What have we learned about cognitive development from neuroimaging?

Changes in many domains of cognition occur with development. In this paper, we discuss neuroimaging approaches to understanding these changes at a neural level. We highlight how modern imaging methods such as functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) are being used to examine how cognitive development is supported by the maturation of the brain. Some reports suggest developmental changes in patterns of brain activity appear to involve a shift from diffuse to more focal activation, likely representing a fine-tuning of relevant neural systems with experience. One of the challenges in investigating the interplay between cognitive development and maturation of the brain is to separate the contributions of neural changes specific to development and learning. Examples are given from the developmental neuroimaging literature. The focus is on the development of cognitive control, as the protracted developmental course of this ability into adolescence raises key issues. Finally, the relevance of normative studies for understanding neural and cognitive changes in developmental disorders is discussed.     

DEVICE‐BASED BRAIN STIMULATION TO AUGMENT FEAR EXTINCTION: IMPLICATIONS FOR PTSD TREATMENT AND BEYOND

Conditioned fear acquisition and extinction paradigms have been widely used both in animals and humans to examine the neurobiology of emotional memory. Studies have also shown that patients suffering from posttraumatic stress disorder (PTSD) exhibit deficient extinction recall along with dysfunctional activation of the fear extinction network, including the ventromedial prefrontal cortex, amygdala, and hippocampus. A great deal of overlap exists between this fear extinction network and brain regions associated with symptom severity in PTSD. This suggests that the neural nodes of fear extinction could be targeted to reduce behavioral deficits that may subsequently translate into symptom improvement. In this article, we discuss potential applications of brain stimulation and neuromodulation methods, which, combined with a mechanistic understanding of the neurobiology of fear extinction, could be used to further our understanding of the pathophysiology of anxiety disorders and develop novel therapeutic tools. To this end, we discuss the following stimulation approaches: deep‐brain stimulation, vagus nerve stimulation, transcranial direct current stimulation, and transcranial magnetic stimulation. We propose new translational research avenues that, from a systems neuroscience perspective, aim to expand our understanding of circuit dynamics and fear processing toward the practical development of clinical tools, to be used alone or in combination with behavioral therapies.     

Alcohol and Drug Use and the Developing Brain

Adolescence is an important neurodevelopmental period marked by rapidly escalating rates of alcohol and drug use. Over the past decade, research has attempted to disentangle pre- and post-substance use effects on brain development by using sophisticated longitudinal designs. This review focuses on recent, prospective studies and addresses the following important questions: (1) what neuropsychological and neural features predate adolescent substance use, making youth more vulnerable to engage in heavy alcohol or drug use, and (2) how does heavy alcohol and drug use affect normal neural development and cognitive functioning? Findings suggest that pre-existing neural features that relate to increased substance use during adolescence include poorer neuropsychological functioning on tests of inhibition and working memory, smaller gray and white matter volume, changes in white matter integrity, and altered brain activation during inhibition, working memory, reward, and resting state. After substance use is initiated, alcohol and marijuana use are associated with poorer cognitive functioning on tests of verbal memory, visuospatial functioning, psychomotor speed, working memory, attention, cognitive control, and overall IQ. Heavy alcohol use during adolescence is related to accelerated decreases in gray matter and attenuated increases in white matter volume, as well as increased brain activation during tasks of inhibition and working memory, relative to controls. Larger longitudinal studies with more diverse samples are needed to better understand the interactive effects of alcohol, marijuana, and other substances, as well as the role of sex, co-occurring psychopathology, genetics, sleep, and age of initiation on substance use.     

