The birth of a memory

Laying down new memories has long been thought to involve interactions between the hippocampus and multiple regions of the neocortex. Functional neuroimaging studies performed over the past four years provide evidence for this proposal. A recent electrophysiological study offers a possible mechanism by which interactions between brain regions take place during memory formation.     

Predictive, interactive multiple memory systems

Most lesion studies in animals, and neuropsychological and functional neuroimaging studies in humans, have focused on finding dissociations between the functions of different brain regions, for example in relation to different types of memory. While some of these dissociations can be questioned, particularly in the case of neuroimaging data, we start by assuming a "modal model" in which at least three different memory systems are distinguished: an episodic system (which stores associations between items and spatial/temporal contexts, and which is supported primarily by the hippocampus); a semantic system (which extracts combinations of perceptual features that define items, and which is supported primarily by anterior temporal cortex); and modality-specific perceptual systems (which represent the sensory features extracted from a stimulus, and which are supported by higher sensory cortices). In most situations however, behavior is determined by interactions between these systems. These interactions reflect the flow of information in both "forward" and "backward" directions between memory systems, where backward connections transmit predictions about the current item/features based on the current context/item. Importantly, it is the resulting "prediction error"--the difference between these predictions and the forward transmission of sensory evidence--that drives memory encoding and retrieval. We describe how this "predictive interactive multiple memory systems" (PIMMS) framework can be applied to human neuroimaging data acquired during encoding or retrieval phases of the recognition memory paradigm. Our novel emphasis is thus on associations rather than dissociations between activity measured in key brain regions; in particular, we propose that measuring the functional coupling between brain regions will help understand how these memory systems interact to guide behavior.     

Limbic structures and networks in children and adolescents with schizophrenia

Studies of adults with schizophrenia provide converging evidence for abnormalities in the limbic system. Limbic structures that show consistent patient/control differences in both postmortem and neuroimaging studies include the anterior cingulate and hippocampus, although differences in the amygdala, parahippocampal gyrus, and fornix have also been observed. Studies of white matter in children and adolescents with schizophrenia tend to show findings that are more focal than those seen in adults. Interestingly, these focal abnormalities in early-onset schizophrenia tend to be more localized to limbic regions. While it is unclear if these early limbic abnormalities are primary in the etiology of schizophrenia, there is evidence that supports a developmental progression with early limbic abnormalities evolving over time to match the neuroimaging profiles seen in adults with schizophrenia. Alternatively, the aberrations in limbic structures may be secondary to a more widespread or global pathological processes occurring with the brain that disrupt neural transmission. The goal of this article is to provide a review of the limbic system and limbic network abnormalities reported in children and adolescents with schizophrenia. These findings are compared with the adult literature and placed within a developmental context. These observations from neuroimaging studies enrich our current understanding of the neurodevelopmental model of schizophrenia and raise further questions about primary vs secondary processes. Additional research within a developmental framework is necessary to determine the putative etiologic roles for limbic and other brain abnormalities in early-onset schizophrenia.     

Sex differences in the responses of the human amygdala.

The amygdala is a structure in the temporal lobe that has long been known to play a key role in emotional responses and emotional memory in both humans and nonhuman animals. Growing evidence from recent neuroimaging studies points to a new, expanded role for the amygdala as a critical structure that mediates sex differences in emotional memory and sexual responses. This review highlights current findings from studies of sex differences in human amygdala response during emotion-related activities, such as formation of emotional memories and sexual behavior, and considers how these findings contribute to the understanding of behavioral differences between men and women. Clinical implications for the understanding of sex differences in the prevalence of affective and anxiety disorders are discussed, and future directions in the study of the amygdala's role in human sex differences are outlined.     

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.     

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.     

How and where: Theory-of-mind in the brain

Theory of mind (ToM) is a core topic in both social neuroscience and developmental psychology, yet theory and data from each field have only minimally constrained thinking in the other. The two fields might be fruitfully integrated, however, if social neuroscientists sought evidence directly relevant to current accounts of ToM development: modularity, simulation, executive, and theory theory accounts. Here we extend the distinct predictions made by each theory to the neural level, describe neuroimaging evidence that in principle would be relevant to testing each account, and discuss such evidence where it exists. We propose that it would be mutually beneficial for both fields if ToM neuroimaging studies focused more on integrating developmental accounts of ToM acquisition with neuroimaging approaches, and suggest ways this might be achieved.     

Considerations for imaging the adolescent brain

In recent years the number of functional neuroimaging studies on adolescence has exploded. These studies have led to important new insights about the relation between functional brain development and behavior. However, special consideration is warranted when working with adolescents. In this review, we review variables, including pubertal stage, sleep patterns and pregnancy, which are particularly relevant for developmental cognitive neuroscience studies involving adolescents. Consideration of the unique challenges associated with adolescence will help the growing field of developmental neuroimaging standardize procedures and will eventually facilitate interpretation across studies.     

