Chronic Brain Disorder Research Articles

Target practice: HDAC inhibitors for schizophrenia

A report in this issue suggests that inhibiting histone deacetylase 2 (HDAC2) could be therapeutic in schizophrenia. Targeting chromatin remodeling in adults to treat a chronic brain disorder is not, however, likely to be easy.

Prevalence and Risk Factors of Epilepsy Among School Children in Eastern Turkey

Epilepsy is a serious chronic brain disorder of childhood. We performed a cross-sectional prevalence study, determined the prevalence of childhood epilepsy, and identified the significance of certain risk factors for epilepsy among 1625 primary-school students aged 6-14 years, living in the center of Kars province. A questionnaire was prepared according to the definitions and principles of the Commission on Epidemiology and Prognosis, International League Against Epilepsy. Twenty-two children were diagnosed as epileptic. The point prevalence of active epilepsy in males was 4.9/1000, and in females 12.4/1000, representing a total of 8.6/1000. The cumulative prevalence in males was 11.0/1000, and 16.1/1000 in females, representing a total of 13.5/1000. Febrile convulsions, family history of epilepsy, serious maternal illness during pregnancy, a history of head trauma, antenatal/postnatal problems, and a history of neonatal jaundice were statistically significantly related to the development of epilepsy.

Medicinal Plants Used to Treat Neurological Disorders in West Africa: A Case Study with Guinea-Bissau Flora

The sub-Saharan region holds a wide variety of indigenous plant species, still offering the possibility to discover very interesting new natural products with potential therapeutic value. Most of the African population depends on traditional medicine for primary health care, however, neurological disorders are often not considered as common diseases and many people with mental illnesses, like epilepsy, are severely affected by health-related stigma and discrimination. Epilepsy is the most common serious chronic brain disorder, estimated to affect at least 10 million people in Africa. Guinea-Bissau is located in West Africa, and its population is mainly rural with very few health services available. Since the earliest times, Guinea-Bissau flora has constituted the main source of materials used in folk medicine and the local population, who is well versed in the uses of these plants and their properties. The aim of this study was to document the existing knowledge and practices related to the treatment of neurological disorders, namely epilepsy and seizures, in Guinea-Bissau and in other West African countries. The results presented from this study provide information not only on the specific plants used to treat neurological disorders, but also on social knowledge brought in by various ethnic groups, each one having its own culture, beliefs and ways of nature appropriation. Taking into account the existing knowledge on the medicinal properties of plants for treatment of neurologic disorders, it is believed that research in the areas of ethnomedicine and ethnopharmacology in Guinea-Bissau can bring promising results capable of adding value to the very rich natural resources of this country of West Africa.

Hippotherapy in Adult Patients with Chronic Brain Disorders: A Pilot Study

ObjectiveTo investigate the effects of hippotherapy for adult patients with brain disorders.MethodEight chronic brain disorder patients (7 males, mean age 42.4±16.6 years) were recruited. The mean duration from injury was 7.9±7.7 years. The diagnoses were stroke (n=5), traumatic brain disorder (n=2), and cerebral palsy (n=1). Hippotherapy sessions were conducted twice a week for eight consecutive weeks in an indoor riding arena. Each hippotherapy session lasted 30 minutes. All participants were evaluated by the Berg balance scale, Tinetti Performance-Oriented Mobility Assessment, 10 Meter Walking Test, Functional Ambulatory Category, Korean Beck Depression Inventory, and Hamilton Depression Rating Scale. We performed baseline assessments twice just before starting hippotherapy. We also assessed the participants immediately after hippotherapy and at eight weeks after hippotherapy.ResultsAll participants showed no difference in balance, gait function, and emotion between the two baseline assessments before hippotherapy. During the eight-week hippotherapy program, all participants showed neither adverse effects nor any accidents; all had good compliance. After hippotherapy, there were significant improvements in balance and gait speed in comparison with the baseline assessment (p<0.05), and these effects were sustained for two months after hippotherapy. However, there was no significant difference in emotion after hippotherapy.ConclusionWe could observe hippotherapy to be a safe and effective alternative therapy for adult patients with brain disorders in improving balance and gait function. Further future studies are warranted to delineate the benefits of hippotherapy on chronic stroke patients.

