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1.  Memory: from the laboratory to everyday life 
One of the key goals of memory research is to develop a basic understanding of the nature and characteristics of memory processes and systems. Another important goal is to develop useful applications of basic research to everyday life. This editorial considers two lines of work that illustrate some of the prospects for applying memory research to everyday life: interpolated quizzing to enhance learning in educational settings, and specificity training to enhance memory and associated functions in individuals who have difficulties remembering details of their past experiences.
PMCID: PMC3898677  PMID: 24459406
memory; memory specificity; episodic simulation; neuroimaging; online learning; interpolated testing; mind wandering
2.  Memory in health and in schizophrenia 
Memory is an important capacity needed for survival in a changing environment, and its principles are shared across species. These principles have been studied since the inception of behavioral science, and more recently neuroscience has helped understand brain systems and mechanisms responsible for enabling aspects of memory. Here we outline the history of work on memory and its neural underpinning, and describe the major dimensions of memory processing that have been evaluated by cognitive neuroscience, focusing on episodic memory. We present evidence in healthy populations for sex differences—females outperforming in verbal and face memory, and age effects—slowed memory processes with age. We then describe deficits associated with schizophrenia. Impairment in schizophrenia is more severe in patients with negative symptoms—especially flat affect—who also show deficits in measures of social cognition. This evidence implicates medial temporal and frontal regions in schizophrenia.
PMCID: PMC3898678  PMID: 24459407
episodic memory; schizophrenia; neurocognition; development; sex difference; aging
3.  The “working” of working memory 
This review examines the evidence for a neurobiological explanation of executive functions of working memory. We suggest that executive control stems from information about task rules acquired by mixed selective, adaptive coding, multifunctional neurons in the prefrontal cortex. The output of these neurons dynamically links the cortex-wide networks needed to complete the task. The linking may occur via synchronizing of neural rhythms, which may explain why we have a limited capacity for simultaneous thought.
PMCID: PMC3898679  PMID: 24459408
basal ganglia; cognition; executive function; oscillation; prefrontal cortex; synchrony; working memory
4.  A neurobiological approach to the cognitive deficits of psychiatric disorders 
Deficits in brain networks that support cognitive regulatory functions are prevalent in many psychiatric disorders. Findings across neuropsychology and neuroimaging point to broad-based impairments that cross traditional diagnostic boundaries. These dysfunctions are largely separate from the classical symptoms of the disorders, and manifest in regulatory problems in both traditional cognitive and emotional domains. As such, they relate to the capacity of patients to engage effectively in their daily lives and activity, often persist even in the face of symptomatically effective treatment, and are poorly targeted by current treatments. Advances in cognitive neuroscience now allow us to ground an understanding of these cognitive regulatory deficits in the function and interaction of key brain networks. This emerging neurobiological understanding furthermore points to several promising routes for novel neuroscience-informed treatments targeted more specifically at improving cognitive function in a range of psychiatric disorders.
PMCID: PMC3898680  PMID: 24459409
amygdala; anxiety; bipolar; cingulate; default mode; depression; emotion regulation; executive function; prefrontal; schizophrenia
5.  Cellular basis of memory for addiction 
Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. Here, we review the types of molecular and cellular adaptations that occur in specific brain regions to mediate addiction-associated behavioral abnormalities. These include alterations in gene expression achieved in part via epigenetic mechanisms, plasticity in the neurophysiological functioning of neurons and synapses, and associated plasticity in neuronal and synaptic morphology mediated in part by altered neurotrophic factor signaling. Each of these types of drug-induced modifications can be viewed as a form of “cellular or molecular memory.” Moreover, it is striking that most addiction-related forms of plasticity are very similar to the types of plasticity that have been associated with more classic forms of “behavioral memory,” perhaps reflecting the finite repertoire of adaptive mechanisms available to neurons when faced with environmental challenges. Finally, addiction-related molecular and cellular adaptations involve most of the same brain regions that mediate more classic forms of memory, consistent with the view that abnormal memories are important drivers of addiction syndromes. The goal of these studies which aim to explicate the molecular and cellular basis of drug addiction is to eventually develop biologically based diagnostic tests, as well as more effective treatments for addiction disorders.
