Chronic Brain Disorder Research Articles

Lipid peroxidation measurement by thiobarbituric acid assay in rat cerebellar slices

Lipid peroxidation by reactive oxygen species (ROS) is known to be involved in the damaging mechanism of several acute and chronic brain disorders. The most prominent and currently used assay as an index for lipid peroxidation products is the thiobarbituric acid assay (TBA test). It is based on the reactivity of an end product of lipid peroxidation, malondialdehyde (MDA) with TBA to produce a red adduct. However, it is known that the MDA levels are frequently overestimated, that the reaction lacks specificity and mainly reflects the susceptibility of brain tissue to the generation and degradation of newly formed lipid hydroperoxides under the TBA test conditions. The present paper shows that artifactual lipid peroxidation by TBA test conditions can be prevented and that the MDA level overestimation can be minimized in cerebellar slices. This can be done by incubating the slices in a continuous tissue perfusion system, by adding butylated hydroxytoluene (BHT) to the homogenization solutions and by carrying out the assay anaerobically on deproteinizated supernatants of cerebellar slice homogenates. The present research also showed that lipid peroxidation products generated during incubation of the slices by hydrogen peroxide (H 2O 2) could be measured without artifactual interference by the TBA test conditions.

Delirium, A Syndrome of Cerebral Insufficiency

Delirium, A Syndrome of Cerebral Insufficiency

Narcolepsy: way beyond sleep - ego's adaptive efficiency, psychological equilibrium and unconscious destinations

Narcolepsy is a chronic brain disorder characterized by excessive daytime sleepiness and sleep attacks. It affects up to one in a thousand people. Rapid eye movement (REM) sleep phenomena such as cataplexy, sleep paralysis and hypnagogic hallucinations can also occur […] Narcolepsy: way beyond sleep – ego’s adaptive efficiency, psychological equilibrium and unconscious destinations. (Abstract). Dissertation, Sao Paulo, 2003.

Development of Immunopharmacotherapy Against Drugs of Abuse

Drug addiction is a major worldwide medical and social problem that continues to escalate. The addiction syndrome is remarkably similar between different drugs of abuse, and can be characterized as a chronic relapsing brain disorder with neurobiological changes that lead to a compulsion to take a drug with loss of control over drug intake. Presently used medications for the treatment of dependence disorders are based on drugs that are either agonists or antagonists of drugs of abuse, and have yielded only limited success. Immunopharmacotherapy is based on the generation or administration of antibodies that are capable of binding the targeted drug before it can reach the brain, whereas replacement strategies based on agonists or antagonists of these drugs generally cause many undesired side effects. A large amount of data has been gathered in recent years on the effects of active and passive immunization against cocaine, nicotine, PCP and methamphetamine in animal models, suggesting potential efficacy of these treatments in humans; and clinical trials are currently underway for vaccines against cocaine and nicotine.

Possible Role of the Extracellular Signal-Regulated Kinase (ERK) in Reward-Controlled Learning and Addiction

Drug addiction is characterized by loss of control over drug consumption, with compulsive drug seeking and taking, despite obvious adverse consequences. It is a chronic brain disorder since the increased risk of relapse to active drug use remains high even after years of abstinence. Current research attempts to identify the cellular and molecular basis for the neuronal modifications underlying these complex behavioural alterations. Strong evidence indicates that the extracellular signal-regulated kinase (ERK) pathway is a conserved intracellular signalling module, critical for various important for reward-controlled learning and addiction. Moreover, pharmacological and genetic approaches support a role of the ERK pathway in some of the long-term effects of addictive drugs. We suggest that drug-induced stimulation of the ERK pathway by dopamine in specific brain areas may be an exaggeration of its normal role in learning controlled by reward, and may contribute significantly to the acquisition of specific behaviours characteristic of drug addiction.

