bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Monocular Visual Loss
Authors: Levin Morris
Published: February 2014

Chapter 10 presents a case regarding acute monocular visual loss, and discusses how ophthalmological evaluation is critical in acute monocular visual loss, and should include a dilated funduscopic exam (prior to which careful pupillary testing should be done), when ophthalmological causes of monocular blindness have been excluded, retinal ischemia, ischemic optic neuritis, and demyelinating optic neuritis must be considered, and that diagnostic testing in acute visual loss should include brain and vascular imaging, ESR, and possibly lumbar puncture.
Thunderclap Headache
Authors: Levin Morris
Published: February 2014

Chapter 11 presents a case regarding thunderclap headache, and discusses how sudden severe headache is a potential emergency and should be evaluated with CT and, if negative, LP to rule out hemorrhage, how several diagnostic possibilities for thunderclap headache may not be diagnosed with CT, LP, or even MRI, and how primary thunderclap headache, thought to be a primary headache disorder, may be the underlying diagnosis, but must be a diagnosis of exclusion.
Febrile Delirium with Rigidity
Authors: Levin Morris
Published: February 2014

Chapter 12 presents a case regarding febrile delirium with rigidity, and discusses that febrile encephalopathy is a dire emergency that requires a speedy workup and may require empiric antibiotic treatment while diagnostic tests are pending, that muscle rigidity and high CK in the setting of febrile encephalopathy are suggestive of NMS, and treatment of NMS includes hydration, cooling, muscle relaxation, and immediate cessation of all neuroleptic medications.
Cardioembolic Stroke with Contraindications to Anticoagulation
Authors: Levin Morris
Published: February 2014

Chapter 14 presents a case of cardioembolic stroke with contraindications to anticoagulation, and discusses that both systemic bleeding and intracerebral bleeding risks must be considered before starting anticoagulation in the acute post-stroke setting, that when starting intravenous anticoagulation in the setting of acute cardioembolic stroke (bridge therapy) the risks of hemorrhagic conversion of the infarction and reinfarction due to subsequent reembolization may be about equal, that MRI of the brain and echocardiography can help the neurologist and patient assess pros and cons for starting heparin, and that if anticoagulation is begun in the acute post-stroke setting, strict control of BP, and close monitoring of bleeding parameters, are essential.
Progressive Posterior Circulation Ischemia
Authors: Levin Morris
Published: February 2014

Chapter 15 presents a case of progressive posterior circulation ischemia, and discusses how basilar thrombosis can present gradually with symptoms and signs referable to the pons and midbrain as well as occipital lobes, that CT scanning is often nondiagnostic, but a hyperdense basilar artery can sometimes be seen, that MRI, cerebrovascular imaging (MRA or CTA), echocardiography, and transcranial Doppler testing are all helpful in confirming the diagnosis and directing therapeutic decisions, and that intravenous thrombolysis, intra-arterial thrombolysis, stenting, and thrombectomy are all possible interventions.
Recurring Transient Ischemic Attacks
Authors: Levin Morris
Published: February 2014

Chapter 16 presents a case of recurring transient ischemic attacks, and discusses that recurrent transient neurological symptoms are best regarded as a warning for impending cerebral ischemic damage unless proven otherwise, that cerebral ischemia tends to produce 'negative phenomena,' whereas migraine and focal epilepsy produce more 'positive symptomatology', that TIAs should warrant a search for the contributing arterial causes as well as risk factors for stroke, and that MRA, CTA, transcranial Doppler, and conventional angiography can all supply important information about arteriopathy in cases of TIA and stroke.
Intractable Status Epilepticus
Authors: Levin Morris
Published: February 2014

Chapter 17 presents a case of intractable status epilepticus, and discusses how status epilepticus is diagnosed when seizure activity continues for more than 30 minutes or when a patient is experiencing repetitive seizures for more than 30 minutes without regaining full consciousness between them, that control of seizures must be achieved as quickly as possible, concurrent with a search for causes including meningitis, stroke, drug intoxication, metabolic derangements, or head trauma, that the general order of medication choices consists of benzodiazepines, phenytoin, phenobarbital, and general anesthesia, and that general medical monitoring for hyperthermia, hypertension, hypoxia, renal dysfunction, electrolyte imbalance, and arrhythmia must occur simultaneously with treatment of SE.
Severe Intractable Headache
Authors: Levin Morris
Published: February 2014

Chapter 18 presents a case of severe intractable headache, and discusses that even patients with a known headache disorder must be thoughtfully evaluated for the presence of a new secondary cause when presenting to the emergency department with intractable pain, howhere are a number of parenteral pharmacological choices for acute migraine treatment, including ketorolac, dihydroergotamine, magnesium, valproate, neuroleptics, and corticosteroids, how occipital nerve blocks may be a useful addition to the treatment options, and that medication overuse may complicate the picture of acute refractory migraine and must be addressed.
Acute Severe Facial Pain
Authors: Levin Morris
Published: February 2014

