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.     

Predictors,moderators, and mediators (correlates) of treatment outcome in major depressive disorder

Major Depressive Disorder (MDD) is a prevalent illness that is frequently associated with significant disability, morbidity and mortality. Despite the development and availability of numerous treatment options for MDD, studies have shown that antidepressant monotherapy yields only modest rates of response and remission. Clearly, there is an urgent need to develop more effective treatment strategies for patients with MDD, One possible approach towards the development of novel pharmacotherapeuiic strategies for MDD involves identifying subpopulations of depressed patients who are more likely to experience the benefits of a given (existing) treatment versus placebo, or versus a second treatment. Attempts have been made to identify such “subpopulations, ” specifically by testing whether a given biological or clinical marker also serves as a moderator, mediator (correlate), or predictor of clinical improvement following the treatment of MDD with standard, first-line antidepressants. In the following article, we will attempt to summarize the literature focusing on several major areas (“leads”) where preliminary evidence exists regarding clinical and biologic moderators, mediators, and predictors of symptom improvement in MDD, Such clinical leads will include the presence of hopelessness, anxious symptoms, or medical comorbidity. Biologic leads will include gene polymorphisms, brain metabolism, quantitative electroencephalography, loudness dependence of auditory evoked potentials, and functional brain asymmetry     

Treatment-refractory anxiety; definition,risk factors,and treatment challenges

A sizable proportion of psychiatric patients will seek clinical evaluation and treatment for anxiety symptoms reportedly refractory to treatment. This apparent lack of response is either due to “pseudo-resistance” (a failure to have received and adhered to a recognized and effective treatment or treatments for their condition) or to true “treatment resistance.” Pseudo-resistance can be due to clinician errors in selecting and delivering an appropriate treatment effectively, or to patient nonadherence to a course of treatment. True treatment resistance can be due to unrecognized exogenous anxiogenic factors (eg, caffeine overuse, sleep deprivation, use of alcohol or marijuana) or an incorrect diagnosis (eg, atypical bipolar illness, occult substance abuse, attention deficit-hyperactivity disorder). Once the above factors are eliminated, treatment should focus on combining effective medications and cognitive behavioral therapy, combining several medications (augmentation), or employing novel medications or psychotherapies not typically indicated as first-line evidence-based anxiety treatments.     

Restoring nervous system structure and function using tissue engineered living scaffolds

Neural tissue engineering is premised on the integration of engineered living tissue with the host nervous system to directly restore lost function or to augment regenerative capacity following nervous system injury or neurodegenerative disease. Disconnection of axon pathways – the long-distance fibers connecting specialized regions of the central nervous system or relaying peripheral signals – is a common feature of many neurological disorders and injury. However, functional axonal regeneration rarely occurs due to extreme distances to targets, absence of directed guidance, and the presence of inhibitory factors in the central nervous system, resulting in devastating effects on cognitive and sensorimotor function. To address this need, we are pursuing multiple strategies using tissue engineered “living scaffolds”, which are preformed three-dimensional constructs consisting of living neural cells in a defined, often anisotropic architecture. Living scaffolds are designed to restore function by serving as a living labeled pathway for targeted axonal regeneration – mimicking key developmental mechanisms– or by restoring lost neural circuitry via direct replacement of neurons and axonal tracts. We are currently utilizing preformed living scaffolds consisting of neuronal clusters spanned by long axonal tracts as regenerative bridges to facilitate long-distance axonal regeneration and for targeted neurosurgical reconstruction of local circuits in the brain. Although there are formidable challenges in preclinical and clinical advancement, these living tissue engineered constructs represent a promising strategy to facilitate nervous system repair and functional recovery.     