Síndrome de Rasmussen: una enfermedad autoinmune

Rasmussen's disease is an inflammatory, chronic and progressive brain disorder that usually presents with neocortical focal seizures resistant to conventional treatment and culminates in severe deterioration with hemiparesis, cognitive decline and aphasia. Viral infections and antibodies to the GluR3 receptor have been implicated in the physiopathology of this illness and T-cell mediation may play a role in the cerebral inflammatory process. Classical treatment consists of hemispherectomy of various magnitudes depending on cerebral involvement. The association between therapy-resistant epilepsy and autoimmune phenomena due to antibodies against glutamic acid decarboxylase (anti-GAD) have very recently begun to be studied. The discovery of this association led to a new focus and alternative therapies with immunosuppressors, immunoglobulins, steroids and plasmapheresis, alone or in combination, have begun to be tested with variable success. We describe a boy who was diagnosed in the early stages of Rasmussen's syndrome. He tested positive for anti-GAD antibodies and received treatment with immunoglobulins and steroids. After treatment the boy tested negative for anti-GAD antibodies and he remains asymptomatic after ten months.

Neuroanatomy and neurophysiology in schizophrenia

Schizophrenia is a major mental disorder, characterized by their set of symptoms, including hallucinatory-delusional symptoms, thought disorder, emotional flattening, and social withdrawal. Since 1980s, advances in neuroimaging and neurophysiological techniques have provided tremendous merits for investigations into schizophrenia as a brain disorder. In this article, we first overviewed neuroanatomical studies using structural magnetic resonance imaging (s-MRI), MR spectroscopy (MRS), and postmortem brains, followed by neurophysiological studies using event-related potentials (ERPs) and magnetoencephalography (MEG), in patients with schizophrenia. Evidences from these studies suggest that schizophrenia is a chronic brain disorder, structurally and functionally affecting various cortical and subcortical regions involved in cognitive, emotional, and motivational aspects of human behavior. Second, we reviewed recent investigations into neurobiological basis for schizophrenic symptoms (auditory hallucinations and thought disorder) using these indices as well as hemodynamic assessments such as positron emission tomography (PET) and functional MRI (f-MRI). Finally, we addressed the issue of the heterogeneity of schizophrenia from the neurobiological perspective, in relation to the neuroanatomical and neurophysiological measures.

Drug addiction: functional neurotoxicity of the brain reward systems.

Drug addiction is a chronic relapsing brain disorder characterized by a compulsion to take a drug with loss of control over drug intake. The hypothesis under discussion here is that chronic drug use produces long-lasting dysfunctions in neurons associated with the brain reward circuitry, and this "functional neurotoxicity" of drugs of abuse leads to vulnerability to relapse and continued drug dependence. Several sources of reinforcement are associated with various components of the drug addiction cycle and much progress has been made in identifying the midbrain-basal forebrain neural elements involved in the positive reinforcing effects of drugs of abuse and more recently in the neural elements involved in the negative reinforcement associated with drug addiction. Key elements for the acute reinforcing effects of drugs of abuse include a macrostructure in the basal forebrain called the extended amygdala that contains parts of the nucleus accumbens and amygdala and involves key neurotransmitters such as dopamine, opioid peptides, serotonin, GABA, and glutamate. Withdrawal from drugs of abuse is associated with subjective symptoms of negative affect and dysregulation of brain reward systems involving some of the same neurochemical systems implicated in the acute reinforcing effects of drugs of abuse. In addition, the functional toxicity of acute withdrawal is accompanied by recruitment of the brain stress neurotransmitter system corticotrophin-releasing factor. During more prolonged abstinence, post-acute withdrawal, evidence is accumulating of continued dysregulation of the neural systems associated with drug reinforcement and stress, regulation that may represent more subtle but persistent functional neurotoxic effects of chronic drug use and could be responsible for long-lasting vulnerability to relapse. Such functional neurotoxicity could be hypothesized to lead to a change in set point for drug reward that may represent an allostatic state contributing to vulnerability to relapse and re-entry into the addiction cycle. Elucidation of the specific neuropharmacological changes contributing to this prolonged functional neurotoxicity will be the challenge of future research on the neurobiology of drug addiction.