Chapter 21 presents a case of acute severe facial pain, and discusses how acute exacerbations of trigeminal neuralgia (TN) can be excruciating and can even lead to suicidality, that prophylactic pharmacological treatment of TN is generally very effective, that there are several options for acute treatment of TN exacerbations, although clear evidence of their efficacy is not yet available, and that atypical facial pain is a somewhat pejorative term that probably represents an overlap syndrome with many features of TN.
Neurological Patients and Decision-making Capacity
Authors: Levin Morris
Published: February 2014

Chapter 22 presents a case of neurological patients and decision-making capacity, and discusses that patients have the right to refuse treatment, that when you suspect that a patient has cognitive incapacity or a psychiatric condition that prevents understanding and/or appreciation of the seriousness of the medical status, and consequences of refusing treatment, a determination of decision-making capacity should be made, and that a court order can be obtained to test or treat, but in emergencies, an exception is generally assumed to be granted.
Functional Paraparesis
Authors: Levin Morris
Published: February 2014

Chapter 23 presents a case of functional paraparesis, and discusses signs of functional weakness, including Hoover’s sign, give-way weakness, inconsistency of findings, and normal reflexes, but also that these can all be misleading on occasion, that patients with weakness on the basis of conversion disorder are entirely unconscious that there is no organic basis to their paresis, and that patients with conscious gain in mind are malingering, and those who are producing symptoms in order to fit into a sick role have factitious disorder.
Nonepileptic Spells
Authors: Levin Morris
Published: February 2014

Chapter 24 presents a case of nonepileptic spells, and discusses that the diagnosis of psychogenic nonepileptic seizures (PNES) is challenging and patients may be misdiagnosed with epilepsy for years, that clues to the diagnosis of PNES can be found in the ictal presentation, as well as in the patient’s description of triggers, that video-EEG monitoring is generally successful in distinguishing PNES from epilepsy, and that communicating the diagnosis to the patient must be done in a clear and consistent but nonaccusatory way.
First Seizure
Authors: Levin Morris
Published: February 2014

Chapter 26 presents a case of first seizure, and discusses that first-time seizures should trigger an extensive workup to exclude intracranial pathology and metabolic causes, that the acute evaluation of a patient with a first-time seizure should include CT scan of the brain, and preferably, EEG, as well as full metabolic evaluation including toxicology, that MRI of the brain, and possibly LP, should also be done in the near future, and that the decision to begin seizure prophylaxis after a first seizure depends on the patient’s risks, preferences, and results of the workup, particularly MRI and EEG.
Severe Headache in a Child with Migraine
Authors: Levin Morris
Published: February 2014

Chapter 27 presents a case of severe headache in a child with migraine, and discusses that with severe migraine in a child, secondary causes must be ruled out, including neurological infections, intracranial mass, and systemic metabolic or infectious disease, how there is little evidence to aid in choosing agents for acute migraine treatment in children, that triptans can be very effective for childhood migraine, as can anti-nauseants and sedatives, and that most children with severe recurrent migraine headaches find them to be emotionally stressful and can benefit from individual and family counselling.
Febrile Seizure
Authors: Levin Morris
Published: February 2014

Chapter 28 presents a case of febrile seizure, and discusses that simple febrile seizures generally do not require lab investigation, that if there is any suggestion of meningitis or encephalitis, lumbar puncture should be strongly considered, how focal seizure activity, prolonged duration of the seizure (> 15 minutes), multiple seizures, older age (> 5 years), or abnormal neurological exam should prompt a more careful investigation, and that prophylaxis is not indicated for single simple febrile seizures.
Acute Ataxia in a Child
Authors: Levin Morris
Published: February 2014

Chapter 29 presents a case of acute ataxia in a child, and discusses that acute childhood ataxia is often due to a benign self-limited postinfectious condition, that an accurate history is important to assure that the ataxia is acute rather than gradually progressive, and to rule out accidental ingestions and accompanying symptoms, and that a workup of acute ataxia in a child should include head CT or MRI, and possibly LP.
Confusion in Childhood with Possible Abuse
Authors: Levin Morris
Published: February 2014

Chapter 30 presents a case of confusion in childhood with possible abuse, and discusses that there are four types of abuse that medics need to be able to diagnose—physical, sexual, psychological, and neglect, that signs of physical abuse are easiest to detect and treat, and should prompt the investigation of other types of abuse, that medics have a responsibility to keep the possibly abused child safe, and that theres is a responsibility to notify child protective services.
Concussion
Authors: Levin Morris
Published: February 2014

Chapter 31 presents a case of concussion, and discusses that concussion is defined as a change in neuropsychiatric function after a blow to the head, with or without loss of consciousness, that severe sequelae of head injury, such as epidural, subdural, and intracerebral hematomata must be ruled out acutely, how cerebral contusions can be delayed and should be investigated if the patient does not improve or regresses, and that there is recent consensus that returning to the field the same day after a sports injury is contraindicated.
Acute Stroke in an Adolescent
Authors: Levin Morris
Published: February 2014