Object recognition memory: neurobiological mechanisms of encoding, consolidation and retrieval

Tests of object recognition memory, or the judgment of the prior occurrence of an object, have made substantial contributions to our understanding of the nature and neurobiological underpinnings of mammalian memory. Only in recent years, however, have researchers begun to elucidate the specific brain areas and neural processes involved in object recognition memory. The present review considers some of this recent research, with an emphasis on studies addressing the neural bases of perirhinal cortex-dependent object recognition memory processes. We first briefly discuss operational definitions of object recognition and the common behavioural tests used to measure it in non-human primates and rodents. We then consider research from the non-human primate and rat literature examining the anatomical basis of object recognition memory in the delayed nonmatching-to-sample (DNMS) and spontaneous object recognition (SOR) tasks, respectively. The results of these studies overwhelmingly favor the view that perirhinal cortex (PRh) is a critical region for object recognition memory. We then discuss the involvement of PRh in the different stages--encoding, consolidation, and retrieval--of object recognition memory. Specifically, recent work in rats has indicated that neural activity in PRh contributes to object memory encoding, consolidation, and retrieval processes. Finally, we consider the pharmacological, cellular, and molecular factors that might play a part in PRh-mediated object recognition memory. Recent studies in rodents have begun to indicate the remarkable complexity of the neural substrates underlying this seemingly simple aspect of declarative memory.     

Imaging evidence for disturbances in multiple learning and memory systems in persons with autism spectrum disorders

Aim The aim of this article is to review neuroimaging studies of autism spectrum disorders (ASD) that examine declarative, socio‐emotional, and procedural learning and memory systems. Method We conducted a search of PubMed from 1996 to 2010 using the terms ‘autism,’‘learning,’‘memory,’ and ‘neuroimaging.’ We limited our review to studies correlating learning and memory function with neuroimaging features of the brain. Results The early literature supports the following preliminary hypotheses: (1) abnormalities of hippocampal subregions may contribute to autistic deficits in episodic and relational memory; (2) disturbances to an amygdala‐based network (which may include the fusiform gyrus, superior temporal cortex, and mirror neuron system) may contribute to autistic deficits in socio‐emotional learning and memory; and (3) abnormalities of the striatum may contribute to developmental dyspraxia in individuals with ASD. Interpretation Characterizing the disturbances to learning and memory systems in ASD can inform our understanding of the neural bases of autistic behaviors and the phenotypic heterogeneity of ASD.     

Bridging divergent neural models of recognition memory: introduction to the special issue and commentary on key issues

This special issue reviews progress that has been made in recent years in understanding neural processing relevant for recognition memory. Here we describe how the nine reviews that comprise this issue weigh in on some of the most pressing and hotly debated issues in the study of recognition memory, including: (1) the number of processes that support recognition, (2) the nature of these processes, and (3) how these processes map onto neural processing events and brain structures. We then discuss the challenges inherent in attempting to incorporate the fundamentally different types of information that result from various cognitive neuroscience methods (e.g., electrophysiological recordings of neurons, lesion-deficit studies, analyses of brain potentials and activations, modeling of behavioral responses, and phenomenological reports), and make suggestions for how to better integrate these disparate data types when making inferences about recognition memory. As the articles in this special issue make clear, great strides have been made in understanding how organisms are able to appreciate repetition. And yet, several controversies in this area have still not been resolved, but these articles clarify the core disagreements as well as the tests that must be conducted to seek resolution. This special issue as a whole should thus facilitate advancements in the future study of the neural mechanisms of recognition.     

Methods and considerations for longitudinal structural brain imaging analysis across development

Magnetic resonance imaging (MRI) has allowed the unprecedented capability to measure the human brain in vivo. This technique has paved the way for longitudinal studies exploring brain changes across the entire life span. Results from these studies have given us a glimpse into the remarkably extended and multifaceted development of our brain, converging with evidence from anatomical and histological studies. Ever-evolving techniques and analytical methods provide new avenues to explore and questions to consider, requiring researchers to balance excitement with caution. This review addresses what MRI studies of structural brain development in children and adolescents typically measure and how. We focus on measurements of brain morphometry (e.g., volume, cortical thickness, surface area, folding patterns), as well as measurements derived from diffusion tensor imaging (DTI). By integrating finding from multiple longitudinal investigations, we give an update on current knowledge of structural brain development and how it relates to other aspects of biological development and possible underlying physiological mechanisms. Further, we review and discuss current strategies in image processing, analysis techniques and modeling of brain development. We hope this review will aid current and future longitudinal investigations of brain development, as well as evoke a discussion amongst researchers regarding best practices.     