Long-term care in dementia: Patients and caregivers

General principles of managing chronic, age-associated diseases apply as much to Alzheimer's disease (AD) and other late-life dementing disorders as they do to congestive heart failure or osteoarthritis. Beyond efforts to maintain residual tissue or organ function, important physician roles include promoting general well-being and helping patients and their caregivers adjust to disease-related limitations. Physicians provide essential information to patients and their families about the disease, its social and legal ramifications, and community resources to facilitate care. Therefore, physicians must be knowledgeable about broadly intersecting medical, legal, financial, and ethical issues surrounding the long-term management of AD and other dementias. The many challenges faced by patients with dementia and their caregivers over time underscore the need for an ongoing diagnostic and therapeutic alliance with primary care physicians. This article reviews salient aspects of long-term care for patients with AD and other dementias, highlighting the vital and varied roles of physicians in managing these chronic brain disorders.

Alzheimer's disease: amyloid beta-peptide antibody vaccine as plaque remover.

Alzheimer’s disease (AD) is a major cause of dementia. It is believed to affect 11% of all humans over 65 years of age and 50% over the age of 85 in caucasian populations. It is a chronic brain disorder with a lengthy preclinical phase followed by a malignant stage associated with neuronal degeneration, loss of specific synaptic connections and progressive erosion of cognitive ability. AD begins with a subtle failure of memory, slowly becoming more severe and eventually incapacitating the patient. Neuronal degeneration in AD is highly selective for certain brain regions and types of neurons and can lead to a profound atrophy of the cerebral cortex. The amygdala, hippocampus and parahippocampus show a high degree of neurodegeneration, whereas the striatum and cerebellum are less affected. Subcortical pathways involving catecholaminergic, seritonergic and cholinergic transmissions are affected, whereas neocortical interneurons such as GABAergic and inhibitory are relatively unaffected. A subset of pyramidal cells in layers II, III and V that use excitatory amino acids as transmitters are highly vulnerable in AD. The loss of neurons has a variable time course between individuals and it could take months to years for a neuron to degenerate. Neuronal degeneration in AD starts rapidly from the medial temporal lobe and gradually spreads to other neocortical areas (Vickers et al 2000).

Is There a Neuropathology of Schizophrenia? Recent Findings Converge on Altered Thalamic-Prefrontal Cortical Connectivity

Schizophrenia is a serious and chronic brain disorder whose underlying neuropathology has proven difficult to identify. This article reviews the current status of neuropathological studies in terms of how they inform the diagnosis, pathogenesis, pathophysiology, and mechanisms of treatment of schizophrenia. Although additional studies are required, substantial data converge on the hypothesis that the pathophysiology of schizophrenia is associated with alterations in thalamic-prefrontal cortical connectivity.

Special Issue: The Neurobiology of Addiction

It is my pleasure to introduce the editor of this special issue on the neurobiology of addiction: Dr. Diane Snow, Director, Psychiatric Nurse Practitioner Program, University of Texas at Arlington, Associate Editor of this journal, and President of the International Nurses Society on Addictions, has assembled articles from a group of experts to bring us up-to-date research findings and some of the most compelling ideas in a vital area of addictions science. While working with Dr. Snow on this issue, I found her to be an earnest scholar committed to the belief that understanding the neurobiology of addiction is essential for nurses and other health care practitioners to provide relevant care in the 21st century. In addition to guest editing this issue, she contributed the article “Neurobiology of Violence, a Chronic Brain Disorder.” This excellent article demonstrates Dr. Snow's compassion for this long-maligned population. She induces readers to rethink some of our ideas as to the precursors of violent be...