Chapter 32 presents a case of acute stroke in an adolescent, and discusses that the causes of stroke in childhood and adolescence include those underlying adult stroke, as well as a number of other diseases, including hypercoagulable disorders and vascular anomalies, and that some conditions can mimic stroke, including hemiplegic migraine and postictal paralysis, that while tPA is probably a useful treatment in many adolescent strokes, the disparity in causation of childhood/adolescent stroke makes it difficult to design a protocol, and that anticoagulation is only indicated in the acute treatment of stroke in this age group when there is a clear cardiac thromboembolic source or cerebral venous thrombosis (and is generally standard treatment of arterial dissection as well).
Central Nervous System Trauma
Authors: Smith Colin
Published: February 2014

This chapter describes and illustrates the various pathological processes that result from head injury. Clinical, neuroradiological, and pathological data allow the separation of focal or diffuse damage. Focal lesions include scalp and skull lesions, contusions and lacerations of the brain, and intracranial hemorrhages. Diffuse lesions in traumatic brain injury include diffuse ischemia, diffuse traumatic axonal injury, and diffuse brain swelling. The consequences of penetrating injuries, blast injuries, and chronic traumatic encephalopathy resulting from repetitive head injury are also described. Separate sections are devoted to spinal cord injury and the consequences of brain injury in infants and children.
Infections of the Central Nervous System
Authors: Gray Françoise , Wong Kum Thong , Scaravilli Francesco , Sharer Leroy R.
Published: February 2014

This chapter describes and illustrates the different lesions observed in CNS infections. A wide variety of pathogenic infectious organisms may affect the CNS. They can be classified as “pathogenic” (causing disease in every individual) or “opportunistic” (affecting only patients with immunodeficiency). Bacteria may cause pyogenic infections or so-called “specific infections,” in which the morphology of the lesions is suggestive of a specific agent. Mycoses and parasitic infections used to be uncommon, restricted to certain countries; however, due to increasing incidence of immunodeficiency conditions and intercontinental travel, they are now more frequently encountered. Viral infections of the CNS cause nonspecific lesions due to immune-mediated reactions or more specific encephalitides. In AIDS, infection by the human immunodeficiency virus causes a unique encephalitis and immunodeficiency with a wide range of secondary opportunistic infections.
Human Prion Diseases
Authors: Ironside James W. , Frosch Matthew P. , Ghetti Bernardino
Published: February 2014

This chapter describes and illustrates the neuropathology of prion diseases, also known as transmissible spongiform encephalopathies. These diseases are characterized pathologically by varying combinations of spongiform change, neuronal loss, reactive gliosis, and prion protein (PrP) deposition. The morphologic pattern depends on the etiology of the disease and the genotype of the patient. Different clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (CJD) have been described depending on the PRNP codon 129 genotype and the PrP isotype. A novel form known as variably protease-sensitive prionopathy has been recently identified. Familial prion diseases include familial CJD, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. Over 40 different PRNP mutations have been identified. Acquired prion diseases include Kuru; iatrogenic CJD, particularly in recipients of contaminated human pituitary hormone, and variant CJD, which seems closely related to bovine spongiform encephalopathy.
Pathology of Degenerative Diseases of the Nervous System
Authors: Duyckaerts Charles , Lowe James , Frosch Matthew
Published: February 2014

Degenerative diseases of the nervous system are characterized by lesions involving specific systems of functionally related neurons. The abnormality is manifest by neuronal loss with variable astrocytic and microglial reactive changes. Accumulation of specific protein aggregates (e.g., Aβ‎, tau, α‎-synuclein, TAR-DNA-binding protein 43, polyglutamine) is a common feature, giving rise to distinctive intracellular inclusions or extracellular deposits. For some diseases, there are well-characterized genetic abnormalities. This chapter describes and illustrates the morphologic changes and genetic data in the different diseases. These are classified, according to the dominant clinical features, into five categories: degenerations of the cerebral cortex (dementia), movement disorders, cerebellar ataxia, motor neuron disease, and conditions associated with autonomic failure.
Hereditary Metabolic Diseases
Authors: Sedel Frédéric , Goebel Hans H. , Anthony Douglas C.
Published: February 2014

This chapter describes and illustrates the morphologic CNS changes in hereditary metabolic disorders. In some disorders, the metabolic derangements are most prominent in the cytosol and are linked to the dysfunction of a single cellular organelle. In these disorders there may be intracellular accumulation of an intermediate metabolite, resulting in a “storage disease” or accumulation of the abnormal substance within the cell. The organelles most commonly involved in these disorders are lysosomes, peroxisomes, mitochondria, and the cytoplasmic compartment. The other disorders are not linked to a specific cellular organelle. They are defined by an enzyme deficiency, the biochemical pathways involved (metabolic disorders of sugars, copper, amino acids, or structural protein), or only by morphologic/clinical features.
Pathology of Skeletal Muscle
Authors: Lidov Hart G. W. , De Girolami Umberto , Amato Anthony A. , Gherardi Romain
Published: February 2014