Genetic influences on brain developmental trajectories on neuroimaging studies: from infancy to young adulthood

Human brain development has been studied intensively with neuroimaging. However, little is known about how genes influence developmental brain trajectories, even though a significant number of genes (about 10,000, or approximately one-third) in the human genome are expressed primarily in the brain and during brain development. Interestingly, in addition to showing differential expression among tissues, many genes are differentially expressed across the ages (e.g., antagonistic pleiotropy). Age-specific gene expression plays an important role in several critical events in brain development, including neuronal cell migration, synaptogenesis and neurotransmitter receptor specificity, as well as in aging and neurodegenerative disorders (e.g., Alzheimer disease or amyotrophic lateral sclerosis). In addition, the majority of psychiatric and mental disorders are polygenic, and many have onsets during childhood and adolescence. In this review, we summarize the major findings from neuroimaging studies that link genetics with brain development, from infancy to young adulthood. Specifically, we focus on the heritability of brain structures across the ages, age-related genetic influences on brain development and sex-specific developmental trajectories.     

Neuroimaging studies of normal brain development and their relevance for understanding childhood neuropsychiatric disorders

ObjectiveTo review the maturational events that occur during prenatal and postnatal brain development and to present neuroimaging findings from studies of healthy individuals that identify the trajectories of normal brain development.MethodHistological and postmortem findings of early brain development are presented, followed by a discussion of anatomical, diffusion tensor, proton spectroscopy, and functional imaging findings from studies of healthy individuals, with special emphasis on longitudinal data.ResultsEarly brain development occurs through a sequence of major events, beginning with the formation of the neural tube and ending with myelination. Brain development at a macroscopic level typically proceeds first in sensorimotor areas, spreading subsequently and progressively into dorsal and parietal, superior temporal, and dorsolateral prefrontal cortices throughout later childhood and adolescence. These patterns of anatomical development parallel increasing activity in frontal cortices that subserves the development of higher-order cognitive functions during late childhood and adolescence. Disturbances in these developmental patterns seem to be involved centrally in the pathogenesis of various childhood psychiatric disorders including childhood-onset schizophrenia, attention-deficit/hyperactivity disorder, developmental dyslexia, Tourette's syndrome, and bipolar disorder.ConclusionsAdvances in imaging techniques have enhanced our understanding of normal developmental trajectories in the brain, which may improve insight into the abnormal patterns of development in various childhood psychiatric disorders.     

Understanding gut–brain interactions in gastrointestinal pain by neuroimaging: lessons from somatic pain studies

Background Neuroimaging research on gut–brain interactions has greatly improved our understanding of the brain mechanisms involved in processing and perceiving visceral pain in health and functional gastrointestinal disorders (FGID). However, discrepancies in the results of these studies continue to exist, which is at least partially due to the fact that important factors contributing to the intrinsic heterogeneity of symptom‐based FGID, including psychological processes and psychiatric comorbidity, are insufficiently integrated in visceral pain neuroimaging research. Purpose This review will defend the thesis that, to increase our understanding of the heterogeneous etiopathogenesis of FGID, visceral pain neuroimaging studies need to be integrated with: (i) epidemiological and behavioral evidence on the influence of psychological processes on visceral pain in health and FGID, and (ii) methodology and evidence from affective, cognitive, and psychiatric neuroimaging studies. To illustrate this point, the somatic pain neuroimaging field will be taken as an example before giving an overview of novel and integrative visceral pain studies in health and FGID. Some limitations of current pain neuroimaging studies will be outlined, before providing a summary of suggestions for moving the visceral pain neuroimaging field forward.     

A role for sleep in brain plasticity

The idea that sleep might be involved in brain plasticity has been investigated for many years through a large number of animal and human studies, but evidence remains fragmentary. Large amounts of sleep in early life suggest that sleep may play a role in brain maturation. In particular, the influence of sleep in developing the visual system has been highlighted. The current data suggest that both Rapid Eye Movement (REM) and non-REM sleep states would be important for brain development. Such findings stress the need for optimal paediatric sleep management. In the adult brain, the role of sleep in learning and memory is emphasized by studies at behavioural, systems, cellular and molecular levels. First, sleep amounts are reported to increase following a learning task and sleep deprivation impairs task acquisition and consolidation. At the systems level, neurophysiological studies suggest possible mechanisms for the consolidation of memory traces. These imply both thalamocortical and hippocampo-neocortical networks. Similarly, neuroimaging techniques demonstrated the experience-dependent changes in cerebral activity during sleep. Finally, recent works show the modulation during sleep of cerebral protein synthesis and expression of genes involved in neuronal plasticity.     

