Learning related interactions among neuronal systems involved in memory processes

Functional neuroimaging techniques using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have provided new insights in our understanding of brain function from the molecular to the systems level. While subtraction strategy based data analyses have revealed the involvement of distributed brain regions in memory processes, covariance analysis based data analysis strategies allow functional interactions between brain regions of a neuronal network to be assessed. The focus of this chapter is to (1) establish the functional topography of episodic and working memory processes in young and old normal volunteers, (2) to assess functional interactions between modules of networks of brain regions by means of covariance based analyses and systems level modelling and (3) to relate neuroimaging data to the underpinning neural networks. Male normal young and old volunteers without neurological or psychiatric illness participated in neuroimaging studies (PET, fMRI) on working and episodic memory. Distributed brain areas are involved in memory processes (episodic and working memory) in young volunteers and show much of an overlap with respect to the network components. Systems level modelling analyses support the hypothesis of bihemispheric, asymmetric networks subserving memory processes and revealed both similarities in general and differences in the interactions between brain regions during episodic encoding and retrieval as well as working memory. Changes in memory function with ageing are evident from studies in old volunteers activating more brain regions compared to young volunteers and revealing more and stronger influences of prefrontal regions. We finally discuss the way in which the systems level models based on PET and fMRI results have implications for the understanding of the underlying neural network functioning of the brain.     

Memory,consciousness and neuroimaging.

Neuroimaging techniques that allow the assessment of memory performance in healthy human volunteers while simultaneously obtaining measurements of brain activity in vivo may offer new information on the neural correlates of particular forms of memory retrieval and their association with consciousness and intention. We consider evidence from studies with positron emission tomography and functional magnetic resonance imaging indicating that priming, a form of implicit retrieval, is associated with decreased activity in various cortical regions. We also consider evidence concerning the question of whether two components of explicit retrieval--intentional or effortful search and successful conscious recollection--are preferentially associated with increased activity in prefrontal and medial temporal regions, respectively. Last, we consider recent efforts to probe the relation between the phenomenological character of remembering and neural activity. In this instance we broaden our scope to include studies employing event-related potentials and consider evidence concerning the neural correlates of qualitatively different forms of memory, including memory that is specifically associated with a sense of self, and the recollection of particular temporal or perceptual features that might contribute to a rich and vivid experience of the past.     

Neural basis for successful encoding and retrieval of prospective memory

Prospective memory (PM) refers to memory for future intentions. Difference due to memory (Dm effect) is the difference in neural activity related to stimuli that were subsequently remembered or forgotten. Using event-related potentials (ERPs), the present study investigated the Dm effect for PM using a subsequent task-switching paradigm. The results showed that a Dm effect of ERP P150 was more positive-going for later PM hit trials than for later PM forgotten trials during 100–200 ms. This Dm effect may reflect the process for the production of future intention or the process for attention. Consistent with previously reported Dm effects of other types of memory, we found that the fbN2 (250–280 ms) and late positivity component (400–700 ms) were stronger in later PM hit trials than in forgotten trials. The fbN2 was evoked by Chinese characters. The late positivity component was related to the precise encoding process. In conclusion, because of the early P150, PM encoding appears to be somewhat different from previously identified Dm effects. However, further research is needed. Our findings reveal that Dm effects of PM share similar characteristics with known Dm effects of other types of episodic memory after the very early stage of neural processing.     

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.     

Origins of spatial working memory deficits in schizophrenia: an event-related FMRI and near-infrared spectroscopy study