This chapter offers a contemporary approach to the classification of diseases of skeletal muscle and describes and illustrates the pathology of muscle disease, particularly from the perspective of the muscle biopsy. After an introductory exposition of the relevant laboratory techniques and a synopsis of the normal appearance of skeletal muscle, the basic reactions to injury are described. The ranges of diseases of skeletal muscle are then systematically considered and their specific morphologic, biochemical, and molecular genetic abnormalities are discussed in detail. The approach is to subdivide muscle disease into two broad categories: conditions that result in denervation of muscle (i.e., neurogenic atrophy) and diseases where the primary abnormality is in the muscle cell itself (i.e. myopathies). Genetically determined diseases of skeletal muscle discussed include muscular dystrophies, congenital myopathies, myofibrillar myopathies, and metabolic myopathies. Next described are the inflammatory myopathies, which are divided into two groups according to whether the causative agent is a known microorganisms or whether the inflammatory process is believed to be an autoimmune phenomenon.
Pathology of Peripheral Nerve
Authors: Vallat Jean-Michel , Anthony Douglas , De Girolami Umberto
Published: February 2014

This chapter gives a current classification of diseases of peripheral nerve and then describes and illustrates the pathology of peripheral nerve, particularly from the perspective of the nerve biopsy. After a description of the clinical indications for the biopsy, an introduction to the general laboratory techniques, and a brief review of the normal morphology of peripheral nerve, the general reactions of peripheral nerve to injury (primary axonal degeneration and primary segmental demyelination) are described. Neuropathies can be separated into acquired and hereditary neuropathies. Inflammatory neuropathies include immunopathological disorders of unknown cause (e.g. inflammatory demyelinating polyradiculoneuropathy), neuropathies due to infectious agents (e.g. leprosy), or those associated with systemic vasculitis. Neuropathy also occurs secondarily, in association with hematological diseases and neoplasms. Metabolic (diabetic) and toxic neuropathies are subsequently discussed. The chapter also gives an account of the importance of incorporating recent advances in molecular genetics in the evaluation of hereditary neuropathies (i.e. hereditary motor and sensory neuropathies, hereditary sensory and autonomic neuropathies, and familial amyloid polyneuropathies).
Diseases of the Pituitary Gland
Authors: Nosé Vânia , Hedley-Whyte E. Tessa
Published: February 2014

A wide variety of distinct pathological conditions may affect the pituitary, causing hormonal dysfunction and/or compression of surrounding structures. This chapter describes and illustrates the main pituitary lesions. Pituitary adenomas represent 10% to 20% of intracranial neoplasms in neurosurgical series. Their classifications are based on multiple factors, including histology and immunohistochemistry, ultrastructure and endocrine activity. Pituitary carcinomas are extremely rare. Pituitary hyperplasia is a rare cause of pituitary hyperfunction. Inflammatory (lymphocytic hypophysitis, granulomatous hypophysitis) and vascular (pituitary infarction, pituitary apoplexy, Sheehan syndrome) lesions can cause hypopituitarism. Craniopharyngiomas are the second most common neoplasm of the sellar region, following pituitary adenomas, and the most common suprasellar neoplasm in children.
Overview of Brain Development
Authors: Rubenstein John L. R.
Published: February 2014

This chapter highlights many of the major processes involved in brain development, including: induction of the central nervous system (CNS), patterning of the primordia of major brain regions, proliferation of neuroepithelial cells, differentiation and migration of immature neurons and glia, formation of axon tracts and synapses, and the establishment and plasticity of neuronal networks.
Neurochemical Systems in the Central Nervous System
Authors: Deutch Ariel Y. , Roth Robert H.
Published: February 2014

Chapter 2 describes the neurochemical organization of the brain. It summarizes the diverse types of molecules that neurons in the brain use as neurotransmitters and neurotrophic factors, and how these molecules are synthesized and metabolized. The chapter also presents the array of receptor proteins through which these molecules regulate target neuron functioning and the reuptake proteins that generally terminate the neurotransmitter signal. Today a large majority of all drugs used to treat psychiatric disorders, as well as most drugs of abuse, still have as their initial targets proteins involved directly in neurotransmitter function.
Principles of Signal Transduction
Authors: Girault Jean-Antoine , Greengard Paul
Published: February 2014

Chapter 4 covers postreceptor intracellular messenger cascades through which neurotransmitters and neurotrophic factors, and their receptors, produce their diverse physiological effects. A major advance over the past generation of research has been an appreciation of the complex webs of intracellular signaling pathways that control every aspect of a neuron’s functioning, from neurotransmitter signaling to cell shape and motility to gene expression. While only a small number of medications used in psychiatry today have as their initial target intracellular signaling proteins, it is likely that drug development efforts will look increasingly to such proteins for the discovery of novel medications with fundamentally new mechanisms of action.
Principles of Molecular Biology
Authors: Hyman Steven E. , Nestler Eric J.
Published: February 2014