PMCID: PMC3898681  PMID: 24459410
gene transcription; epigenetics; CREB; ΔFosB; synaptic plasticity; whole cell plasticity; nucleus accumbens; ventral tegmental area; dendritic spines
6.  Memory loss in Alzheimer's disease 
Loss of memory is among the first symptoms reported by patients suffering from Alzheimer's disease (AD) and by their caretakers. Working memory and long-term declarative memory are affected early during the course of the disease. The individual pattern of impaired memory functions correlates with parameters of structural or functional brain integrity. AD pathology interferes with the formation of memories from the molecular level to the framework of neural networks. The investigation of AD memory loss helps to identify the involved neural structures, such as the default mode network, the influence of epigenetic and genetic factors, such as ApoE4 status, and evolutionary aspects of human cognition. Clinically, the analysis of memory assists the definition of AD subtypes, disease grading, and prognostic predictions. Despite new AD criteria that allow the earlier diagnosis of the disease by inclusion of biomarkers derived from cerebrospinal fluid or hippocampal volume analysis, neuropsychological testing remains at the core of AD diagnosis.
PMCID: PMC3898682  PMID: 24459411
memory; Alzheimer's disease; neuropsychological test; brain atrophy; default mode network
7.  Disorders of memory and plasticity in psychiatric disease 
Plasticity is found throughout the nervous system and is thought to underlie key aspects of development, learning and memory, and repair. Neuropiastic processes include synaptic plasticity, cellular growth and remodeling, and neurogenesis. Dysregulation of these processes can contribute to a variety of neuropsychiatric diseases. In this review we explore three different ways in which dysregulation of neuropiastic and mnemonic processes can contribute to psychiatric illness. First, impairment of the mechanisms of plasticity can lead to cognitive deficits; this is most obvious in dementia and amnesia, but is also seen in more subtle forms in other conditions. We explore the relationship between stress, major depression, and impaired neuroplasticity in some detail. Second, enhanced memories can be pathogenic; we explore the example of post-traumatic stress disorder, in which intrusive trauma associated memories, accompanied by hyperactivity of the normal fear learning circuitry, are core aspects of the pathology. Third, impaired modulation of the relationship between parallel memory systems can contribute to maladaptive patterns of behavior; we explore the bias towards inflexible, habit-like behavior patterns in drug addiction and obsessive-compulsive disorder. Together, these examples illustrate how different abnormalities in the mechanisms of neuroplasticity and memory formation can contribute to various forms of psychopathology. It is hoped that a growing understanding of these relationships, and of the fundamental mechanisms underlying neuroplasticity in the normal brain, will pave the way for new understandings of the mechanisms of neuropsychiatric disease and the development of novel treatment strategies.
PMCID: PMC3898683  PMID: 24459412
plasticity; LTP; neurogenesis; memory; major depressive disorder; stress; post-traumatic stress disorder; multiple memory systems; drug addiction; obsessive-compulsive disorder
8.  Non-Alzheimer's disease—related memory impairment and dementia 
Although Alzheimer's disease (AD) is a common cause of memory impairment and dementia in the elderly disturbed memory function is a widespread subjective and/or objective symptom in a variety of medical conditions. The early detection and correct distinction of AD from non-AD memory impairment is critically important to detect possibly treatable and reversible underlying causes. In the context of clinical research, it is crucial to correctly distinguish between AD or non-AD memory impairment in order to build homogenous study populations for the assessment of new therapeutic possibilities. The distinction of AD from non-AD memory impairment may be difficult, especially in mildly affected patients, due to an overlap of clinical symptoms and biomarker alterations between AD and certain non-AD conditions. This review aims to describe recent aspects of the differential diagnosis of AD and non-AD related memory impairment and how these may be considered in the presence of memory deficits.