Understanding the Neural Bases of Implicit and Statistical Learning

Both implicit learning and statistical learning focus on the ability of learners to pick up on patterns in the environment. It has been suggested that these two lines of research may be combined into a single construct of “implicit statistical learning.” However, by comparing the neural processes that give rise to implicit versus statistical learning, we may determine the extent to which these two learning paradigms do indeed describe the same core mechanisms. In this review, we describe current knowledge about neural mechanisms underlying both implicit learning and statistical learning, highlighting converging findings between these two literatures. A common thread across all paradigms is that learning is supported by interactions between the declarative and nondeclarative memory systems of the brain. We conclude by discussing several outstanding research questions and future directions for each of these two research fields. Moving forward, we suggest that the two literatures may interface by defining learning according to experimental paradigm, with “implicit learning” reserved as a specific term to denote learning without awareness, which may potentially occur across all paradigms. By continuing to align these two strands of research, we will be in a better position to characterize the neural bases of both implicit and statistical learning, ultimately improving our understanding of core mechanisms that underlie a wide variety of human cognitive abilities.     

Potential consequences of altered neurogenesis on learning and memory in the epileptic brain

Studies of epilepsy and memory are tied by their common dependence on the hippocampal formation and the adjacent brain structures in the temporal lobe. With the discovery of adult neurogenesis and the consequent revisions of our understanding of how the hippocampus works, the role of neurogenesis in epilepsy needs to be addressed. In this article, we outline two theories describing how neurogenesis contributes to the hippocampus-dependent learning. We speculate that any drastic changes in neurogenesis will negatively impact the hippocampal memory processing.     

Imaging and neural modelling in episodic and working memory processes.

Neuroimaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have revealed the involvement of distributed brain regions in memory processes mainly by the use of subtraction strategy based data analyses. Covariance analysis based data analysis strategies have been introduced more recently which allow functional interactions between brain regions of a neuronal network to be assessed. This contribution focuses on studies aiming 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, (3) to characterise the temporal dynamics by the use of magnetoencephalography (MEG) and (4) 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, MEG). Studies were approved by the ethical committee and federal authorities. Our results in young volunteers show distributed brain areas that are involved in memory processes (episodic and working memory) 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 functional topographic studies in old volunteers activating more brain regions as compared to young volunteers. There are more and stronger influences of prefrontal regions in elderly volunteers comparing the functional models between old and young subjects. We discuss the way that the systems level models of the PET and fMRI results have implications for the underlying neural network functioning of the brain. This is done by developing simplifying assumptions, which lead from the equations describing the activities of the coupled neural modules to the systems level model equations. The resulting implications for the neural interactions are then discussed, in terms of a set of synaptically coupled neural modules. Finally, we consider how a similar analysis could be extended from the spatial to the temporal domain thus including the EEG and MEG results. The implication of preliminary MEG results presented here for the temporality arising in the interaction between the coupled neural modules in a working memory paradigm is discussed in terms of the previously developed neural network models arising from the PET and fMRI data.     