This chapter provides an overview of the fundamental molecular processes by which information is encoded in the genome and how this information is expressed within an environmental context. We describe what genes are, how they function, and how their expression into RNA and protein is regulated by signals from outside the cell. Particular attention is given to a series of stimulus-regulated transcription factors, which play important roles in transducing information from the cell surface to the nucleus. Work in this area has shown that the control of gene expression by extracellular signals is a critical arena for gene–environment interactions that are highly relevant to psychiatry.
Transgenic Tools and Animal Models of Mental Illness
Authors: Monteggia Lisa M. , Carlezon William A. , Dileone Ralph J.
Published: February 2014

Animal models of neuropsychiatric disorders are important to elucidate the pathophysiological mechanisms underlying these disorders as well as develop better treatment options. There has been tremendous progress made in the field of mouse genetics, and more recently in rats, to manipulate the genome in order to assess the impact of specific genetic manipulations on the animal. These approaches are particularly important as new genes are implicated in specific mental disorders allowing one to directly assess their relevance in a complete animal system. These genetic approaches in mice have also complemented and extended our understanding of pharmacological models of psychiatric diseases. This chapter will provide a brief overview of transgenic mice, knockout mice, as well as viral-mediated gene transfer approaches in neurobiology and provide select examples of how these approaches have contributed to our understanding of brain function with implications for molecular psychiatry.
Application of Stem Cells to Understanding Psychiatric Disorders
Authors: Christian Kimberly M. , Hongjun Song , Guo-li Ming
Published: February 2014

Due to the remarkable discovery that somatic cells from adult humans could be reprogrammed into pluripotent stem cells, we now have the opportunity to create renewable sources of human neurons and glial cells to investigate the mechanisms underlying psychiatric disease. These induced stem cells are genetically identical to the donor individual and allow an unprecedented opportunity to investigate neurodevelopmental and neurodegenerative processes in a genetic context known to be permissive for disease. Although many higher-order features of mental disorders are inaccessible in cellular and animal models, we can gain insight into causal mechanisms underlying dysregulated neural circuitry by characterizing the functional capacity of human neurons in different environmental and genetic contexts. The field is now in its infancy and researchers are just beginning to explore the phenotypes of neurons derived from patients with complex psychiatric disorders such as schizophrenia and autism. Here we review some of the major breakthroughs and significant challenges in the effort to leverage this resource to develop innovative therapeutic strategies for psychiatric disease.
Genetic Methodologies and Applications
Authors: Purcell Shaun M.
Published: February 2014

There have been tremendous advances in the molecular technologies and data-analytic methods at our disposal for studying the genetic bases of complex d diseases and traits. These advances have enabled the creation of comprehensive catalogs of different forms of human genetic variation, as well as large-scale studies focused on specific diseases or traits. This chapter outlines the general principles behind some of these advances and discusses their application to studying complex genetic traits, with a focus on neuropsychiatric disease in particular. Different genetic strategies that are underway in psychiatric genetics include studies of de novo variation in exome sequencing, large deletion and duplication copy number variants, rare and low-frequency variants segregating in populations, and common polymorphisms.
The Brain and Its Epigenome
Authors: Mitchell Amanda C. , Jiang Yan , Peter Cyril J. , Goosens Ki A. , Akbarian Schahram
Published: February 2014

Exploration of the epigenome—collectively defined by DNA methylation, post-translational histone modifications, histone variants and other regulators of genome organization and function—has emerged as one of the most prolific areas of the basic and clinical neurosciences alike. This is due to a number of recent developments, including a wealth of genetic information on psychiatric disorders indicating that many risk-associated DNA variants and mutations do not affect protein coding sequences. Furthermore, the hopeful prospect of chromatin modifying drugs to lead to novel therapeutic options—while largely based on preclinical studies in small laboratory animals such as rats and mice— has infiltrated many areas of medicine, including neurology and psychiatry. Here, we summarize current concepts and emerging insights on epigenetic regulation in the nervous system, with focus on the human brain and the neurobiology and pharmacology of cognitive and emotional disease.
Network Methods for Elucidating the Complexity of Common Human Diseases
Authors: Schadt Eric E.
Published: February 2014

As big data comes to define the landscape in the life and biomedical sciences, carrying out successful research or providing the most appropriate diagnosis and treatment path for a given patient will more and more come to depend upon one’s ability to master the big data, to derive meaning and understanding from it. We can now score variations in DNA across whole genomes, RNA levels and alternative isoforms, metabolite levels, protein levels and protein state information, protein–protein interactions, and protein–DNA interactions, in a comprehensive fashion in entire populations of individuals. Interactions among these molecular entities define the complex web of biological processes that give rise to all higher order phenotypes, including disease. Most common forms of human disease such as schizophrenia, Alzheimer’s disease, and autism are not the result of single changes to single genes but rather emergent properties of the complex networks that define our systems at multiple scales (molecular, cellular, tissue, organ, organism, community). In order to elucidate the complexity of common human disease and other complex phenotypes, biological systems such as ourselves must be modeled as highly modular, fluid systems exhibiting a plasticity that allows them to adapt to a vast array of conditions. Leveraging the vast mountains of data to model biological systems in this way demands the development of analytical approaches that simultaneously integrate different dimensions of data. Here I motivate the need to take a more holistic approach to modeling biological systems and then detail different approaches that have been recently developed to carry out this type of modeling, from leveraging DNA variation as a systematic perturbation source to infer causal relationships among traits of interest, to the application of more advanced Bayesian network reconstruction algorithms to construct predictive network models of disease.
Brain Imaging Methodologies
Authors: Lu Hanzhang , Yang Yihong , Liu Peiying
Published: February 2014