PMCID: PMC3898684  PMID: 24459413
Alzheimer's disease; Lewy body dementia; frontotemporal dementia; depression; differential diagnosis; biomarker
9.  Memory as a new therapeutic target 
This review aims to demonstrate how an understanding of the brain mechanisms involved in memory provides a basis for; (i) reconceptualizing some mental disorders; (ii) refining existing therapeutic tools; and (iii) designing new ones for targeting processes that maintain these disorders. First, some of the stages which a memory undergoes are defined, and the clinical relevance of an understanding of memory processing by the brain is discussed. This is followed by a brief review of some of the clinical studies that have targeted memory processes. Finally, some new insights provided by the field of neuroscience with implications for conceptualizing mental disorders are presented.
PMCID: PMC3898685  PMID: 24459414
memory; reconsolidation; forgetting; psychotherapy
10.  Imaging autobiographical memory 
Autobiographical memory (AM) defines the memory systems that encode, consolidate, and retrieve personal events and facts, AM is strongly related to self-perception and self representation. We review here the neural correlates of AM retrieval. AM retrieval encompasses a large neural network including the prefrontal, temporal, and parietal cortex, and limbic structures. All these regions subserve the cognitive processes (episodic remembering, cognitive control, self-processing, and scene construction) at play during memory retrieval. We emphasize the specific role of medial prefrontal cortex and precuneus in self-processing during autobiographical memory retrieval. Overall, these data call for further studies in psychiatric patients, to investigate the neural underpinnings of autobiographical memory and self-representation in mental disorders.
PMCID: PMC3898686  PMID: 24459415
autobiographical memory; medial prefrontal cortex; precuneus; retrieval; self
11.  BRAIN: innovative neurotechnologies for imaging and therapeutics  
Conceived with the aim of meeting the needs of the neurobiology and clinical communities, the Brain Research through Advancing Innovative Technologies (BRAIN) Initiative builds on the lessons learned from major projects in genetics, such as the Human Genome Project. It concentrates on the use of new imaging technologies in conjunction with genomics to inform therapeutic decisions.
PMCID: PMC3811097  PMID: 24174897
BRAIN Initiative; imaging; Genome Project; genomics
12.  Structure and function of complex brain networks 
An increasing number of theoretical and empirical studies approach the function of the human brain from a network perspective. The analysis of brain networks is made feasible by the development of new imaging acquisition methods as well as new tools from graph theory and dynamical systems. This review surveys some of these methodological advances and summarizes recent findings on the architecture of structural and functional brain networks. Studies of the structural connectome reveal several modules or network communities that are interlinked by hub regions mediating communication processes between modules. Recent network analyses have shown that network hubs form a densely linked collective called a “rich club,” centrally positioned for attracting and dispersing signal traffic. In parallel, recordings of resting and task-evoked neural activity have revealed distinct resting-state networks that contribute to functions in distinct cognitive domains. Network methods are increasingly applied in a clinical context, and their promise for elucidating neural substrates of brain and mental disorders is discussed.
PMCID: PMC3811098  PMID: 24174898
neuroimaging; connectome; graph theory; resting state; diffusion imaging; tractography; functional MRI
13.  Animal models and high field imaging and spectroscopy 
A plethora of magnetic resonance (MR) techniques developed in the last two decades provide unique and noninvasive measurement capabilities for studies of basic brain function and brain diseases in humans. Animal model experiments have been an indispensible part of this development. MR imaging and spectroscopy measurements have been employed in animal models, either by themselves or in combination with complementary and often invasive techniques, to enlighten us about the information content of such MR methods and/or verify observations made in the human brain. They have also been employed, with or independently of human efforts, to examine mechanisms underlying pathological developments in the brain, exploiting the wealth of animal models available for such studies. In this endeavor, the desire to push for ever-higher spatial and/or spectral resolution, better signal-to-noise ratio, and unique image contrast has inevitably led to the introduction of increasingly higher magnetic fields. As a result, today, animal model studies are starting to be conducted at magnetic fields ranging from ~ 11 to 17 Tesla, significantly enhancing the armamentarium of tools available for the probing brain function and brain pathologies.