Emotor control: computations underlying bodily resource allocation,emotions, and confidence

Emotional processes are central to behavior, yet their deeply subjective nature has been a challenge for neuroscientific study as well as for psychiatric diagnosis. Here we explore the relationships between subjective feelings and their underlying brain circuits from a computational perspective. We apply recent insights from systems neuroscience—approaching subjective behavior as the result of mental computations instantiated in the brain—to the study of emotions. We develop the hypothesis that emotions are the product of neural computations whose motor role is to reallocate bodily resources mostly gated by smooth muscles. This “emotor” control system is analagous to the more familiar motor control computations that coordinate skeletal muscle movements. To illustrate this framework, we review recent research on “confidence.” Although familiar as a feeling, confidence is also an objective statistical quantity: an estimate of the probability that a hypothesis is correct. This model-based approach helped reveal the neural basis of decision confidence in mammals and provides a bridge to the subjective feeling of confidence in humans. These results have important implications for psychiatry, since disorders of confidence computations appear to contribute to a number of psychopathologies. More broadly, this computational approach to emotions resonates with the emerging view that psychiatric nosology may be best parameterized in terms of disorders of the cognitive computations underlying complex behavior.     

Inflammation in depression: is adiposity a cause?

Mounting evidence indicates that inflammation may play a significant role in the development of depression. Patients with depression exhibit increased inflammatory markers, and administration of cytokines and other inflammatory stimuli can induce depressive symptoms. Mechanisms by which cytokines access the brain and influence neurotransmitter systems relevant to depression have also been described, as have preliminary findings indicating that antagonizing inflammatory pathways may improve depressive symptoms. One primary source of inflammation in depression appears to be adiposity. Adipose tissue is a rich source of inflammatory factors including adipokines, chemokines, and cytokines, and a bidirectional relationship between adiposity and depression has been revealed. Adiposity is associated with the development of depression, and depression is associated with adiposity, reflecting a potentional vicious cycle between these two conditions which appears to center around inflammation. Treatments targeting this vicious cycle may be especially relevant for the treatment and prevention of depression as well as its multiple comorbid disorders such as cardiovascular disease, diabetes, and cancer, all of which have also been associated with both depression and inflammation.     

A history of anxiety: from Hippocrates to DSM

This article describes the history of the nosology of anxiety disorders. Greek and Latin physicians and philosophers distinguished anxiety from other types of negative affect, and identified it as a medical disorder. Ancient Epicurean and Stoic philosophers suggested techniques to reach an anxiety-free state of mind that are reminiscent of modern cognitive psychology. Between classical antiquity and the late 19^th century there was a long interval during which anxiety was not classified as a separate illness. However, typical cases of anxiety disorders kept being reported, even if under different names. In the 17^th century, Robert Burton described anxiety in The Anatomy of Melancholy. Panic attacks and generalized anxiety disorder may be recognized in the “panophobias” in the nosology published by Boissier de Sauvages in the 18^th century. Also, anxiety symptoms were an important component of new disease constructs, culminating in neurasthenia in the 19^th century. Emil Kraepelin devoted much attention to the possible presence of severe anxiety in manic-depressive illness, thereby anticipating the “anxious distress” specifier of bipolar disorders in DSM-5. A pitfall to consider is that the meaning of common medical terms, such as melancholia, evolves according to places and epochs.     

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.     

Research Domain Criteria: toward future psychiatric nosologies

The Research Domain Criteria (RDoC) project was initiated by the National Institute of Mental Health (NIMH) in early 2009 as the implementation of Goal 1.4 of its just-issued strategic plan. In keeping with the NIMH mission, to “transform the understanding and treatment of mental illnesses through basic and clinical research,” RDoC was explicitly conceived as a research-related initiative. The statement of the relevant goal in the strategic plan reads: “Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures.” Due to the novel approach that RDoC takes to conceptualizing and studying mental disorders, it has received widespread attention, well beyond the borders of the immediate research community. This review discusses the rationale for the experimental framework that RDoC has adopted, and its implications for the nosology of mental disorders in the future.     

