Structural neuroimaging in Alzheimer's disease: do white matter hyperintensities matter?

The targeted brain dysfunction that accompanies aging can have a devastating effect on cognitive and intellectual abilities. A significant proportion of older adults experience precipitous cognitive decline that negatively impacts functional activities. Such individuals meet clinical diagnostic criteria for dementia, which is commonly attributed to Alzheimer''s disease (AD). Structural neuroimaging, including magnetic resonance imaging (MRI), has contributed significantly to our understanding of the morphological and pathology-related changes that may underlie normal and disease-associated cognitive change in aging. White matter hyperintensities (WMH), which are distributed patches of increased hyperintense signal on T2-weighted MRI, are among the most common structural neuroimaging findings in older adults. In recent years, WMH have emerged as robust radiological correlates of cognitive decline. Studies suggest that WMH distributed in anterior brain regions are related to decline in executive abilities that is typical of normal aging, whereas WMH distributed in more posterior brain regions are common in AD. Although epidemiological, observational, and pathological studies suggest that WMH may be ischemic in origin and caused by consistent or variable hypoperfusion, there is emerging evidence that they may also reflect vascular deposition of (β-amyloid, particularly when they are distributed in posterior areas and are present in patients with AD. Findings from the literature highlight the potential contribution of small-vessel cerebrovascular disease to the pathogenesis of AD, and suggest a mechanistic interaction, but future longitudinal studies using multiple imaging modalities are required to fully understand the complex role of WMH in AD.     

Cerebral aging: integration of brain and behavioral models of cognitive function

There are substantial declines in behavioral measures of cognitive function with age, including decreased function of executive processes and long-term memory. There is also evidence that, with age, there is a decrease in brain volume, particularly in the frontal cortex. When young and older adults perform cognitive tasks that depend heavily on frontal function, neuroimaging evidence indicates that older adults recruit additional brain regions in order to perform the tasks. This additional neural recruitment is termed "dedifferentiation," and can take multiple forms. This recruitment of additional neural tissue with age to perform cognitive tasks was not reflected in the behavioral literature, and suggests that there is more plasticity in the ability to organize brain function than was previously suspected. We review both behavioral and neuroscience perspectives on cognitive aging, and then connect the findings in the two areas. From this integration, we suggest important unresolved questions and directions for future research.     

Functional neuroimaging studies of the effects of psychotherapy

It has been long established that psychological interventions can markedly alter patients'' thinking patterns, beliefs, attitudes, emotional states, and behaviors. Little was known about the neural mechanisms mediating such alterations before the advent of functional neuroimaging techniques. Since the turn of the new millenium, several functional neuroimaging studies have been conducted to tackle this important issue. Some of these studies have explored the neural impact of various forms of psychotherapy in individuals with major depressive disorder. Other neuroimaging studies have investigated the effects of psychological interventions for anxiety disorders. I review these studies in the present article, and discuss the putative neural mechanisms of change in psychotherapy. The findings of these studies suggest that mental and behavioral changes occurring during psychotherapeutic interventions can lead to a normalization of functional brain activity at a global level.     

Structural plasticity of the adult brain

The adult brain has long been considered stable and unchanging, except for the inevitable decline that occurs with aqinq. This view is now being challenged with clear evidence that structural changes occur in the brain throughout life, including the generation of new neurons and other brain cells, and connections between and among neurons. What is as remarkable is that the changes that occur in the adult brain are influenced by the behaviors an individual engages in, as well as the environment in which an individual lives, works, and plays. Learning how behavior and environment regulate brain structure and function will lead to strategies to live more effective lives and perhaps protect from, or repair, brain damage and brain disease.     

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.     

Functional magnetic resonance imaging in schizophrenia

The integration of functional magnetic resonance imaging (fMRI) with cognitive and affective neuroscience paradigms enables examination of the brain systems underlying the behavioral deficits manifested in schizophrenia; there have been a remarkable increase in the number of studies that apply fMRI in neurobiological studies of this disease. This article summarizes features of fMRI methodology and highlights its application in neurobehavioral studies in schizophrenia. Such work has helped elucidate potential neural substrates of deficits in cognition and affect by providing measures of activation to neurobehavioral probes and connectivity among brain regions. Studies have demonstrated abnormalities at early stages of sensory processing that may influence downstream abnormalities in more complex evaluative processing. The methodology can help bridge integration with neuropharmacologic and genomic investigations.     