Neuroimaging allows the study of psychiatric and neurological disorders on a systems level. It contains many sub-modalities that can reflect different aspects of brain anatomy, physiology, and function. Collectively, they provide a powerful toolbox for researchers and clinician to better understand the neurobiology of the disease and improve diagnosis. The greatest advantage of neuroimaging is that most modalities can be performed noninvasively, thereby it represents the most direct means to “look” inside the brain in living humans. This chapter focuses on several emerging neuroimaging methodologies in magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET) that are capable of making a major impact in the understanding, diagnostics and treatment monitoring of mental illness in the coming years.
Image-Guided Brain Stimulation
Authors: George Mark S. , Taylor Joseph J. , Henderson Jaimie M.
Published: February 2014

With our ability to image the brain’s structure or function we now have more sophisticated models, or maps, of how the brain works in health and disease. Luckily, in concert with the advances in brain imaging, there has been a steady expansion of new techniques that can focally stimulate the brain either invasively or non-invasively. These new brain stimulation or neuromodulation methods work hand in hand with brain imaging methods in order to determine where to stimulate or to examine the effects of stimulation.This chapter provides an overview of the ways in which the brain stimulation methods interact with, and even inform, brain imaging. We will particularly discuss the techniques where imaging is used to guide or target the stimulation.
Diagnosis of the Psychoses
Authors: Smith Lianne Morris , Messinger Julie W. , Malaspina Dolores
Published: February 2014

The phenomenon of psychosis has inspired and intrigued clinicians and scientists for centuries, from its diagnosis to its treatment and from its molecular basis to its behavioral presentation. This chapter focuses on diagnosis. It begins with an overview of the characteristic signs and symptoms that constitute the syndrome of psychosis, as well as the historical frame in which these features came to be recognized and categorized. This text also addresses the ongoing debate about the appropriate classification of psychosis within a disease category. This deliberation has been ongoing for over a century as, despite the fact that psychosis can be diagnosed with high reliability, there is wide variability in the natural history of patients with psychosis. The major variations discussed in this section include the presence of concurrent affective symptoms, episodicity, and prognosis. Given this variability, the question arises as to whether psychosis should be split into two distinct diagnostic categories according to the degree of prominence of affective symptoms (as in Kraepelin’s dichotomy between dementia praecox and manic-depressive insanity) or whether it constitute its own diagnostic category of “the psychoses” which presents variably with other symptoms across a spectrum (the unitary theory of psychosis)? To address this controversial subject, the next section of the chapter is devoted to a historical review of the major theories on the diagnostic classification or nosology of the psychoses. It also describes and contrasts the most prominently accepted systems of classification: the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Disease (ICD), as well as two research-based systems (the Feighner Criteria and the Research Diagnostic Criteria). The chapter concludes with a description of the frontiers of diagnostic classification which currently include the DSM5 (slated for publication in 2013) as well a novel project by the National Institute of Mental Health, called the Research Domain Criteria (RDoC) that promises to recast our conceptualization of mental illness.
Neuroimaging of Psychotic Disorders
Authors: Heckers Stephan , Woodward Neil , ÖNgür Dost
Published: February 2014

Neuroimaging studies of brain structure and function have significantly advanced our understanding of psychotic disorders by capturing the pathology with brain images. This chapter provides an overview of the neuroimaging studies of psychotic disorders (mainly schizophrenia and schizoaffective disorder). This will focus on meta-analyses and comprehensive reviews, but will include some seminal studies that have shaped the current understanding of psychotic disorders. The ability to study brain structure and function repeatedly and to correlate it with cognitive and clinical outcomes are unique strengths of neuroimaging studies and will ensure a prominent position of this research methodology in the study of psychotic disorders.
Mouse Models of Schizophrenia and Bipolar Disorder
Authors: Pletnikov Mikhail V. , Ross Christopher A.
Published: February 2014

Despite the recent advances in research into schizophrenia and bipolar disorder, the neurobiology of these maladies remains poorly understood. Animal models can be instrumental in elucidating the underlying mechanisms of neuropsychiatric disorders. Early animal models of schizophrenia and bipolar disorder used lesion methods, pharmacologic challenges or environmental interventions to mimic pathogenic features of the diseases. The recent progress in genetics has stimulated the development of etiological models that have begun to provide insight into pathogenesis. In this review, we evaluate the strengths and weaknesses of the existing genetic mouse models of schizophrenia and discuss potential developments for the future.
Cortical GABA Neurons in Schizophrenia
Authors: Curley Allison A. , Lewis David A.
Published: February 2014