Abnormal prefrontal functioning plays a central role in the working memory (WM) deficits of schizophrenic patients, but the nature of the relationship between WM and prefrontal activation remains undetermined. Using two functional neuroimaging methods, we investigated the neural correlates of remembering and forgetting in schizophrenic and healthy participants. We focused on the brain activation during WM maintenance phase with event-related functional magnetic resonance imaging (fMRI). We also examined oxygenated hemoglobin changes in relation to memory performance with the near-infrared spectroscopy (NIRS) using the same spatial WM task. Distinct types of correct and error trials were segregated for analysis. fMRI data indicated that prefrontal activation was increased during WM maintenance on correct trials in both schizophrenic and healthy subjects. However, a significant difference was observed in the functional asymmetry of frontal activation pattern. Healthy subjects showed increased activation in the right frontal, temporal and cingulate regions. Schizophrenic patients showed greater activation compared with control subjects in left frontal, temporal and parietal regions as well as in right frontal regions. We also observed increased 'false memory' errors in schizophrenic patients, associated with increased prefrontal activation and resembling the activation pattern observed on the correct trials. NIRS data replicated the fMRI results. Thus, increased frontal activity was correlated with the accuracy of WM in both healthy control and schizophrenic participants. The major difference between the two groups concerned functional asymmetry; healthy subjects recruited right frontal regions during spatial WM maintenance whereas schizophrenic subjects recruited a wider network in both hemispheres to achieve the same level of memory performance. Increased "false memory" errors and accompanying bilateral prefrontal activation in schizophrenia suggest that the etiology of memory errors must be considered when comparing group performances. Finally, the concordance of fMRI and NIRS data supports NIRS as an alternative functional neuroimaging method for psychiatric research.     

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.     

统计学习的认知机制及其神经基础

本文主要探讨了人类统计学习研究的起源和发展、影响统计学习的因素及统计学习的脑神经基础.人类统计学习的研究起源于20世纪90年代关于婴儿听觉语音流切分的实验,之后,大量研究又考察了对听觉非语言信息及视觉图形的统计学习.这些研究表明,统计学习是一种具有一般性的、涉及发现和提取规则的学习类型,但是不同范畴的统计学习又受到与特定范畴有关因素的制约.例如,语言统计学习受到语言因素的制约,而非语言统计学习与呈现刺激的特征以及呈现的通道有关.近些年,研究者开始采用事件相关电位(event-related potentials,ERPs)技术考察统计学习的时间进程,以及采用功能核磁共振成像(functional magnetic resonance imaging,fMRI)技术考察统计学习的脑激活模式.ERPs研究较一致地发现400 ms左右产生的负波与统计信息的提取有关,而脑成像研究结果表明,与统计学习相关的脑区有大脑左侧颞上回(superiortemporal gyrus)、右侧纹状体(right striatum)和右侧颞叶内侧记忆系统(right medial temporal memory system).     

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.     

When Learning and Remembering Compete: A Functional MRI Study

Recent functional neuroimaging evidence suggests a bottleneck between learning new information and remembering old information. In two behavioral experiments and one functional MRI (fMRI) experiment, we tested the hypothesis that learning and remembering compete when both processes happen within a brief period of time. In the first behavioral experiment, participants intentionally remembered old words displayed in the foreground, while incidentally learning new scenes displayed in the background. In line with a memory competition, we found that remembering old information was associated with impaired learning of new information. We replicated this finding in a subsequent fMRI experiment, which showed that this behavioral effect was coupled with a suppression of learning-related activity in visual and medial temporal areas. Moreover, the fMRI experiment provided evidence that left mid-ventrolateral prefrontal cortex is involved in resolving the memory competition, possibly by facilitating rapid switching between learning and remembering. Critically, a follow-up behavioral experiment in which the background scenes were replaced with a visual target detection task provided indications that the competition between learning and remembering was not merely due to attention. This study not only provides novel insight into our capacity to learn and remember, but also clarifies the neural mechanisms underlying flexible behavior.     

Monitoring the mind: the neurocognitive correlates of metamemory

Memory performance in everyday life is often far from perfect and therefore needs to be monitored and controlled by metamemory evaluations, such as judgments of learning (JOLs). JOLs support monitoring for goal-directed modification of learning. Behavioral studies suggested retrieval processes as providing a basis for JOLs. Previous functional imaging research on JOLs found a dissociation between processes underlying memory prediction, located in the medial prefrontal cortex (mPFC), and actual encoding success, located in the medial temporal lobe. However, JOL-specific neural correlates could not be identified unequivocally, since JOLs were given simultaneously with encoding. Here, we aimed to identify the neurocognitive basis of JOLs, i.e., the cognitive processes and neural correlates of JOL, separate from initial encoding. Using functional magnetic resonance imaging (fMRI), we implemented a face-name paired associative design. In general, we found that actual memory success was associated with increased brain activation of the hippocampi bilaterally, whereas predicted memory success was accompanied by increased activation in mPFC, orbital frontal and anterior cingulate cortices. Masking brain activation during predicted memory success with activation during retrieval success revealed BOLD increases of the mPFC. Our findings indicate that JOLs actually incorporate retrieval processes.     

