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.     

Mapping connectivity in the developing brain

Recently, there has been a wealth of research into structural and functional brain connectivity, and how they change over development. While we are far from a complete understanding, these studies have yielded important insights into human brain development. There is an ever growing variety of methods for assessing connectivity, each with its own advantages. Here we review research on the development of structural and/or functional brain connectivity in both typically developing subjects and subjects with neurodevelopmental disorders. Space limitations preclude an exhaustive review of brain connectivity across all developmental disorders, so we review a representative selection of recent findings on brain connectivity in autism, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Turner syndrome, and ADHD. Major strides have been made in understanding the developmental trajectory of the human connectome, offering insight into characteristic features of brain development and biological processes involved in developmental brain disorders. We also discuss some common themes, including hemispheric specialization – or asymmetry – and sex differences. We conclude by discussing some promising future directions in connectomics, including the merger of imaging and genetics, and a deeper investigation of the relationships between structural and functional connectivity.     

Reprint of: Mapping connectivity in the developing brain

Recently, there has been a wealth of research into structural and functional brain connectivity, and how they change over development. While we are far from a complete understanding, these studies have yielded important insights into human brain development. There is an ever growing variety of methods for assessing connectivity, each with its own advantages. Here we review research on the development of structural and/or functional brain connectivity in both typically developing subjects and subjects with neurodevelopmental disorders. Space limitations preclude an exhaustive review of brain connectivity across all developmental disorders, so we review a representative selection of recent findings on brain connectivity in autism, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Turner syndrome, and ADHD. Major strides have been made in understanding the developmental trajectory of the human connectome, offering insight into characteristic features of brain development and biological processes involved in developmental brain disorders. We also discuss some common themes, including hemispheric specialization – or asymmetry – and sex differences. We conclude by discussing some promising future directions in connectomics, including the merger of imaging and genetics, and a deeper investigation of the relationships between structural and functional connectivity.     

Control of cortical synapse development and plasticity by MET receptor tyrosine kinase,a genetic risk factor for autism

The key developmental milestone events of the human brain, such as neurogenesis, synapse formation, maturation, and plasticity, are determined by a myriad of molecular signaling events, including those mediated by a number of receptor tyrosine kinases (RTKs) and their cognate ligands. Aberrant or mistimed brain development and plasticity can lead to maladaptive changes, such as dysregulated synaptic connectivity and breakdown of circuit functions necessary for cognition and adaptive behaviors, which are hypothesized pathophysiologies of many neurodevelopmental and neuropsychiatric disorders. Here we review recent literature that supports autism spectrum disorder as a likely result of aberrant synapse development due to mistimed maturation and plasticity. We focus on MET RTK, a prominent genetic risk factor for autism, and discuss how a pleiotropic molecular signaling system engaged by MET exemplifies a genetic program that controls cortical circuit development and plasticity by modulating the anatomical and functional connectivity of cortical circuits, thus conferring genetic risk for neurodevelopmental disorders.     

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.     

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 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.     

Conceptualization of the liability for schizophrenia: clinical implications

Historically, the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for schizophrenia have emphasized several features, including symptoms of psychosis, a dissociation of symptoms from their etiology, a reliance on clinical symptoms, and a categorical approach to classifying the disorder. Although these emphases are quite useful, they have limitations. We review these here, and stress the importance of incorporating recent data on the genetic /biological and neurodevelopmental origins of schizophrenia into current conceptions of the disorder. We also review "schizotaxia, " which is a concept thai embodies this point of view, occurs before the onset of psychosis, and is hypothesized to represent the liability for schizophrenia. If our hypothesis on this point is correct, the identification of schizotaxic individuals will eventually facilitate the development of prevention strategies by identifying a premorbid (but clinically significant) condition for schizophrenia. Moreover, the identification of biological or neuropsychological components of schizotaxia will provide more specific bases for developing novel treatment interventions. Our initial attempts to develop protocols for the assessment and treatment of schizotaxia are encouraging, and will be reviewed.     

Psychiatric aspects of organic sleep disorders

In recent years, a number of studies have attempted to characterize psychological disturbances related to various sleep disorders. The objective of this type of research is to investigate the possibility that psychopathology may represent an etiological factor, a complication, and/or a target for treatment. In addition, disordered sleep can present itself in a complex and atypical fashion in which the primary sleep-related component may not be immediately apparent. This article reviews the evidence for a relationship between organic sleep disorders and psychiatric morbidity. Generally, it can be concluded that organic sleep disorders have a profound negative impact on most domains of health-related quality of life. Results for the sleep disorders that have been studied (narcolepsy idiopathic hypersomnia, sleep apnea/hypopnea syndrome, restless legs syndrome, periodic limb movement disorder, and circadian sleep disorders) show strong evidence for an association with mood disorders. After treatment, depression scores may or may not improve to the level of population norms, suggesting that this relationship is more complex than one of mere cause and effect.     

Targeting brain microvascular endothelial cells: a therapeutic approach to neuroprotection against stroke

Brain microvascular endothelial cells form the interface between nervous tissue and circulating blood, and regulate central nervous system homeostasis. Brain microvascular endothelial cells differ from peripheral endothelial cells with regards expression of specific ion transporters and receptors, and contain fewer fenestrations and pinocytotic vesicles. Brain microvascular endothelial cells also synthesize several factors that influence blood vessel function. This review describes the morphological characteristics and functions of brain microvascular endothelial cells, and summarizes current knowledge regarding changes in brain microvascular endothelial cells during stroke progression and therapies. Future studies should focus on identifying mechanisms underlying such changes and developing possible neuroprotective therapeutic interventions.     