Knowledge of the abnormalities in brain circuitry that give rise to the cognitive abnormalities found in schizophrenia is critical for developing new treatments. The cells that synthesize and release GABA, called GABA neurons (or interneurons), exhibit a variety of abnormalities in schizophrenia. Thus, alterations in GABA neurons are thought to underlie the cognitive deficits of schizophrenia. This chapter provides an introduction to interneurons and their role in cognition, a description of the GABAergic alterations found in schizophrenia, a review of potential mechanisms underlying these alterations, and a discussion of the consequences of impaired GABA signaling. The chapter concentrates on the prefrontal cortex (PFC), a brain area especially critical for cognition and where interneurons have been most extensively studied in schizophrenia.
Synaptic Disease in Psychiatry
Authors: Grant Seth G. N.
Published: February 2014

Human synapses contain over 1000 proteins forming the synapse proteome and diseases that disrupt these proteins cause synaptopathy. Hundreds of gene mutations in synapse proteins cause over 130 brain diseases including major psychiatric, neurological and childhood developmental disorders. The synapse proteome is organized into the presynaptic and postsynaptic proteome and each is further organized into macromolecular multiprotein complexes that perform key functions. Disruption of these complexes underlies a common etiology of diseases with related clinical features such as Schizophrenia, Autism and Intellectual Disability. Mutations in the different genes encoding the proteins comprising these complexes also underlies the multigenic nature of diseases. Synaptic disease is emerging as a major cause of brain disease and understanding the organization and function of the synapse proteome opens important new avenues for disease classification and therapeutic intervention.
Neurodevelopment and Schizophrenia
Authors: Kwon Ester J. , Soda Takahiro , Tsai Li-Huei
Published: February 2014

A neurodevelopmental model of schizophrenia postulates that some of the key aspects of brain development that normally occur both pre- and post-natally are not occurring correctly, either in time or space. Complex neural circuitry needs to form and be modulated by experience. Classically, proliferation, migration, arborization and myelination occur prenatally. Elaboration and refining of dendritic trees and synapses as well as myelination of the nervous system continues through the first two-decade of life. There are opportunities for genetic and environmental abnormalities and variation to profoundly influence the trajectories of all of these critical functional processes.
Neurobiology of Mental Illness Psychosis Proneness
Authors: Gur Raquel E.
Published: February 2014

Attenuated psychotic symptoms characterize the prodromal phase of schizophrenia spectrum disorders. Becausemany help-seeking individuals who manifest such symptoms do not transition to psychosis, the incorporation of brain behavior measures that canidentify psychosis proneness may help understand potentially contributing neurobiological mechanisms.

Neurobehavioral studiesin clinical risk groups show diffuse deficits across multiple domains.The pattern is similar, but less severe, than that observed in schizophrenia. Neuroimaging studies of brain structure, connectivity and activation, also indicate abnormalities in a pattern similar to that evident in schizophrenia. Limited longitudinal studies suggest that transition to psychosis is associated with greater aberrations of neurobehavioral and neuroimaging measures. These findings pave the way to developing models that can predict progression and offer avenues for interventions.
Psychotic Disorders: Neurochemistry and Pharmacotherapy
Authors: Tamminga Carol A. , Ivleva Elena I.
Published: February 2014

This paper starts with the conceptualization of psychosis as an intermediate phenotype and argues for its usefulness. The goal of such a re-conceptualization includes the possibility of advantaging the molecular, cellular and systems understanding(s) of psychosis and promoting novel treatment development. Molecular hypotheses of schizophrenia exist but have not heretofore been correct. Although current understandings of the biological basis of psychosis remain hypothetical, it is clear that current hypotheses are more directly based on brain biochemistry, structure and function. In this context the use of traditional and experimental treatments for schizophrenia are reviewed, drugs which might enhance cognition in schizophrenia as well as antipsychotic drugs.
The Neurobiology of Bipolar Disorder
Authors: Burdick Katherine E. , Haggarty Stephen J. , Perlis Roy
Published: February 2014

The focus of this chapter is squarely on bipolar disorder. Bipolar disorder is a severe mood disorder that often has psychotic features. Its most severe forms are more common than thought and significantly more likely to cause disability than originally thought. Studies of high-risk children have found them to be at increased risk for a variety of symptoms and neurobiological abnormalities. In contrast to schizophrenia, there is no formal prodromal syndrome that has been identified and cognitive abnormalities do not precede the onset of the disorder. Abnormal sleep and circadian rhythms are prominent and have led to intriguing biological models. Neurobiological experiments have primarily focused on candidate pathways and include circadian abnormalities, epigenetic processes including histone modification, Wnt/GSK3 signaling, other modulators of neuroplasticity, and mitochondrial dysfunction. Recent data suggest that bipolar disorder is a highly polygenic disease and that integration of prior modeling and data with the wide variety of new genetic risk loci will be productive in the future.
The Diagnosis of Mood Disorders
Authors: Fawcett Jan , Hager Brant
Published: February 2014