NR2B subunit in the prefrontal cortex: A double-edged sword for working memory function and psychiatric disorders

The prefrontal cortex (PFC) is a brain region featured with working memory function. The exact mechanism of how working memory operates within the PFC circuitry is unknown, but persistent neuronal firing recorded from prefrontal neurons during a working memory task is proposed to be the neural correlate of this mnemonic encoding. The PFC appears to be specialized for sustaining persistent firing, with N-methyl-d-aspartate (NMDA) receptors, especially slow-decay NR2B subunits, playing an essential role in the maintenance of sustained activity and normal working memory function. However, the NR2B subunit serves as a double-edged sword for PFC function. Because of its slow kinetics, NR2B endows the PFC with not only “neural psychic” properties, but also susceptibilities for neuroexcitotoxicity and psychiatric disorders. This review aims to clarify the interplay among working memory, the PFC, and NMDA receptors; demonstrate the importance of NR2B in the maintenance of persistent activity; understand the risks and vulnerabilities of how NR2B is related to the development of neuropsychiatric disorders; identify gaps that currently exist in our understanding of these processes; and provide insights regarding future directions that may clarify these issues. We conclude that the PFC is a specialized brain region with distinct delayed maturation, unique neuronal circuitry, and characteristic NMDA receptor function. The unique properties and development of NMDA receptors, especially enrichment of NR2B subunits, endow the PFC with not only the capability to generate sustained activity for working memory, but also serves as a major vulnerability to environmental insults and risk factors for psychiatric disorders.     

Neural correlates of recognition memory of social information in people with schizophrenia

Background

Social dysfunction is a hallmark characteristic of schizophrenia. Part of it may stem from an inability to efficiently encode social information into memory and retrieve it later. This study focused on whether patients with schizophrenia show a memory boost for socially relevant information and engage the same neural network as controls when processing social stimuli that were previously encoded into memory.

Methods

Patients with schizophrenia and healthy controls performed a social and nonsocial picture recognition memory task while being scanned. We calculated memory performance using d′. Our main analysis focused on brain activity associated with recognition memory of social and nonsocial pictures.

Results

Our study included 28 patients with schizophrenia and 26 controls. Healthy controls demonstrated a memory boost for socially relevant information. In contrast, patients with schizophrenia failed to show enhanced recognition sensitivity for social pictures. At the neural level, patients did not engage the dorsomedial prefrontal cortex (DMPFC) as much as controls while recognizing social pictures.

Limitations

Our study did not include direct measures of self-referential processing. All but 3 patients were taking antipsychotic medications, which may have altered both the behavioural performance during the picture recognition memory task and brain activity.

Conclusion

Impaired social memory in patients with schizophrenia may be associated with altered DMPFC activity. A reduction of DMPFC activity may reflect less involvement of self-referential processes during memory retrieval. Our functional MRI results contribute to a better mapping of the neural disturbances associated with social memory impairment in patients with schizophrenia and may facilitate the development of innovative treatments, such as transcranial magnetic stimulation.     

The neuroscience of persuasion: A review with an emphasis on issues and opportunities

Persuasion, a prevalent form of social influence in humans, refers to an active attempt to change a person’s attitudes, beliefs, or behavior. There is a growing literature on the neural correlates of persuasion. As is often the case in an emerging literature, however, there are a number of questions, concerns, and alternative interpretations that can be raised about the research and interpretations. We provide a critical review of the research, noting potential problems and issues that warrant attention to move the field forward. Among the recommendations are greater integration of neuroimaging approaches with existing behavioral theories and methods on the information processes (cognitive and affective) underlying persuasion, and moving beyond solely correlative approaches for specifying underlying neural mechanisms. Work in this area has the potential to contribute to our understanding of brain–behavior relationships as well as to advance our understanding of persuasion and social influence more generally.     

Ontogenetic Ritualization of Primate Gesture as a Case Study in Dyadic Brain Modeling

This paper introduces dyadic brain modeling – the simultaneous, computational modeling of the brains of two interacting agents – to explore ways in which our understanding of macaque brain circuitry can ground new models of brain mechanisms involved in ape interaction. Specifically, we assess a range of data on gestural communication of great apes as the basis for developing an account of the interactions of two primates engaged in ontogenetic ritualization, a proposed learning mechanism through which a functional action may become a communicative gesture over repeated interactions between two individuals (the ‘dyad’). The integration of behavioral, neural, and computational data in dyadic (or, more generally, social) brain modeling has broad application to comparative and evolutionary questions, particularly for the evolutionary origins of cognition and language in the human lineage. We relate this work to the neuroinformatics challenges of integrating and sharing data to support collaboration between primatologists, neuroscientists and modelers that will help speed the emergence of what may be called comparative neuro-primatology.     