Pursuit of the “truth” about mental illness: the significance of findings in neuropsychiatric research,and lessons from the past

Technology in genetics and brain imaging has advanced so rapidly that it is difficult to be knowledgeable about all the new tools being used in the pursuit of progress toward understanding and treating mental illness. While findings from new studies remain promising, caution is needed with regard to their current applicability to clinical use, both to predict who is likely to become ill and who is likely to respond to medication. A perspective on the past, using schizophrenia as an example, illustrates important findings that were published, had much visibility, and caused a flurry of new related studies, but then slowly disappeared, either to be abandoned as an artifact of the assay or study design, an epiphenomenon, or as simply nonreplicated findings not leading to further progress. Remembering that good science is “the pursuit of the truth” and not joining the latest “bandwagon fad” of “believers” is an important principle to adhere to when participating in the politics of science.     

Focus on psychosis

The concept of psychosis has been shaped by traditions in the concepts of mental disorders during the last 170 years. The term “psychosis” still lacks a unified definition, but denotes a clinical construct composed of several symptoms. Delusions, hallucinations, and thought disorders are the core clinical features. The search for a common denominator of psychotic symptoms points toward combinations of neuropsychological mechanisms resulting in reality distortion. To advance the elucidation of the causes and the pathophysiology of the symptoms of psychosis, a deconstruction of the term into its component symptoms is therefore warranted. Current research is dealing with the delineation from “normality”, the genetic underpinnings, and the causes and pathophysiology of the symptoms of psychosis.     

The Kraepelinian tradition

Emil Kraepelin (1856-1926) was an influential figure in the history of psychiatry as a clinical science. This paper, after briefly presenting his biography, discusses the conceptual foundations of his concept of mental illness and follows this line of thought through to late 20th-century “Neo-Kraepelinianism,” including recent criticism, particularly of the nosological dichotomy of endogenous psychoses. Throughout his professional life, Kraepelin put emphasis on establishing psychiatry as a clinical science with a strong empirical background. He preferred pragmatic attitudes and arguments, thus underestimating the philosophical presuppositions of his work. As for nosology, his central hypothesis is the existence and scientific accessibility of “natural disease entities” (“natürliche Krankheitseinheiten”) in psychiatry. Notwithstanding contemporary criticism that he commented upon, this concept stayed at the very center of Kraepelin''s thinking, and therefore profoundly shaped his clinical nosology.     

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.     

Nerve autografts and tissue-engineered materials for the repair of peripheral nerve injuries: a 5-year bibliometric analysis

With advances in biomedical methods, tissue-engineered materials have developed rapidly as an alternative to nerve autografts for the repair of peripheral nerve injuries. However, the materials selected for use in the repair of peripheral nerve injuries, in particular multiple injuries and large-gap defects, must be chosen carefully. Various methods and materials for protecting the healthy tissue and repairing peripheral nerve injuries have been described, and each method or material has advantages and disadvantages. Recently, a large amount of research has been focused on tissue-engineered materials for the repair of peripheral nerve injuries. Using the keywords “pe-ripheral nerve injury”, “autotransplant”, “nerve graft”, and “biomaterial”, we retrieved publications using tissue-engineered materials for the repair of peripheral nerve injuries appearing in the Web of Science from 2010 to 2014. The country with the most total publications was the USA. The institutions that were the most productive in this field include Hannover Medical School (Germany), Washington University (USA), and Nantong University (China). The total number of publications using tissue-engineered materials for the repair of peripheral nerve injuries grad-ually increased over time, as did the number of Chinese publications, suggesting that China has made many scientific contributions to this field of research.     

Structural plasticity of the adult brain: how animal models help us understand brain changes in depression and systemic disorders related to depression