PMCID: PMC3811099  PMID: 24174899
functional imaging; brain function; spectroscopy; neurometabolism
14.  Functional neuroimaging and schizophrenia: a view towards effective connectivity modeling and polygenic risk 
We review critical trends in imaging genetics as applied to schizophrenia research, and then discuss some future directions of the field. A plethora of imaging genetics studies have investigated the impact of genetic variation on brain function, since the paradigm of a neuroimaging intermediate phenotype for schizophrenia first emerged. It was initially posited that the effects of schizophrenia susceptibility genes would be more penetrant at the level of biologically based neuroimaging intermediate phenotypes than at the level of a complex and phenotypically heterogeneous psychiatric syndrome. The results of many studies support this assumption, most of which show single genetic variants to be associated with changes in activity of localized brain regions, as determined by select cognitive controlled tasks. From these basic studies, functional neuroimaging analysis of intermediate phenotypes has progressed to more complex and realistic models of brain dysfunction, incorporating models of functional and effective connectivity, including the modalities of psycho-physiological interaction, dynamic causal modeling, and graph theory metrics. The genetic association approaches applied to imaging genetics have also progressed to more sophisticated multivariate effects, including incorporation of two-way and three-way epistatic interactions, and most recently polygenic risk models. Imaging genetics is a unique and powerful strategy for understanding the neural mechanisms of genetic risk for complex CNS disorders at the human brain level.
PMCID: PMC3811100  PMID: 24174900
schizophrenia; intermediate phenotype; functional neuroimaging; functional connectivity; effective connectivity; polygenic risk score
15.  Brain oscillations in neuropsychiatric disease 
The term “brain (or neural) oscillations” refers to the rhythmic and/or repetitive electrical activity generated spontaneously and in response to stimuli by neural tissue in the central nervous system. The importance of brain oscillations in sensory-cognitive processes has become increasingly evident. It has also become clear that event-related oscillations are modified in many types of neuropathology, in particular in cognitive impairment. This review discusses methods such as evoked/event-related oscillations and spectra, coherence analysis, and phase locking. It gives examples of applications of essential methods and concepts in bipolar disorder that provide a basis for fundamental notions regarding neurophysiologic biomarkers in cognitive impairment. The take-home message is that in the development of diagnostic and pharmacotherapeutic strategies, neurophysiologic data should be analyzed in a framework that uses a multiplicity of methods and frequency bands.
PMCID: PMC3811101  PMID: 24174901
oscillation; bipolar disorder; schizophrenia; alpha; beta; gamma; theta; delta; phase synchrony
16.  High-frequency oscillations and the neurobiology of schizophrenia 
Neural oscillations at low- and high-frequency ranges are a fundamental feature of large-scale networks. Recent evidence has indicated that schizophrenia is associated with abnormal amplitude and synchrony of oscillatory activity, in particular, at high (beta/gamma) frequencies. These abnormalities are observed during task-related and spontaneous neuronal activity which may be important for understanding the pathophysiology of the syndrome. In this paper, we shall review the current evidence for impaired beta/gamma-band oscillations and their involvement in cognitive functions and certain symptoms of the disorder. In the first part, we will provide an update on neural oscillations during normal brain functions and discuss underlying mechanisms. This will be followed by a review of studies that have examined high-frequency oscillatory activity in schizophrenia and discuss evidence that relates abnormalities of oscillatory activity to disturbed excitatory/inhibitory (E/I) balance. Finally, we shall identify critical issues for future research in this area.
PMCID: PMC3811102  PMID: 24174902
oscillations; gamma; synchrony; cognition; schizophrenia; neurobiology
17.  Molecular imaging as a guide for the treatment of central nervous system disorders 
Molecular imaging techniques have a number of advantages for research into the pathophysiology and treatment of central nervous system (CNS) disorders. Firstly, they provide a noninvasive means of characterizing physiological processes in the living brain, enabling molecular alterations to be linked to clinical changes. Secondly, the pathophysiological target in a given CNS disorder can be measured in animal models and in experimental human models in the same way, which enables translational research. Moreover, as molecular imaging facilitates the detection of functional change which precedes gross pathology, it is particularly useful for the early diagnosis and treatment of CNS disorders.
This review considers the application of molecular imaging to CNS disorders focusing on its potential to inform the development and evaluation of treatments. We focus on schizophrenia, Parkinson's disease, depression, and dementia as major CNS disorders. We also review the potential of molecular imaging to guide new drug development for CNS disorders.