Protective and damaging effects of stress mediators: central role of the brain

The mind involves the whole body and two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Stress is a condition of the mind-body interaction, and a factor in the expression of disease that differs among individuals. It is notjust the dramatic stressful events that exact their toll, but rather the many events of daily life that elevate and sustain activities of physiological systems and cause sleep deprivation, overeating, and other health-damaging behaviors, producing the feeling of being "stressed out." Over time, this results in wear and tear on the body which is called "allostatic load," and it reflects not only the impact of life experiences but also of genetic load, individual lifestyle habits reflecting items such as diet, exercise, and substance abuse, and developmental experiences that set life-long patterns of behavior and physiological reactivity. Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation by the process known as allostasis, but in the long run allostatic load causes changes in the body that can lead to disease. The brain is the key organ of stress, allostasis, and allostatic load, because it determines what is threatening and therefore stressful, and also determines the physiological and behavioral responses. Brain regions such as the hippocampus, amygdala, and prefrontal cortex respond to acute and chronic stress by undergoing structural remodeling, which alters behavioral and physiological responses. Translational studies in humans with structural and functional imaging reveal smaller hippocampal volume in stress-related conditions, such as mild cognitive impairment in aging and prolonged major depressive illness, as well as in individuals with low self-esteem. Alterations in amygdala and prefrontal cortex are also reported. Besides pharmaceuticals, approaches to alleviate chronic stress and reduce allostatic load and the incidence of diseases of modern life include lifestyle change, and policies of government and business that would improve the ability of individuals to reduce their own chronic stress burden.     

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.     

Cognitive neuroscience and brain imaging in bipolar disorder

Bipolar disorder is characterized by a combination of state-related changes in psychological function that are restricted to illness episodes, coupled with trait-related changes that persist through periods of remission, irrespective of symptom status. This article reviews studies that have investigated the brain systems involved in these state- and trait-related changes, using two techniques: (i) indirect measures of neurocognitive function, and (ii) direct neuroimaging measures of brain function during performance of a cognitive task. Studies of neurocognitive function in bipolar disorder indicate deficits in three core domains: attention, executive function, and emotional processing. Functional imaging studies implicate pathophysiology in distributed neural circuitry that includes the prefrontal and anterior cingulate cortices, as well as subcortical limbic structures including the amygdala and the ventral striatum. Whilst there have been clear advances in our understanding of brain changes in bipolar disorder, there are limited data in bipolar depression, and there is limited understanding of the influence of clinical variables including medication status, illness severity, and specific symptom dimensions.     

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.     

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.     

Affective neuroscience of the emotional BrainMind: evolutionary perspectives and implications for understanding depression

Cross-species affective neuroscience studies confirm that primary-process emotional feelings are organized within primitive subcortical regions of the brain that are anatomically, neurochemically, and functionally homologous in all mammals that have been studied. Emotional feelings (affects) are intrinsic values that inform animals how they are faring in the quest to survive. The various positive affects indicate that animals are returning to "comfort zones" that support survival, and negative affects reflect "discomfort zones" that indicate that animals are in situations that may impair survival. They are ancestral tools for living--evolutionary memories of such importance that they were coded into the genome in rough form (as primary brain processes), which are refined by basic learning mechanisms (secondary processes) as well as by higher-order cognitions/thoughts (tertiary processes). To understand why depression feels horrible, we must fathom the affective infrastructure of the mammalian brain. Advances in our understanding of the nature of primary-process emotional affects can promote the development of better preclinical models of psychiatric disorders and thereby also allow clinicians new and useful ways to understand the foundational aspects of their clients' problems. These networks are of clear importance for understanding psychiatric disorders and advancing psychiatric practice.     

The involvement of the striatum in decision making

Decision making has been extensively studied in the context of economics and from a group perspective, but still little is known on individual decision making. Here we discuss the different cognitive processes involved in decision making and its associated neural substrates. The putative conductors in decision making appear to be the prefrontal cortex and the striatum. Impaired decision-making skills in various clinical populations have been associated with activity in the prefrontal cortex and in the striatum. We highlight the importance of strengthening the degree of integration of both cognitive and neural substrates in order to further our understanding of decision-making skills. In terms of cognitive paradigms, there is a need to improve the ecological value of experimental tasks that assess decision making in various contexts and with rewards; this would help translate laboratory learnings into real-life benefits. In terms of neural substrates, the use of neuroimaging techniques helps characterize the neural networks associated with decision making; more recently, ways to modulate brain activity, such as in the prefrontal cortex and connected regions (eg, striatum), with noninvasive brain stimulation have also shed light on the neural and cognitive substrates of decision making. Together, these cognitive and neural approaches might be useful for patients with impaired decision-making skills. The drive behind this line of work is that decision-making abilities underlie important aspects of wellness, health, security, and financial and social choices in our daily lives.     

Genetics of bipolar disorder

Bipolar disorder especially the most severe type (type I), has a strong genetic component. Family studies suggest that a small number of genes of modest effect are involved in this disorder. Family-based studies have identified a number of chromosomal regions linked to bipolar disorder, and progress is currently being made in identifying positional candidate genes within those regions. A number of candidate genes have also shown evidence of association with bipolar disorder, and genome-wide association studies are now under way, using dense genetic maps. Replication studies in larger or combined datasets are needed to definitively assign a role for specific genes in this disorder. This review covers our current knowledge of the genetics of bipolar disorder, and provides a commentary on current approaches used to identify the genes involved in this complex behavioral disorder.     