What can emerging cortical face networks tell us about mature brain organisation?

This opinion paper suggests that developmental neuroimaging studies investigating emerging cortical networks for specific cognitive functions can contribute substantially to our understanding of mature brain organisation. Based on a review of the literature on the neural correlates of face processing abilities, this paper shows how developmental neuroimaging can help resolve outstanding issues, such as whether specific brain regions actually start out by responding to specific stimulus classes, and how this response changes with development. It has been suggested for example, that improving specialisation in a particular brain regions may be the result of increasing connectivity with other network regions supporting the same cognitive function. Developmental neuroimaging studies are particularly well suited to disentangle the interplay between changes at different network levels, such as improving behavioural proficiencies and functional and structural brain development, as well as overall network configuration changes. However, much of the future progress will depend on whether developmental changes are assessed by combining multiple network observations. This paper makes specific suggestions as to how such a multifaceted approach may look like by exploring the suitability of different theoretical frameworks, such as the neural re-use theory or the neuroconstructivist approach for providing guiding principles for future research.     

Neuroimaging in developmental disorders

PURPOSE OF REVIEW: This review considers the role of neuroimaging in developmental disorders by highlighting recent studies in two distinct, but overlapping, developmental disorders: autism and fragile X syndrome. RECENT FINDINGS: After a decade of conflicting results in neuroimaging studies of autism, recent studies have provided some convergent data. One well-replicated finding is that autistic subjects have larger brains. Further, this enlargement, present as early as 3 years of age, appears to represent accelerated growth in infancy and may be followed by slowed growth in late childhood. Other findings are discussed but considered preliminary in the absence of converging evidence or replication studies. Recent work in fragile X syndrome suggests aberrant fronto-striatal and fronto-parietal networks and relates these abnormalities "forward" to behavior and "backward" to decreased protein expression. SUMMARY: As the field of neuroimaging has matured, it has revealed its promise as a safe, reliable, in-vivo tool in the study of developmental disorders. By insisting on larger, more homogeneous patient groups and longitudinal rather than cross-sectional studies, the field is poised to fulfill its ultimate role of linking defects in molecular biology to aberrant behavior.     

Contribution of noninvasive cortical stimulation to the study of memory functions

In the memory domain, a large body of experimental evidence about subsystems of memory has been collected from classic lesion studies and functional brain imaging. Animal studies have provided information on molecular mechanisms of memory formation. Compared to this work, transcranial magnetic stimulation and transcranial direct current stimulation have made their own unique contribution. Here, we describe how noninvasive brain stimulation has been used to study the functional contribution of specific cortical areas during a given memory task, how these techniques can be used to assess LTP- and LTD-like plasticity in the living human brain, and how they can be employed to modulate memory formation in humans, suggesting an adjuvant role in neurorehabilitative treatments following brain injury.     

Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited

Obsessive-compulsive disorder (OCD) is a common, heritable and disabling neuropsychiatric disorder. Theoretical models suggest that OCD is underpinned by functional and structural abnormalities in orbitofronto-striatal circuits. Evidence from cognitive and neuroimaging studies (functional and structural magnetic resonance imaging (MRI) and positron emission tomography (PET)) have generally been taken to be supportive of these theoretical models; however, results from these studies have not been entirely congruent with each other. With the advent of whole brain-based structural imaging techniques, such as voxel-based morphometry and multivoxel analyses, we consider it timely to assess neuroimaging findings to date, and to examine their compatibility with cognitive studies and orbitofronto-striatal models. As part of this assessment, we performed a quantitative, voxel-level meta-analysis of functional MRI findings, which revealed consistent abnormalities in orbitofronto-striatal and other additional areas in OCD. This review also considers the evidence for involvement of other brain areas outside orbitofronto-striatal regions in OCD, the limitations of current imaging techniques, and how future developments in imaging may aid our understanding of OCD.     

Development of a superior frontal-intraparietal network for visuo-spatial working memory

Working memory capacity increases throughout childhood and adolescence, which is important for the development of a wide range of cognitive abilities, including complex reasoning. The spatial-span task, in which subjects retain information about the order and position of a number of objects, is a sensitive task to measure development of spatial working memory. This review considers results from previous neuroimaging studies investigating the neural correlates of this development. Older children and adolescents, with higher capacity, have been found to have higher brain activity in the intraparietal cortex and in the posterior part of the superior frontal sulcus, during the performance of working memory tasks. The structural maturation of white matter has been investigated by diffusion tensor magnetic resonance imaging (DTI). This has revealed several regions in the frontal lobes in which white matter maturation is correlated with the development of working memory. Among these is a superior fronto-parietal white matter region, located close to the grey matter regions that are implicated in the development of working memory. Furthermore, the degree of white matter maturation is positively correlated with the degree of cortical activation in the frontal and parietal regions. This suggests that during childhood and adolescence, there is development of networks related to specific cognitive functions, such as visuo-spatial working memory. These networks not only consist of cortical areas but also the white matter tracts connecting them. For visuo-spatial working memory, this network could consist of the superior frontal and intraparietal cortex.     