The brain interprets experiences and translates them into behavioral and physiological responses. Stressful events are those which are threatening or, at the very least, unexpected and surprising, and the physiological and behavioral responses are intended to promote adaptation via a process called "allostasis. " Chemical mediators of allostasis include cortisol and adrenalin from the adrenal glands, other hormones, and neurotransmitters, the parasympathetic and sympathetic nervous systems, and cytokines and chemokines from the immune system. Two brain structures, the amygdala and hippocampus, play key roles in interpreting what is stressful and determining appropriate responses. The hippocampus, a key structure for memories of events and contexts, expresses receptors that enable it to respond to glucocorticoid hormones in the blood, it undergoes atrophy in a number of psychiatric disorders; it also responds to stressors with changes in excitability, decreased dendritic branching, and reduction in number of neurons in the dentate gyrus. The amygdala, which is important for "emotional memories, " becomes hyperactive in posttraumatic stress disorder and depressive illness, in animal models of stress, there is evidence for growth and hypertrophy of nerve cells in the amygdala. Changes in the brain after acute and chronic stressors mirror the pattern seen in the metabolic, cardiovascular, and immune systems, that is, short-term adaptation (allostasis) followed by long-term damage (allostatic load), eg, atherosclerosis, fat deposition obesity, bone demineralization, and impaired immune function. Allostatic load of this kind is seen in major depressive illness and may also be expressed in other chronic anxiety and mood disorders.     

Antidepressant chronotherapeutics for bipolar depression

Chronotherapeutics refers to treatments based on the principles of circadian rhythm organization and sleep physiology, which control the exposure to environmental stimuli that act on biological rhythms, in order to achieve therapeutic effects in the treatment of psychiatric conditions. It includes manipulations of the sleep-wake cycle such as sleep deprivation and sleep phase advance, and controlled exposure to light and dark. The antidepressant effects of chronotherapeutics are evident in difficult-to-treat conditions such as bipolar depression, which has been associated with extremely low success rates of antidepressant drugs in naturalistic settings and with stable antidepressant response to chronotherapeutics in more than half of the patients. Recent advances in the study of the effects of chronotherapeutics on neurotransmitter systems, and on the biological clock machinery, allow us to pinpoint its mechanism of action and to transform it from a neglected or “orphan” treatment to a powerful clinical instrument in everyday psychiatric practice.     

Pharmacogenomic strategy for individualizing antidepressant therapy

Despite remarkable progress, pharmacotherapy in general, including that for the treatment of depressive conditions, has often ignored the magnitude and clinical significance of the huge interindividual variations in pharmacokinetics and pharmacodynamics, resulting in poor compliance, suboptimal therapeutic effects, and treatment resistance. Advances in pharmacogenomics and computer modeling technologies hold promise for achieving the goals of “individualized” (“personalized”) medicine. However, the challenges for realizing such goals remain substantial. These include the packaging and interpretation of genotyping results, changes in medical practice (innovation diffusion), and infrasiructural, financing, ethical, and organizational issues related to the use of new information.     

The effectiveness of anticonvulsants in psychiatric disorders

Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, affective disorders, bipolar affective disorders in particular, and, to some extent, personality disorders. A further area in which neurology and psychiatry overlap is pain conditions, in which some anticonvulsants, and also typical psychiatric medications such as antidepressants, are helpful. From the beginning of their psychiatric use, anticonvulsants have also been used to ameliorate specific symptoms of psychiatric disorders independently of their causality and underlying illness, eg, aggression, and, more recently, cognitive impairment, as seen in affective disorders and schizophrenia. With new anticonvulsants currently under development, it is likely that their use in psychiatry will further increase, and that psychiatrists need to learn about their differential efficacy and safety profiles to the same extent as do neurologists.     

Symptom dimensions and subtypes of obsessive-compulsive disorder: a developmental perspective

In the absence of definitive etiological markers for obsessive-compulsive disorder (OCD), obsessive-compulsive (OC) symptom dimensions may offer a fruitful point of orientation. These dimensions can be understood as defining potentially overlapping clinical features that may be continuous with “normal” worries first evident in childhood. Although the understanding of the dimensional structure of OC symptoms is still imperfect, a recent large-scale meta-analysis has confirmed the presence of at least four separable symptom dimensions in children, as well as adults, with OCD, A dimensional approach does not exclude other methods to parse OCD. Thus far, a pediatric age of onset, the presence of other family members with OCD, and the individual''s “ticrelated” status appear to be potentially useful categorical distinctions. Although the OC symptom dimensions appear to be valid for all ages, it is unlikely that the underlying genetic vulnerability factors and neurobiological substrates for each of these symptom dimensions are the same across the course of development.