Neurobiology of Violence, Viewed as a Chronic Brain Disorder

In summary, although there are many socio-cultural explanations for violent behavior, it is critical that health care providers adopt a stress-vulnerability model that carefully weighs the biologic factors contributing to violence as well as the environmental influences. In this way new and effective psychobiological interventions will offer hope and safety to the individual who is affected and the family and society that are at risk from that individual's violent behavior. Violence must be approached holistically, including spiritual interventions and complementary therapies that should be administered. In the future gene therapy may even offer hope of a cure. All of the therapies have the potential to alter brain chemistry and help heal this chronic brain disorder that involves inappropriate and potentially dangerous behavior.

Neurobiology of addiction. Toward the development of new therapies.

Drug addiction is a chronic relapsing brain disorder characterized by neurobiological changes that lead to a compulsion to take a drug with loss of control over drug intake. The hypothesis outlined here is that knowledge of the neurochemical systems involved in the transition from drug use to the compulsive use of addiction will provide the rational basis for development of pharmacotherapies for drug addiction. Much evidence has been obtained in identifying the midbrain-basal forebrain neural elements involved in the positive reinforcing effects of drugs of abuse and more recently in the neural elements involved in the negative reinforcement associated with drug addiction. Key elements for the acute reinforcing effects of drugs of abuse include a macrostructure in the basal forebrain called the extended amygdala that contains parts of the nucleus accumbens and amgydala and involves key neurotransmitters such as dopamine, opioid peptides, serotonin, GABA, and glutamate. Withdrawal from drugs of abuse is associated with subjective symptoms of negative affect, such as dysphoria, depression, irritability and anxiety, and dysregulation of brain reward systems involving some of the same neurochemical systems implicated in the acute reinforcing effects of drugs of abuse. In addition, acute withdrawal is accompanied by recruitment of the brain stress neurotransmitter system, corticotropin-releasing factor. Animal models of craving involve not only conditioning models but also models of excessive drug intake during prolonged abstinence, post-acute withdrawal, that may reflect continued dysregulation of drug reinforcement that could lead to vulnerability to relapse and represent an important focus for pharmacotherapy. Such changes have been hypothesized to involve a change in set point for drug reward that may represent an allostatic state contributing to vulnerability to relapse and re-entry into the addiction cycle. Elucidation of the specific neuropharmacological changes contributing to this prolonged functional dysregulation will be the challenge of future research on the neurobiology of drug addiction.

Ciliary neurotrophic factor protects hippocampal neurons from excitotoxic damage

The loss of neurons is responsible for many acute neurological disorders as well as chronic neurodegenerative diseases. This cell loss might be prevented by a direct delivery of neurotrophic factors. Therefore, we investigated the capacity of ciliary neurotrophic factor (CNTF) and nerve growth factor (NGF) as well as the combination of both growth factors on the glutamate-induced excitotoxic damage in hippocampal cultures. The exposure of hippocampal neuronal/glial co-cultures to 0.5 mM l-glutamate for 1 h induced pronounced neurotoxicity evaluated 18 h later by trypan blue staining and morphological criteria. The damaged neurons showed both apoptotic and necrotic features. However, CNTF (1–1000 pg/ml) reduced neuronal degeneration when administered 6 and 24 h before induction of injury and remained in contact with the cells until evaluation of neuronal damage. Furthermore, NGF (1 ng/ml) also rescued the hippocampal neurons under the same experimental conditions and with a similar to CNTF potency. However, the co-administration of NGF and CNTF (but not either factor alone) restored the neuronal survival to control levels. Our results support the hypothesis that administering neurotrophic factors could represent an alternative strategy for the treatment of acute and chronic brain disorders.

