be reasonably applied for the assessment of memory decline in AD. Furthermore, it will be illustrated how these imaging procedures have been employed to improve early and specific diagnosis of the disease, to understand specific pathomechanisms of memory dysfunction and associated compensatory mechanisms, and to draw reverse conclusions on physiological function of memory.     

Top-down processes in object identification: evidence from experimental psychology,neuropsychology and functional anatomy.

Many models of object identification are bottom-up and serial in nature; processing at a first stage needs to be complete before it is passed on to a subsequent stage, and there is no top-down feedback from the later to the earlier stages. However, data on picture identification in normal observers contradict a strict serial account of processing, since effects of variables on early and late stages of object identification combine in an interactive rather than an additive manner. Recent neuropsychological and functional anatomical data also indicate that object identification involves top-down activation of earlier stages of visual processing. In neuropsychological patients, subtle perceptual deficits can produce naming problems, even when there is good access to associated semantic knowledge; in functional activation studies, there is increased activity in visual processing areas when conditions require object naming relative to object recognition. These studies provide evidence that increased visual processing occurs in identification tasks, suggesting that there is re-current feedback during the identification process.