PMCID: PMC3811103  PMID: 24174903
molecular imaging; positron emission tomography; single photon emission computed tomography; schizophrenia; depression; Parkinson's disease, dementia
18.  Use of proton magnetic resonance spectroscopy in the treatment of psychiatric disorders: a critical update 
Because of the wide availability of hardware as well as of standardized analytic quantification tools, proton magnetic resonance spectroscopy (1H-MRS) has become widely used to study psychiatric disorders. 1H-MRS allows measurement of brain concentrations of more traditional singlet neurometabolites like N-acetylaspartate, choline, and creatine. More recently, quantification of the more complex multiplet spectra for glutamate, glutamine, inositol, and γ-aminobutyric acid have also been implemented. Here we review applications of 1H-MRS in terms of informing treatment options in schizophrenia, bipolar disorder, and major depressive disorders. We first discuss recent meta-analytic studies reporting the most reliable findings. Then we evaluate the more sparse literature focused on 1H-MRS-detected neurometabolic effects of various treatment approaches in psychiatric populations. Finally we speculate on future developments that may result in translation of these tools to improve the treatment of psychiatric disorders.
PMCID: PMC3811104  PMID: 24174904
schizophrenia; spectroscopy; NAA; glutamate; glutamine
19.  Schizophrenia and abnormal brain network hubs 
Schizophrenia is a heterogeneous psychiatric disorder of unknown cause or characteristic pathology. Clinical neuroscientists increasingly postulate that schizophrenia is a disorder of brain network organization. In this article we discuss the conceptual framework of this dysconnection hypothesis, describe the predominant methodological paradigm for testing this hypothesis, and review recent evidence for disruption of central/hub brain regions, as a promising example of this hypothesis. We summarize studies of brain hubs in large-scale structural and functional brain networks and find strong evidence for network abnormalities of prefrontal hubs, and moderate evidence for network abnormalities of limbic, temporal, and parietal hubs. Future studies are needed to differentiate network dysfunction from previously observed gray- and white-matter abnormalities of these hubs, and to link endogenous network dysfunction phenotypes with perceptual, behavioral, and cognitive clinical phenotypes of schizophrenia.
PMCID: PMC3811105  PMID: 24174905
schizophrenia; neuroimaging; connectome; network; hub
20.  The brain's default network: origins and implications for the study of psychosis 
The brain's default network is a set of regions that is spontaneously active during passive moments. The network is also active during directed tasks that require participants to remember past events or imagine upcoming events. One hypothesis is that the network facilitates construction of mental models (simulations) that can be used adaptively in many contexts. Extensive research has considered whether disruption of the default network may contribute to disease. While an intriguing possibility, a specific challenge to this notion is the fact that it is difficult to accurately measure the default network in patients where confounds of head motion and compliance are prominent. Nonetheless, some intriguing recent findings suggest that dysfunctional interactions between front-oparietal control systems and the default network contribute to psychosis. Psychosis may be a network disturbance that manifests as disordered thought partly because it disrupts the fragile balance between the default network and competing brain systems.
PMCID: PMC3811106  PMID: 24174906
functional MRI; default mode network; resting-state; prospection
21.  Typical and atypical brain development: a review of neuroimaging studies 
In the course of development, the brain undergoes a remarkable process of restructuring as it adapts to the environment and becomes more efficient in processing information. A variety of brain imaging methods can be used to probe how anatomy, connectivity, and function change in the developing brain. Here we review recent discoveries regarding these brain changes in both typically developing individuals and individuals with neurodevelopmental disorders. We begin with typical development, summarizing research on changes in regional brain volume and tissue density, cortical thickness, white matter integrity, and functional connectivity. Space limits preclude the coverage of all neurodevelopmental disorders; instead, we cover a representative selection of studies examining neural correlates of autism, attention deficit/hyperactivity disorder, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Down syndrome, and Turner syndrome. Where possible, we focus on studies that identify an age by diagnosis interaction, suggesting an altered developmental trajectory. The studies we review generally cover the developmental period from infancy to early adulthood. Great progress has been made over the last 20 years in mapping how the brain matures with MR technology. With ever-improving technology, we expect this progress to accelerate, offering a deeper understanding of brain development, and more effective interventions for neurodevelopmental disorders.