The neural systems of tool and action semantics: a perspective from functional imaging.

This review discusses the contributions of functional imaging (fMRI/PET) to our understanding of how action and tool concepts are represented and processed in the human brain. Category-selective deficits in neuropsychological patients have suggested a fine-grained functional specialization within the neural systems of semantics. However, the underlying principles of semantic organization remain controversial. The feature-based account of semantic memory (or 'sensory-motor theory') predicates category-selective effects (e.g. tool vs. animals) on anatomical segregation for different semantic features (e.g. action vs. visual). Within this framework, we will review functional imaging evidence that semantic processing of tools and actions may rely on activations within the visuo-motor system.     

High-resolution functional magnetic resonance imaging of the animal brain

To fully understand brain function, one must look beyond the level of a single neuron. By elucidating the spatial properties of the columnar and laminar functional architectures, information regarding the neural processing in the brain can be gained. To map these fine functional structures noninvasively and repeatedly, functional magnetic resonance imaging (fMRI) can be employed. In this article the basic principles of fMRI are introduced, including specific hardware requirements and the equipment necessary for animal magnetic resonance research. Since fMRI measures a change in secondary hemodynamic responses induced by neural activity, it is critical to understand the principles and potential pitfalls of fMRI techniques. Thus, the underlying physics of conventional blood oxygenation, cerebral blood flow, and cerebral blood volume-based fMRI techniques are extensively discussed. Tissue-specific signal change is close to the site of neural activity, while signals from large vessels can be distant from the actual active site. Thus, methods to minimize large vessel contributions and to maximize tissue signals are described. The fundamental limitation of fMRI spatial resolution is the intrinsic hemodynamic response. Based on our high-resolution fMRI studies, the hemodynamic response is regulated at submillimeter functional domains and thus spatial resolution can be achieved to an order of 100 microm. Since hemodynamic responses are sluggish, it is difficult to obtain very high temporal resolution. By using an approach with multiple experiments with different stimulus conditions, temporal resolution can be improved on the order of 100 ms. With current fMRI technologies, submillimeter columnar- and laminar-specific specific functional images can be obtained from animal brains.     

Investigating the Effects of Antipsychotics and Schizotypy on the N400 Using Event-Related Potentials and Semantic Categorization

Within the field of cognitive neuroscience, functional magnetic resonance imaging (fMRI) is a popular method of visualizing brain function. This is in part because of its excellent spatial resolution, which allows researchers to identify brain areas associated with specific cognitive processes. However, in the quest to localize brain functions, it is relevant to note that many cognitive, sensory, and motor processes have temporal distinctions that are imperative to capture, an aspect that is left unfulfilled by fMRI’s suboptimal temporal resolution. To better understand cognitive processes, it is thus advantageous to utilize event-related potential (ERP) recording as a method of gathering information about the brain. Some of its advantages include its fantastic temporal resolution, which gives researchers the ability to follow the activity of the brain down to the millisecond. It also directly indexes both excitatory and inhibitory post-synaptic potentials by which most brain computations are performed. This sits in contrast to fMRI, which captures an index of metabolic activity. Further, the non-invasive ERP method does not require a contrast condition: raw ERPs can be examined for just one experimental condition, a distinction from fMRI where control conditions must be subtracted from the experimental condition, leading to uncertainty in associating observations with experimental or contrast conditions. While it is limited by its poor spatial and subcortical activity resolution, ERP recordings’ utility, relative cost-effectiveness, and associated advantages offer strong rationale for its use in cognitive neuroscience to track rapid temporal changes in neural activity. In an effort to foster increase in its use as a research imaging method, and to ensure proper and accurate data collection, the present article will outline – in the framework of a paradigm using semantic categorization to examine the effects of antipsychotics and schizotypy on the N400 – the procedure and key aspects associated with ERP data acquisition.     

多方式认知功能成像研究进展

对大脑结构和功能的深入研究要求认知功能成像技术同时具有高时间分辨率和高空间分辨率.多方式认知功能成像通过不同成像技术fMRI/PET和EEG/MEG的结合,能够同时在空间定位和时间过程上研究大脑认知活动的动态过程.多方式认知功能成像已经被成功地应用于选择性注意、视觉通路、随意运动和语义加工等的研究,并揭示了相关大脑活动的空间和时间特征.今后的研究将进一步提高多方式认知功能成像的时空分辨率和准确性,以更深入地探索认知功能的神经机制.     