Sleep and Its Disorders

Sleep disorders are very prevalent in the general population and are associated with significant medical, psychological, and social disturbances. Insomnia is the most common. When chronic, it usually reflects psychological/behavioral disturbances. Most insomniacs can be evaluated in an office setting, and a multidimensional approach is recommended, including sleep hygiene measures, psychotherapy, and medication. The parasomnias, including sleepwalking, night terrors, and nightmares, have benign implications in childhood but often reflect psychopathology or significant stress in adolescents and adults and organicity in the elderly. Excessive daytime sleepiness is typically the most frequent complaint and often reflects organic dysfunction. Narcolepsy and idiopathic hypersomnia are chronic brain disorders with an onset at a young age, whereas sleep apnea is more common in middle age and is associated with obesity and cardiovascular problems. Therapeutic naps, medications, and supportive therapy are recommended for narcolepsy and hypersomnia; continuous positive airway pressure, weight loss, surgery, and oral devices are the common treatments for sleep apnea.

Microbes and the brain

“Many authors assure us that mental alienation is epidemic. It is certain that there are years when, independently of moral causes, insanity seems snddenly to extend to a great number of individuals” Esquirol, 1845 The roles of nature and nurture as determinants of human behaviour have been grist for philosophers for millennia. For much of the twentieth century infectious diseases captured the popular imagination with the hope that vaccines and antibiotics would provide cures not only for diseases clearly due to microbes such as poliomyelitis, rabies, and syphilis, but also for chronic brain disorders of unknown pathogenesis such as multiple sclerosis, depression, and schizophrenia. Proponents of infectious bases for these disorders have cited such evidence as discordance for disease in monozygotic twins (schizophrenia). increased prevalence with distance from the equator (schizophrenia and multiple sclerosis), and preponderance of second-trimester matemal exposure to respiratory tract infections, particularly influenza (autism, schizophrenia). More recently, we became enamoured with the notion that panaceas will arise through genome projects. Frustration with the ability to move beyond simple allelic Van Gogh: infected with microbes? associations to genetic causation has led to models based on interactions of genes. Although such models are plausible, it is reasonable to reintroduce the environment into the equation. As with most complex dialectics, the answers are likely to be found in synthesis: susceptibility genes coupled with environmental factors such as infectious agents, toxins, and psychosocial stressors. Most people would agree that if the relationship between any microbial agents and schizophrenia, affective disorders, or multiple sclerosis were elementary, the influence of such environmental factors on disease expression should already be apparent. A number of scenarios have been proposed to explain the difficulties in apprehending specific microbes through routine strategies for pathogen detection: low-level persistence in neural tissues, “hit-and-run” mechanisms, or indirect effects of pathogens through mechanisms such as molecular mimicry, where immune responses to an agent cross-react with normal host tissues to cause disease. Alternatively, environmental factors might also be inappropriately dismissed in cases where a wide variety of pathogens, neurotoxins, or general stressors induce nonspecific damage through elaboration of cellular or soluble immune mediators that lead to a final common pathway resulting in immediate or delayed brain dysfunction. The advent of molecular tools for detecting microbial footprints, such as subtractive cloning, polymerase chain reaction, and in-situ hybridisation, and also of methods for defining targets of immune responses, has rekindled interest in the search for a role of pathogens in idiopathic brain disorders. Examples include proposed linkages between multiple sclerosis and human herpes virus 6 or retroviruses, Alzheimer's disease and herpes simplex virus 1 in patients having the type 4 allele of the apolipoprotein E gene, E gene, neuropsychiatric disorders (major depression, bipolar disorder, schizophrenia, or chronic fatigue syndrome) and Bornaviruses, and paediatric obsessive-compulsive disorder and streptococci. Although intriguing, none of these relationships is established either as causative or as associative; however, each remains open and controversial despite ongoing investigation. Indeed, clinical trials are in progress for antimicrobial treatment of some of these disorders based on what many would consider to be only preliminary data. It is clear that neither Koch's postulates nor an updated facsimile inclusive of molecular technology will serve us here. The new era of microbial neuropathogenesis will require teams of diagnosticians, microbiologists, immunologists, geneticists, developmental neurobiologists, and epidemiologists who appreciate the complexity of host:microbe interactions and their implications for brain dysfunction.

