Deep brain stimulation in the treatment of depression

Major depressive disorder is a worldwide disease with debilitating effects on a patient''s life. Common treatments include pharmacotherapy, psychotherapy, and electroconvulsive therapy. Many patients do not respond to these treatments; this has led to the investigation of alternative therapeutic modalities. Deep brain stimulation (DBS) is one of these modalities. It was first used with success for treating movement disorders and has since been extended to the treatment of psychiatric disorders. Although DBS is still an emerging treatment, promising efficacy and safety have been demonstrated in preliminary trials in patients with treatment-resistant depression (TRD). Further, neuroimaging has played a pivotal role in identifying some DBS targets and remains an important tool for evaluating the mechanism of action of this novel intervention. Preclinical animal studies have broadened knowledge about the possible mechanisms of action of DBS for TRD, Given that DBS involves neurosurgery in patients with severe psychiatric impairment, ethical questions concerning capacity to consent arise; these issues must continue to be carefully considered.     

A systematic review of the neural bases of psychotherapy for anxiety and related disorders

Brain imaging studies over two decades have delineated the neural circuitry of anxiety and related disorders, particularly regions involved in fear processing and in obsessive-compulsive symptoms. The neural circuitry of fear processing involves the amygdala, anterior cingulate, and insular cortex, while cortico-striatal-thalamic circuitry plays a key role in obsessive-compulsive disorder. More recently, neuroimaging studies have examined how psychotherapy for anxiety and related disorders impacts on these neural circuits. Here we conduct a systematic review of the findings of such work, which yielded 19 functional magnetic resonance imaging studies examining the neural bases of cognitive-behavioral therapy (CBT) in 509 patients with anxiety and related disorders. We conclude that, although each of these related disorders is mediated by somewhat different neural circuitry, CBT may act in a similar way to increase prefrontal control of subcortical structures. These findings are consistent with an emphasis in cognitive-affective neuroscience on the potential therapeutic value of enhancing emotional regulation in various psychiatric conditions.     

Cellular plasticity and resilience and the pathophysiology of severe mood disorders

Recent advances in the identification of the neural circuits, neurochemicals, and signal transduction mechanisms involved in the pathophysiology and treatment of mood disorders have led to much progress toward understanding the roles of genetic factors and psychosocial stressors. The monoaminergic neurotransmitter systems have received the most attention, partly because of the observation that effective antidepressant drugs exert their primary biochemical effects by regulating intrasynaptic concentrations of serotonin and norepinephrine. Furthermore, the monoaminergic systems are extensively distributed throughout the network of limbic, striatal, and prefrontal cortical neuronal circuits thought to support the behavioral and visceral manifestations of mood disorders. Increasing numbers of neuroimaging, neuropathological, and biochemical studies indicate impairments in cellular plasticity and resilience in patients who suffer from severe, recurrent mood disorders. In this paper, we describe studies identifying possible structural, functional, and cellular abnormalities associated with depressive disorders, which are potentially the cellular underpinnings of these diseases. We suggest that drugs designed to enhance cellular plasticity and resilience, and attenuate the activity of maladaptive stress-responsive systems, may be useful for the treatment of severe mood 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.     

Neuroimaging in anxiety disorders

Over the last few years, neuroimaging techniques have contributed greatly to the identification of the structural and functional neuroanatomy of anxiety disorders. The amygdala seems to be a crucial structure for fear and anxiety, and has consistently been found to be activated in anxiety-provoking situations. Apart from the amygdala, the insula and anterior cinguiate cortex seem to be critical, and ail three have been referred to as the "fear network." In the present article, we review the main findings from three major lines of research. First, we examine human models of anxiety disorders, including fear conditioning studies and investigations of experimentally induced panic attacks. Then we turn to research in patients with anxiety disorders and take a dose look at post-traumatic stress disorder and obsessive-compulsive disorder. Finally, we review neuroimaging studies investigating neural correlates of successful treatment of anxiety, focusing on exposure-based therapy and several pharmacological treatment options, as well as combinations of both.     

Habit formation

Habits, both good ones and bad ones, are pervasive in animal behavior. Important frameworks have been developed to understand habits through psychological and neurobiological studies. This work has given us a rich understanding of brain networks that promote habits, and has also helped us to understand what constitutes a habitual behavior as opposed to a behavior that is more flexible and prospective. Mounting evidence from studies using neural recording methods suggests that habit formation is not a simple process. We review this evidence and take the position that habits could be sculpted from multiple dissociable changes in neural activity. These changes occur across multiple brain regions and even within single brain regions. This strategy of classifying components of a habit based on different brain signals provides a potentially useful new way to conceive of disorders that involve overly fixed behaviors as arising from different potential dysfunctions within the brain''s habit network.     