Mood disorders have been described by physicians since antiquity. Current categorical approaches to mood disorder diagnosis have undergone much study and revision, and have yielded some useful clinical and neurobiologic findings. However, current categorical approaches to mood disorder diagnosis have also presented problems for clinical care and research, including as yet limited prognostic and treatment predictive power, as well as weak associations with biomarkers and risk-conferring genes. Improved empirical efforts to understand mood disorder subtypes, extra-syndromic behavioral components, and cross-syndromic dimensional constructs, may serve better to elucidate candidate mechanisms for neurobiologic investigation and treatment intervention.
Genetics of Depression
Authors: Levinson Douglas F.
Published: February 2014

Categorical major depressive disorder has been the focus of most genetic studies, although some studies use continuous measures or consider both depression and anxiety. Lifetime risk of major depression is high (12-20%), heritability is below 40%, and the relative risk to first-degree relatives is approximately 3. These characteristics are challenging for current genetic methods. There have been several significant linkage findings which do not consistently replicate. Genomewide association studies have not produced significant findings, but analyses that cut across diagnostic boundaries seem promising. Candidate gene studies have been fraught with methodological problems, although the largest meta-analysis to date supported the hypothesis that 5-HTTLPR genotype and specific stressors interact to predict depressive episodes (but not lifetime risk of depression). Future steps include application of sequencing and stem cell technologies. Methods are need to build larger samples with more detailed clinical assessment. Outstanding genetic epidemiological issues should be addressed by new studies.
Neurobiology of Depression in Later Life
Authors: Rama Krishnan K. Ranga
Published: February 2014

Large-scale epidemiological work suggest that multiple pathways can lead to depression in the elderly. These pathways include a strong vascular component. The vascular pathway is one that we and others have suggested is critical in the development of depression in the elderly.

Vascular disease predisposes to depression, but depression may also heighten the risk for vascular disease and worsen the prognosis of vascular disease. We note that vascular lesions in prefrontal and basal ganglia regions lead to a vulnerability to depression. They do this by disrupting key circuits that regulate mood. Besides vascular factors neurodegenerative disorders also lead to increased depression presumably by similar disruption of pathways.
Gonadal Steroids and Mood Disorders
Authors: Rubinow David R. , Schmidt Peter J. , Craft Claire D.
Published: February 2014

Major depression is twice as common in women as in men, and there is mounting evidence that some women are particularly vulnerable to mood disorders during periods of reproductive change. The presence of these reproductive endocrine-related mood disorders, which include psychiatric disturbances during menarche, pregnancy or postpartum, the perimenopause, or the menstrual cycle, suggests a role for gonadal steroid hormones in affective regulation. Here we highlight the biological effects of estradiol and other gonadal steroid hormones and describe how these effects overlap with the pathophysiology of depression. We also review research into the mechanisms responsible for and treatment of reproductive-related mood disorders in women.
Depression and Medical Illness
Authors: Benton Tami D. , Blume Joshua , Crits-Christoph Paul , Dubé Benoit , Evans Dwight L.
Published: February 2014

The World Health Organization projects that depression will be the leading cause of life lost to disability in 2030, and there is increasing evidence that depression is a risk factor for the onset and progression of physical and social disability. Research suggests depression is prevalent among the medically ill, and depressed individuals may die years earlier from their medical illnesses than their non-depressed medically ill counterparts. Research examining the relationship between depression and medical illness point to a bi-directional relationship.We review the relevant research on the mechanisms linking depression and medical illness: cardiac disease, diabetes, HIV/AIDS and cancer. We provide an outline for the assessment of depression in the context of medical illnesses and treatment considerations.
Treatments for Depression
Authors: Iosifescu Dan V. , Murrough James W. , Charney Dennis S.
Published: February 2014

Since major depression is associated with significant morbidity and functional impairment, effective treatments are very important. This chapter reviews several categories of currently available antidepressant treatments (including the major classes of pharmacotherapies, somatic treatments, psychotherapies and natural remedies), attempting to review key findings regarding mechanisms of action, antidepressant efficacy and major side effects. We will also review significant data related to biomarkers of treatment outcome and to treatment of depression in special populations (e.g., psychotic, melancholic, atypical, postpartum, bipolar). We will conclude with a review of future antidepressant treatments currently in development.
Diagnosis of Anxiety Disorders
Authors: Keough Meghan E. , Stein Murray B. , Roy-Byrne Peter P.
Published: February 2014

This chapter is intended to familiarize the reader with the current nosological framework of anxiety disorders as well as its future directions. To provide a historical context for the current anxiety nosology, we begin by briefly reviewing the history and development of the current diagnostic criteria.We then discuss the DSM-5 by highlighting the current validators for the disorders, the proposed move of OCD and PTSD outside of the anxiety disorder categorization, and the specific proposed revisions to the criteria of the various anxiety disorders. The chapter also examines many of the controversies and shortcomings of the current nosology and explores the call for a new framework based on underlying mechanisms of disordered behavior.