Cerebral aging: neuropsychological, neuroradiological, and neurometabolic correlates

The aging process is associated with a progressive cognitive decline, but both the extent of this decline and the profile of age-related cognitive changes remain to be clearly established. Currently, cognitive deficits associated with aging may be diagnosed under the categories of age-associated memory impairment, age-associated cognitive impairment, or the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) category of age-related cognitive decline. Age-related decline has been reported for several cognitive domains, such as language (eg, verb naming, verbal fluency), visuospatial abilities (eg, facial discrimination), executive functions (eg, set shifting, problem solving), and memory functions (eg, declarative learning, source memory). There is an age-related decline in brain cortical volume, which primarily involves association cortices and limbic regions. Studies of brain metabolic activity demonstrate an age-related decline in neocortical areas. Activation studies using cognitive tasks demonstrate that older healthy individuals have a different pattern of activation from younger subjects, suggesting thai older subjects may recruit additional brain areas in order to maintain performance.     

Cellular abnormalities in depression: evidence from postmortem brain tissue

During the past two decades, in vivo neuroimaging studies have permitted significant insights into the general location of dysfunctional brain regions in depression. In parallel and often intersecting ways, neuroanatomical, pharmacological, and biochemical studies of postmortem brain tissue are permitting new insights into the pathophysiology of depression. In addition to long-recognized neurochemical abnormalities in depression, novel studies at the microscopic level support the contention that mood disorders are associated with abnormalities in cell morphology and distribution. In the past 6 years, cell-counting studies have identified changes in the density and size of both neurons and glia in a number of frontolimbic brain regions, including dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortex, and the amygdala and hippocampus. Convergence of cellular changes at the microscopic level with neuroimaging changes detected in vivo provides a compelling integration of clinical and basic research for disentangling the pathophysiology of depression. The ultimate integration of these two research approaches will occur with premortem longitudinal clinical studies on well-characterized patients linked to postmortem studies of the same subjects.     

Regulation of cellular plasticity and resilience by mood stabilizers: the role of AMPA receptor trafficking

There is increasing evidence from a variety of sources that severe mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamaiergic system (which is known to play a major role in neuronal plasticity and cellular resilience) may be involved in the pathophysiology and treatment of mood disorders. Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluR1 receptor trafficking plays a critical role in regulating various forms of neural plasticity. It is thus noteworthy that recent studies have shown that structurally dissimilar mood stabilizers lithium and valproate regulate GluR1 receptor subunit trafficking and localization at synapses. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raises the possibility that agents more directly affecting synaptic GluR1 represent novel therapies for these devastating illnesses.     

Emergent processes in cognitive-emotional interactions

Emotion and cognition have been viewed as largely separate entities in the brain. Within this framework, significant progress has been made in understanding specific aspects of behavior. Research in the past two decades, however, has started to paint a different picture of brain organization, one in which network interactions are key to understanding complex behaviors. From both basic and clinical perspectives, the characterization of cognitive-emotional interactions constitutes a fundamental issue in the investigation of the mind and brain. This review will highlight the interactive and integrative potential that exists in the brain to bring together the cognitive and emotional domains. First, anatomical evidence will be provided, focusing on structures such as hypothalamus, basal forebrain, amygdala, cingulate cortex, orbitofrontal cortex, and insula. Data on functional interactions will then be discussed, followed by a discussion of a dual competition framework, which describes cognitive-emotional interactions in terms of perceptual and cognitive competition mechanisms.     

Neurocircuitry of the nicotinic cholinergic system

Continuing to discover how the brain works is one of the great challenges ahead of us. Although understanding the brain anatomy and its functional organization provided a first and indispensable foundation, it became clear that a static view was insufficient. To understand the complexity of neuronal communication, it is necessary to examine the chemical nature of the neurotransmission and, using the example of the acetylcholine receptors, follow the different layers of networks that can be distinguished. The natural alkaloid nicotine contained in tobacco leaves acts as an agonist with a subclass of acetylcholine receptors, and provides an interesting tool to approach brain functions. Analysis of the nicotinic acetylcholine receptors, which are ligand gated channels, revealed that these receptors are expressed at different critical locations on the neurons including the synaptic boutons, neurites, cell bodies, and even on the axons. These receptors can modulate the activity at the microcircuit synaptic level, in the cell processing of information, and, by acting on the velocity of action potential, the synchrony of communication between brain areas. These actions at multiple levels of brain organization provide an example of the complexity of brain neurocircuitry and an illustration of the relevance of this knowledge for psychiatry.