Spatio-temporal modeling of localized brain activity

Functional neuroimaging, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), plays an important role in identifying specific brain regions associated with experimental stimuli or psychiatric disorders such as schizophrenia. PET and fMRI produce massive data sets that contain both temporal correlations from repeated scans and complex spatial correlations. Several methods exist for handling temporal correlations, some of which rely on transforming the response data to induce either a known or an independence covariance structure. Despite the presence of spatial correlations between the volume elements (voxels) comprising a brain scan, conventional methods perform voxel-by-voxel analyses of measured brain activity. We propose a two-stage spatio-temporal model for the estimation and testing of localized activity. Our second-stage model specifies a spatial auto-regression, capturing correlations within neural processing clusters defined by a data-driven cluster analysis. We use maximum likelihood methods to estimate parameters from our spatial autoregressive model. Our model protects against type-I errors, enables the detection of both localized and regional activations (including volume of interest effects), provides information on functional connectivity in the brain, and establishes a framework to produce spatially smoothed maps of distributed brain activity for each individual. We illustrate the application of our model using PET data from a study of working memory in individuals with schizophrenia.     

Brain imaging and memory systems in humans: the contribution of PET methods

The development of neuroimaging methods such as PET, has provided a new impulse to the study of the neural basis of cognitive functions, and has extended the field of inquiry from the analysis of the consequences of brain lesions to the functional investigations of brain activity, either in patients with selective neuropsychological deficits or in normal subjects engaged in cognitive tasks. Specific patterns of hypometabolism in neurological patients are associated with different profiles of memory deficits. [¹⁸F]FDG PET studies have confirmed the association of episodic memory with the structures of Papez's circuit and have shown correlations between short-term and semantic memory and the language areas. The identification of anatomo-functional networks involved in specific components of memory function in normal subjects is the aim of several PET activation studies. The results are in agreement with ‘neural network’ models of the neural basis of memory, as complex functions subserved by multiple interconnected cortical and subcortical structures.     

Linking variability in brain chemistry and circuit function through multimodal human neuroimaging

Identifying neurobiological mechanisms mediating the emergence of individual differences in behavior is critical for advancing our understanding of relative risk for psychopathology. Neuroreceptor positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) can be used to assay in vivo regional brain chemistry and function, respectively. Typically, these neuroimaging modalities are implemented independently despite the capacity for integrated data sets to offer unique insight into molecular mechanisms associated with brain function. Through examples from the serotonin and dopamine system and its effects on threat- and reward-related brain function, we review evidence for how such a multimodal neuroimaging strategy can be successfully implemented. Furthermore, we discuss how multimodal PET-fMRI can be integrated with techniques such as imaging genetics, pharmacological challenge paradigms and gene-environment interaction models to more completely map biological pathways mediating individual differences in behavior and related risk for psychopathology and inform the development of novel therapeutic targets.     

Coupling of total hemoglobin concentration,oxygenation, and neural activity in rat somatosensory cortex

Recent advances in brain imaging techniques, including functional magnetic resonance imaging (fMRI), offer great promise for noninvasive mapping of brain function. However, the indirect nature of the imaging signals to the underlying neural activity limits the interpretation of the resulting maps. The present report represents the first systematic study with sufficient statistical power to quantitatively characterize the relationship between changes in blood oxygen content and the neural spiking and synaptic activity. Using two-dimensional optical measurements of hemodynamic signals, simultaneous recordings of neural activity, and an event-related stimulus paradigm, we demonstrate that (1) there is a strongly nonlinear relationship between electrophysiological measures of neuronal activity and the hemodynamic response, (2) the hemodynamic response continues to grow beyond the saturation of electrical activity, and (3) the initial increase in deoxyhemoglobin that precedes an increase in blood volume is counterbalanced by an equal initial decrease in oxyhemoglobin.     

Remembering the past to imagine the future: the prospective brain

A rapidly growing number of recent studies show that imagining the future depends on much of the same neural machinery that is needed for remembering the past. These findings have led to the concept of the prospective brain; an idea that a crucial function of the brain is to use stored information to imagine, simulate and predict possible future events. We suggest that processes such as memory can be productively re-conceptualized in light of this idea.