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.     

Structural and functional connectivity in traumatic brain injury

Traumatic brain injury survivors often experience cognitive deficits and neuropsychiatric symptoms.However,the neurobiological mechanisms underlying specific impairments are not fully understood.Advances in neuroimaging techniques(such as diffusion tensor imaging and functional MRI)have given us new insights on structural and functional connectivity patterns of the human brain in both health and disease.The connectome derived from connectivity maps reflects the entire constellation of distributed brain networks.Using these powerful neuroimaging approaches,changes at the microstructural level can be detected through regional and global properties of neuronal networks.Here we will review recent developments in the study of brain network abnormalities in traumatic brain injury,mainly focusing on structural and functional connectivity.Some connectomic studies have provided interesting insights into the neurological dysfunction that occurs following traumatic brain injury.These techniques could eventually be helpful in developing imaging biomarkers of cognitive and neurobehavioral sequelae,as well as predicting outcome and prognosis.     

Light treatment of mood disorders

In 1981, seven patients with nonseasonal depression were treated with bright white light in 1982, bright artificial light was used to treat a manic-depressive patient with a seasonal mood cycle. In the last 20 years, a plethora of studies have further defined the depressive populations, who are responsive to light treatment; the optimal timing, intensity, spectral frequency, and duration of treatment; its comparison with other pharmacological interventions; predictors of response; side-effect profiles; viable placebo-control conditions; alternative devices and forms of administration; potential mechanisms and anatomical pathways mediating light's physiological effects; and its application to other disorders and subsyndromaI states. These studies have been conducted across multiple countries with surprisingly consistent results. Further work is needed, as highlighted in this review, to clarify the specific mechanism of action in subtypes of depressive disorders and differential age and gender effects. Although the majority of work in this area is relatively new, it behooves the reader to remember that Solomon, almost 3000 years ago, wrote in Ecclesiastes: "Truly the light is sweet and a pleasant thing it is for the eyes to behold the sun" (11:7).     

Attention deficit-hyperactivity disorder and early-onset bipolar disorder: two facets of one entity?

Early-onset bipolar disorder (BD) and attention-deficithyperactivity disorder (ADHD) have recently been the subject of highly controversial debate, due to theories regarding underlying pathophysiological processes and a clinical overlap of symptoms. Epidemiological data, clinical aspect, neuroimaging, neurochemical, and genetic studies suggest that there may be a possible relationship between biological factors and clinical characteristic in the development of symptoms. However, longitudinal data supporting the hypothesis of a diagnostic shift from BD to ADHD symptoms and vice versa are currently not available. These would be essential to enable further investigations into whether these two disorders possibly represent two different aspects of an underlying common psychopathophysioiogical entity.     

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.     

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.     

Striatal dopamine,reward, and decision making in schizophrenia

Elevated striatal dopamine function is one of the best-established findings in schizophrenia. In this review, we discuss causes and consequences of this striata! dopamine alteration. We first summarize earlier findings regarding striatal reward processing and anticipation using functional neuroimaging. Secondly, we present a series of recent studies that are exemplary for a particular research approach: a combination of theory-driven reinforcement learning and decision-making tasks in combination with computational modeling and functional neuroimaging. We discuss why this approach represents a promising tool to understand underlying mechanisms of symptom dimensions by dissecting the contribution of multiple behavioral control systems working in parallel. We also discuss how it can advance our understanding of the neurobiological implementation of such functions. Thirdly, we review evidence regarding the topography of dopamine dysfunction within the striatum. Finally, we present conclusions and outline important aspects to be considered in future studies.     

The epidemiology of anxiety disorders: a review

Epidemiological studies show that anxiety disorders are highly prevalent and an important cause of functional impairment; they constitute the most frequent menial disorders in the community. Phobias are the most common with the highest rates for simple phobia and agoraphobia. Panic disorder (PD) and obsessive-compulsive disorder (OCD) are less frequent (2% lifetime prevalence), and there are discordant results for social phobia (SP) (2%-16%) and generalized anxiety disorder (GAD) (3%-30%). These studies underline the importance of an accurate definition of disorders using unambiguous diagnostic and assessment criteria. The boundaries between anxiety disorders are often ill defined and cases may vary widely according to the definition applied. Simple phobia, agoraphobia, and GAD are more common in vmrnen, while there is no gender différence for SP, PD, and OCD, Anxiety disorders are more common in separated, divorced, and widowed subjects; their prevalence is highest in subjects aged 25 to 44 years and lowest in subjects aged >65 years. The age of onset of the different types of anxiety disorders varies widely: phobic disorders begin early in life, whereas PD occurs in young adulthood. Clinical - rather than epidemiological - studies have examined risk factors such as life events, childhood experiences, and familial factors. Anxiety disorders have a chronic and persistent course, and are frequently comorbid with other anxiety disorders, depressive disorders, and substance abuse. Anxiety disorders most frequently precede depressive disorders or substance abuse, Comorbid diagnoses may influence risk factors like functional impairment and quality of life. It remains unclear whether certain anxiety disorders (eg, PD) are risk factors for suicide. The comorbidity of anxiety disorders has important implications for assessment and treatment and the risk factors should be explored. The etiology, natural history, and outcome of these disorders need to be further addressed in epidemiological studies.     