Conceptual and methodological challenges for neuroimaging studies of autistic spectrum disorders

Autistic Spectrum Disorders (ASDs) are a set of complex developmental disabilities defined by impairment in social interaction and communication, as well as by restricted interests or repetitive behaviors. Neuroimaging studies have substantially advanced our understanding of the neural mechanisms that underlie the core symptoms of ASDs. Nevertheless, a number of challenges still remain in the application of neuroimaging techniques to the study of ASDs. We review three major conceptual and methodological challenges that complicate the interpretation of findings from neuroimaging studies in ASDs, and that future imaging studies should address through improved designs. These include: (1) identification and implementation of tasks that more specifically target the neural processes of interest, while avoiding the confusion that the symptoms of ASD may impose on both the performance of the task and the detection of brain activations; (2) the inconsistency that disease heterogeneity in persons with ASD can generate on research findings, particularly heterogeneity of symptoms, symptom severity, differences in IQ, total brain volume, and psychiatric comorbidity; and (3) the problems with interpretation of findings from cross-sectional studies of persons with ASD across differing age groups. Failure to address these challenges will continue to hinder our ability to distinguish findings that outline the causes of ASDs from brain processes that represent downstream or compensatory responses to the presence of the disease. Here we propose strategies to address these issues: 1) the use of simple and elementary tasks, that are easier to understand for autistic subjects; 2) the scanning of a more homogenous group of persons with ASDs, preferably at younger age; 3) the performance of longitudinal studies, that may provide more straight forward and reliable results. We believe that this would allow for a better understanding of both the central pathogenic processes and the compensatory responses in the brain of persons suffering from ASDs.     

Age-related memory decline: current concepts and future directions

The effect of age on memory and the brain has been the focus of many studies. Results have identified critical questions that need to be addressed to further our understanding of age-related memory decline: Is cognitive decline diffuse or selective? Where does memory decline localize to anatomically? Does decline represent an abnormal state? What are the causes of memory decline? What level of analysis is needed to investigate age-related cortical changes? These questions are reviewed herein, and attempts at early answers are discussed.     

Functional network estimation using multigraph learning with application to brain maturation study

Although most dramatic structural changes occur in the perinatal period, a growing body of evidences demonstrates that adolescence and early adulthood are also important for substantial neurodevelopment. We were thus motivated to explore brain development during puberty by evaluating functional connectivity network (FCN) differences between childhood and young adulthood using multi‐paradigm task‐based functional magnetic resonance imaging (fMRI) measurements. Different from conventional multigraph based FCN construction methods where the graph network was built independently for each modality/paradigm, we proposed a multigraph learning model in this work. It promises a better fitting to FCN construction by jointly estimating brain network from multi‐paradigm fMRI time series, which may share common graph structures. To investigate the hub regions of the brain, we further conducted graph Fourier transform (GFT) to divide the fMRI BOLD time series of a node within the brain network into a range of frequencies. Then we identified the hub regions characterizing brain maturity through eigen‐analysis of the low frequency components, which were believed to represent the organized structures shared by a large population. The proposed method was evaluated using both synthetic and real data, which demonstrated its effectiveness in extracting informative brain connectivity patterns. We detected 14 hub regions from the child group and 12 hub regions from the young adult group. We show the significance of these findings with a discussion of their functions and activation patterns as a function of age. In summary, our proposed method can extract brain connectivity network more accurately by considering the latent common structures between different fMRI paradigms, which are significant for both understanding brain development and recognizing population groups of different ages.