Memory formation, amnesia, improved memory and reversed amnesia: 5-HT role

Traditionally, the search for memory circuits has been focused on examinations of amnesic and AD patients, cerebral lesions and neuroimaging. A complementary alternative has become the use of autoradiography with radioligands, aiming to identify neurobiological markers associated with memory formation, amnesia states and (more recently) recovery from memory deficits. Indeed, ex vivo autoradiographic studies offer the advantage of detecting functionally active receptors altered by pharmacological tools during memory formation, amnesia states and memory recovery. Moreover, serotonin (5-hydroxytryptamine, 5-HT) systems have become a pharmacological and genetic target in the treatment of memory disorders. Herein evidence from studies involving expression of 5-HT(1A), 5-HT(2A), 5-HT(4), and 5-HT(6) receptors in memory formation, amnesia conditions (e.g., pharmacological models or aging) and recovery of memory is reviewed. Thus, specific 5-HT receptors were expressed in trained animals relative to untrained in brain areas such as cortex, hippocampus and amygdala. However, relative to the control group, rats showing amnesia or recovered memory, showed in the hippocampus, region where explicit memory is formed, a complex pattern of 5-HT receptor expression. An intermediate expression occurred in amygdala, septum and some cortical areas in charge of explicit memory storage. Even in brain areas thought to be in charge of procedural memory such as basal ganglia, animals showing recovered memory displayed an intermediate expression, while amnesic groups, depending on the pharmacological amnesia model, showed up- or down-regulation. In conclusion, evidence indicates that autoradiography, by using specific radioligands, offers excellent opportunities to map dynamic changes in brain areas engaged in these cognitive processes. The 5-HT modulatory role strengthens or suppresses memory is critically depend on the timing of the memory formation.     

Growing up with bilateral hippocampal atrophy: from childhood to teenage

The respective roles of the medial temporal lobe (MTL) structures in memory are controversial. Some authors put forward a modular account according to which episodic memory and recollection-based processes are crucially dependent on the hippocampal formation whereas semantic acquisition and familiarity-based processes rely on the adjacent parahippocampal gyri. Others defend a unitary view.We report the case of VJ, a boy with developmental amnesia of most likely perinatal onset diagnosed at the age of 8. Magnetic resonance imaging (MRI), including quantitative volumetric measurements of the hippocampal formation and of the entorhinal, perirhinal, and temporopolar cortices, showed severe, bilateral atrophy of the hippocampal formation, fornix and mammillary bodies; by contrast, the perirhinal cortex was within normal range and the entorhinal and temporopolar cortex remained within two standard deviations (SDs) from controls’ mean. We examined the development of his semantic knowledge from childhood to teenage as well as his recognition and cued recall memory abilities. On tasks tapping semantic memory, VJ increased his raw scores across years at the same rate as children from large standardisation samples, except for one task; he achieved average performance, consistent with his socio-educational background. He performed within normal range on 74% of recognition tests and achieved average to above average scores on 42% of them despite very severe impairment on 82% of episodic recall tasks. Both faces and landscapes-scenes gave rise to above average scores when tested with coloured stimuli. Cued recall, although impaired, was largely superior to free recall.This case supports a modular account of the MTL with episodic, but not semantic memory depending on the hippocampal formation. Furthermore, the overall pattern of findings is consistent with evidence from both brain-damaged and neuroimaging studies indicating that recollection requires intact hippocampal formation and familiarity relies, at least partly, on the adjacent temporal lobe cortex.     

Review of structural neuroimaging in patients with refractory obsessivecompulsive disorder

The notion that some special brain regions may be involved in the pathogenesis of obsessive-compulsive disorder (OCD) dates back to the beginning of the twentieth century. Structural neuroimaging studies in the past 2 decades have revealed important findings that facilitate understanding of OCD pathogenesis. Current knowledge based on functional and structural neuroimaging investigations largely emphasizes abnormalities in fronto-striatal-thalamic-cortical and orbitofronto-striato-thalamic circuits in the pathophysiology of OCD. However, these neuroimaging studies did not focus on refractory OCD. The present review mainly focused on structural neuroimaging performed in OCD, which had been ignored previously, and highlighted current evidence supporting that orbito-frontal cortex and thalamus are key brain regions, and that the hippocampus-amygdala complex is associated with refractoriness to the available treatment strategies. However, to fully reveal the neuroanatomy of refractoriness, longitudinal studies with larger samples are required.