Neural plasticity: consequences of stress and actions of antidepressant treatment

Neural plasticity is emerging as a fundamental and critical mechanism of neuronal function, which allows the brain to receive information and make the appropriate adaptive responses to subsequent related stimuli. Elucidation of the molecular and cellular mechanisms underlying neural plasticity is a major goal of neuroscience research, and significant advances have been made in recent years. These mechanisms include regulation of signal transduction and gene expression, and also structural alterations of neuronal spines and processes, and even the birth of new neurons in the adult brain. Altered plasticity could thereby contribute to psychiatric and neurological disorders. This article revievi/s the literature demonstrating altered plasticity in response to stress, and evidence that chronic antidepressant treatment can reverse or block the effects, and even induce neural piasiicity-iike responses. Continued elucidation of the mechanisms underlying neural plasticity will lead to novel drug targets that could prove to be effective and rapidly acting therapeutic interventions.     

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.     

Neuropsychological and neuroimaging findings in traumatic brain injury and post-traumatic stress disorder

Advances in imaging technology, coupled with military personnel returning home from Iraq and Afghanistan with traumatic brain injury (TBI) and/or post-traumatic stress disorder (PTSD), have increased interest in the neuropsychology and neurobiology of these two conditions. There has been a particular focus on differential diagnosis. This paper provides an overviev of findings regarding the neuropsychological and neurobiological underpinnings of TBI and for PTSD. A specific focus is on assessment using neuropsychological measures and imaging techniques. Challenges associated with the assessment of individuals with one or both conditions are also discussed. Although use of neuropsychological and neuroimaging test results may assist with diagnosis and treatment planning, further work is needed to identify objective biomarkers for each condition. Such advances would be expected to facilitate differential diagnosis and implementation of best treatment practices.     

Sleep and anxiety disorders

Sleep disturbances-particularly insomnia - are highly prevalent in anxiety disorders and complaints such as insomnia or nightmares have even been incorporated in some anxiety disorder definitions, such as generalized anxiety disorder and posttraumatic stress disorder. In the first part of this review, the relationship between sleep and anxiety is discussed in terms of adaptive response to stress. Recent studies suggested that the corticotropin-releasing hormone system and the locus ceruleus-autonomic nervous system may play major roles in the arousal response to stress. It has been suggested that these systems may be particularly vulnerable to prolonged or repeated stress, further leading to a dysfunctional arousal state and pathological anxiety states, Polysomnographic studies documented limited alteration of sleep in anxiety disorders. There is some indication for alteration in sleep maintenance in generalized anxiety disorder and for both sleep initiation and maintenance in panic disorder; no clear picture emerges for obsessive-compulsive disorder or posttraumatic stress disorder. Finally, an unequivocal sleep architecture profile that could specifically relate to a particular anxiety disorder could not be evidenced; in contrast, conflicting results are often found for the same disorder. Discrepancies between studies could have been related to illness severity, diagnostic comorbidity, and duration of illness. A brief treatment approach for each anxiety disorder is also suggested with a special focus on sleep.     

Neuroimaging-based biomarkers for treatment selection in major depressive disorder

The use of neuroimaging approaches to identify likely treatment outcomes in patients with major depressive disorder is developing rapidly. Emerging work suggests that resting state pretreatment metabolic activity in the fronto-insular cortex may distinguish between patients likely to respond to psychotherapy or medication and may function as a treatment-selection biomarker. In contrast, high metabolic activity in the subgenual anterior cingulate cortex may be predictive of poor outcomes to both medication and psychotherapy, suggesting that nonstandard treatments may be pursued earlier in the treatment course. Although these findings will require replication before clinical adoption, they provide preliminary support for the concept that brain states can be measured and applied to the selection of a specific treatment most likely to be beneficial for an individual patient.