PMCID: PMC3811107  PMID: 24174907
development; MRI; DTI; rsfMRI; brain structure; brain connectivity; neurodevelopmental disorder; autism; ADHD; 22q; fragile X; Turner syndrome; Williams syndrome; Down syndrome
22.  Simultaneous EEG and fMRI: towards the characterization of structure and dynamics of brain networks 
Progress in the understanding of normal and disturbed brain function is critically dependent on the methodological approach that is applied. Both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are extremely efficient methods for the assessment of human brain function. The specific appeal of the combination is related to the fact that both methods are complementary in terms of basic aspects: EEG is a direct measurement of neural mass activity and provides high temporal resolution. FMRI is an indirect measurement of neural activity and based on hemodynamic changes, and offers high spatial resolution. Both methods are very sensitive to changes of synaptic activity, suggesting that with simultaneous EEG and fMRI the same neural events can be characterized with both high temporal and spatial resolution. Since neural oscillations that can be assessed with EEG are a key mechanism for multi-site communication in the brain, EEG-fMRI can offer new insights into the connectivity mechanisms of brain networks.
PMCID: PMC3811108  PMID: 24174908
EEG; fMRI; multimodal imaging; neuroimaging; functional magnetic resonance imaging
23.  A perspective on the current issues in the DSM-5 classification of personality disorders 
David Kupfer chaired the DSM-5 Task Force, and Andrew Skodol the working group, on personality disorders. Various initial propositions were posted on the Internet in 2010 for comment and discussion: new general definition, new criteria, new diagnostic procedures, reduction in the number of categories, and dimensional representation. Following numerous criticisms, the Task Force's final decisions were made public on December 1, 2012. Personality disorders now figure alongside other mental disorders, because of the deletion of Axis II. The methodology concerning personality traits is in a third section to promote new studies. The new proposed hybrid system has not, to date, proven better than the categories of the DSM-IV. These various decisions are commented upon.
PMCID: PMC3811084  PMID: 24174887
personality disorder; DSM-5; dimensional model; categorical model; personality functioning; prototype matching approach; hybrid model
24.  Dimensional models of personality: the five-factor model and the DSM-5 
It is evident that the classification of personality disorder is shifting toward a dimensional trait model and, more specifically, the five-factor model (FFM). The purpose of this paper is to provide an overview of the FFM of personality disorder. It will begin with a description of this dimensional model of normal and abnormal personality functioning, followed by a comparison with a proposal for future revisions to DSM-5 and a discussion of its potential advantages as an integrative hierarchical model of normal and abnormal personality structure.
PMCID: PMC3811085  PMID: 24174888
five-factor model; dimensional; trait; personality; personality disorder; DSM-IV-TR; DSM-5
25.  Milestones in the history of personality disorders 
This paper analyzes the major historical milestones in the study of normal and abnormal personality, from antiquity up until the 20th century. Special attention is paid to the interaction between dimensional and typological approaches, which was a major issue during the preparation of DSM-5. Theories of personality started with the humoral theory of Greek medicine. Pinel, and later Esquirol and Prichard, are credited with the first descriptions of abnormal personalities in textbooks of psychiatry. Between the late 19th and early 20th centuries, elaborate systems of normal and abnormal personality, associating to some degree types and dimensions, were devised by a succession of European psychologists, such as Ribot, Heymans, and Lazursky. Emil Kraepelin and Kurt Schneider proposed classifications of abnormal personality types. In parallel, psychoanalysts stressed the role of early life experiences. Towards the mid-20th century, statistical methods were applied to the scientific validation of personality dimensions with pioneers such as Cattell, anticipating the five-factor model.
PMCID: PMC3811086  PMID: 24174889
personality; temperament; character; personality disorder; personality type; personality dimension; history of psychiatry; history of psychology; Théodule Ribot; Gerard Heymans; Aleksandr Lazursky; Emil Kraepelin; Kurt Schneider; DSM

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