Seizure classification in dogs from a nonreferral-based population

Summary On initial evaluation for onset of seizure disorders at nonreferral veterinary practices, 50 previously healthy dogs were enrolled in a study to determine the probability of identifying a specific cause for the seizures. Treatment was not administered prior to entry of dogs in the study. On the basis of antemortem and postmortem test results, 22 dogs (44%) were classified as having primary epileptic seizures (pes; idiopathic or without identifiable cause), 23 (46%) had secondary epileptic seizures (ses; identifiable intracranial cause), and 5 (10%) had reactive epileptic seizures (res; metabolic or transient noxious cause). Forty-one dogs (82%) had 2 or more seizures before evaluation, with 37 (90%) of these dogs classified as having epilepsy on the basis of an underlying chronic brain disorder. For these 41 dogs, 17 (41%) had pes, 20 (49%) had ses, and 4 (10%) had res. Among the 9 dogs (18%) with nonrecurring seizures, 5 had pes, 3 had ses, and 1 had res. Generalized seizures were the most common first-observed seizure type associated with all etiologic classifications in all dogs with recurring and nonrecurring seizures. Diagnosis of ses was statistically more probable when the dog was less than 1 or more than 7 years old at the first seizure, when the first seizure was a partial seizure, or when the first seizure occurred between midnight and 8 am. A diagnosis of res was statistically more probable only when the interval between the first and second seizure was brief (≤ 4 weeks). A diagnosis of pes was statistically more probable when the dog was between 1 and 5 years of age at the first seizure, when the dog was a large breed (> 15 kg), when the seizure occurred between 8 am and midnight, or when the interval between the first and second seizure was long (> 4 weeks).

Static Encephalopathies of Infancy and Childhood

The term static encephalopathy is a fancy phrase used by neurologists in recent years to refer to chronic nonprogressive brain disorders in children, primarily cerebral palsy and mental retardation. While numerous writings on these two topics may be found in various arenas, few textbooks are devoted to the topic itself. The authors, a pediatric geneticist and pediatric neurologist from Pennsylvania State University College of Medicine, note that these disorders are important and extensive, afflicting millions of children around the world. The book is divided into five major sections: the cerebral palsies and mental retardation, some specific congenital mental retardation syndromes, congenital malformations, acquired causes of static encephalopathy, and static encephalopathies associated with neuromuscular disorders. The authors have included solid neurological basics as well as recent advances in genetics, technology, imaging, and metabolic disorders. Appropriate illustrations of various syndromes and helpful tables are included. Especially helpful were the tables listing the

A sensitive ELISA for glial fibrillary acidic protein: application in CSF of children

In the present study we describe a sensitive ELISA for determination of glial fibrillary acidic protein (GFAP). To validate the method combined determinations of GFAP and S-100 protein were performed in cerebrospinal fluid (CSF) of normal children and children with autism. The GFAP ELISA is of sandwich type and uses the biotin-avidin system. Sensitivity was 16 pg/ml. Between-day precision was 0.079 (coeff. of varience). S-100 protein concentrations were measured using a commercially available ELISA kit. Normal CSF from children and young adults were analysed. The CSF levels of GFAP in normal children were low (16–163 pg/ml). Both GFAP and S-100 protein concentrations correlated with age ( P < 0.01 and P < 0.05, respectively), but the GFAP increment was more pronounced, probably reflecting the age-dependent expansion of the fibrillary astrocytes in the central nervous system (CNS). GFAP levels in children with infantile autism were higher than those in normal children of the same age range. S-100 protein concentrations were similar in both groups. High levels of GFAP in combination with normal S-100 protein concentrations in CSF indicates reactive astrogliosis in the CNS. In conclusion, the sensitive ELISA described makes it possible to measure low levels of GFAP present in the CSF of children. Combined assays of GFAP and S-100 protein can be used to discriminate between acute and chronic brain disorders in children.