Genetics of drug dependence

Drug-dependence disorders (we focus here on cocaine, opioid, and nicotine dependence) are genetically influenced. Risk genes have been located based primarily on genetic linkage studies, and identified primarily based on genetic association studies. In this article we review salient results from linkage, association, and genome-wide association study methodologies, and discuss future prospects for risk allele identification based on these, and on newer, methodologies. Although considerable progress has been made, it is likely that the application of more extensive sequencing than has previously been practical will be required to identify a fuller range of risk variants.     

Research Domain Criteria: cognitive systems, neural circuits, and dimensions of behavior

Current diagnostic systems for mental disorders were established before the tools of neuroscience were available, and although they have improved the reliability of psychiatric classification, progress toward the discovery of disease etiologies and novel approaches to treatment and prevention may benefit from alternative conceptualizations of mental disorders. The Research Domain Criteria (RDoC) initiative is the centerpiece of NIMH's effort to achieve its strategic goal of developing new methods to classify mental disorders for research purposes. The RDoC matrix provides a research framework that encourages investigators to reorient their research perspective by taking a dimensional approach to the study of the genetic, neural, and behavioral features of mental disorders, RDoCs integrative approach includes cognition along with social processes, arousal/regulatory systems, and negative and positive valence systems as the major domains, because these neurobehavioral systems have all evolved to serve the motivational and adaptive needs of the organism. With its focus on neural circuits informed by the growing evidence of the neurodevelopmental nature of many disorders and its capacity to capture the patterns of co-occurrence of behaviors and symptoms, the RDoC approach holds promise to advance our understanding of the nature of mental disorders.     

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.     

Empathy: shared circuits and their dysfunctions

Observing another individual acting upon an object triggers cerebral activity well beyond the visual cortex of the observer in areas directly involved in planning and executing actions. This we will call action simulation. Importantly, the brain does not solely simulate the actions of others but also the sensations they feel, and their emotional responses. These simulation mechanisms are most active in individuals who report being very empathic. Simulation may indeed be instrumental for our understanding of the emotional and mental state of people in our sight, and may contribute heavily to the social interactions with our peers by providing a first-person perspective on their inner feelings. Simulation mechanisms are at work at an early stage of social development and might be defective in young individuals with autism spectrum disorders (ASD). However, the results to date regarding ASD are not clearcut, and an equal number of studies report positive and negative findings.     

The rise of moral emotions in neuropsychiatry

Clinical psychopathology has largely ignored the developments in the field of social neuroscience. The so-called moral emotions are a group of affective experiences thought to promote cooperation, group cohesion, and reorganization. In this review, we: (i) briefly describe a provisional taxonomy of a limited set of moral emotions and their neural underpinnings; and (ii) discuss how disgust, guilt, anger/indignation, and shame/embarrassment can be conceptualized as key affective experiences in different neuropsychiatric disorders. Based on a concise review of the literature linking moral emotions, psychopathology, and neuropsychiatry, we have devised a simple and preliminary scheme where we conjecture how specific moral emotions can be implicated in some categories of DSM-5 diagnoses, potentially helping to bridge psychopathology and neurobiologically plausible variables, in line with the Research Domain Criteria initiative. We hope this stimulates new empirical work exploring how moral emotional changes and their underlying neurobiology can help elucidating the neural underpinnings of mental disorders.     

Developmental programming of brain and behavior by perinatal diet: focus on inflammatory mechanisms

Obesity is now epidemic worldwide. Beyond associated diseases such as diabetes, obesity is linked to neuropsychiatric disorders such as depression. Alarmingly maternal obesity and high-fat diet consumption during gestation/lactation may “program” offspring longterm for increased obesity themselves, along with increased vulnerability to mood disorders. We review the evidence that programming of brain and behavior by perinatal diet is propagated by inflammatory mechanisms, as obesity and high-fat diets are independently associated with exaggerated systemic levels of inflammatory mediators. Due to the recognized dual role of these immune molecules (eg, interleukin [IL]-6, 11-1β) in placental function and brain development, any disruption of their delicate balance with growth factors or neurotransmitters (eg, serotonin) by inflammation early in life can permanently alter the trajectory of fetal brain development. Finally, epigenetic regulation of inflammatory pathways is a likely candidate for persistent changes in metabolic and brain function as a consequence of the perinatal environment.     

A plausible model of schizophrenia must incorporate psychological and social, as well as neuro developmental, risk factors

Subtle alterations in brain development caused by genes or early environmental hazards, such as obstetric complications, play a role in projecting some individuals on a trajectory toward schizophrenia. High-risk and cohort studies demonstrate that children destined to develop schizophrenia tend to have delayed milestones and subtle neuromotor and cognitive impairments (particularly in coordination and language). These neurocognitive problems lead to difficulties in interpersonal relations, and their progressive alienation makes these at-risk children more likely to harbor odd or paranoid ideas. This cascade of increasingly deviant development may then be compounded by brain maturational changes during adolescence with a resultant lability of the dopaminergic response to stress. As a result, the individual is more susceptible to the effects of the abuse of dopamine-releasing drugs, and to other risk factors such as migration or stressful life events; social isolation may be a common pathway underlying several of the social risk factors.