Families and Addiction

Definitions vary but most are in agreement with the statement that addiction is a chronic brain disorder. According to Dr. Nora Volkow of the National Institute on Drug Abuse scientists are working...

Genetics of GABAergic signaling in nicotine and alcohol dependence.

Both nicotine and alcohol addictions are common chronic brain disorders that are of great concern to individuals and society. Although genetics contributes significantly to these disorders, the susceptibility genes and variants underlying them remain largely unknown. Many years of genome-wide linkage and association studies have implicated a number of genes and pathways in the etiology of nicotine and alcohol addictions. In this communication, we focus on current evidence, primarily from human genetic studies, supporting the involvement of genes and variants in the GABAergic signaling system in the etiology of nicotine dependence and alcoholism based on linkage, association, and gene-by-gene interaction studies. Current efforts aim not only to replicate these findings in independent samples, but also to identify which variant contributes to the detected associations and through what molecular mechanisms.

An initial study of identifying and controlling episode separations

Objective To imitate the process of identifying episode separations,which helps to improve the methodology of control episode separations.Methods Abstracts of inpatient record on all patients discharged from the hospitals in Beijing in 2010 were drawn from Beijing Public Health Information Center.Risk-adjusted by Diagnosis Related Groups-Beijing version (BJ-DRGs),two-weeks readmission rate was calculated at the whole city and hospital levels respectively.Comparing the readmission rate between these two levels,“suspicious objects”of episode separations can be found.In turn,the episode separations can be identified by detail analysis of these suspicious objects.Results In 2010,there were 13 DRGs with readmission rate exceeding 10％.Take the cases of dementia and other chronic brain disorders for example,the readmission rate for this type of inpatients in hospital G was much higher than the average level of the whole city.After the detail analysis of hospital G,the episode separations were found.Conclusion It is an effective method to indentify episode separations that calculating readmission rate based on the DRG risk-adjustment and using city level readmission rate as bench-mark. Key words: Episode separations; Evaluation; Diagnosis related groups(DRGs)

Nitric Oxide and Schizophrenia: Present Knowledge and Emerging Concepts of Therapy

Schizophrenia is a devastating, chronic brain disorder afflicting about 1 percent of the population. The etiology, neuropathology, and pathophysiology of schizophrenia remain elusive. Intense research has been conducted in order to identify specific biological markers of schizophrenia. The gas nitric oxide (NO) is an important signaling molecule involved in many cellular events that take place in the cardiovascular, immune and nervous systems of animals. This present review aims to show that NO and its metabolites play eminent roles in schizophrenia and have a significant influence on our understanding of the development, progression and, possibly, treatment of the disease. Special emphasis is given to aspects of genetic linkage between NO generating and modulating proteins and schizophrenia, and the impact of NO metabolism on processes known to be disturbed in this neuropsychiatric disorder (i. e., nerve cell migration, formation and maintenance of synapses, N-methyl-D-aspartic acid receptor mediated neurotransmission, adult hippocampal neurogenesis, membrane pathology and cognitive abilities). Although certain alterations of brain NO metabolism are not unique to, or indicative of, schizophrenia, their modulation might be a promising therapeutic option for the future.

Protracted abstinence from distinct drugs of abuse shows regulation of a common gene network

Addiction is a chronic brain disorder. Prolonged abstinence from drugs of abuse involves dysphoria, high stress responsiveness and craving. The neurobiology of drug abstinence, however, is poorly understood. We previously identified a unique set of hundred mu-opioid receptor-dependent genes in the extended amygdala, a key site for hedonic and stress processing in the brain. Here we examined these candidate genes either immediately after chronic morphine, nicotine, Δ9-tetrahydrocannabinol or alcohol, or following 4 weeks of abstinence. Regulation patterns strongly differed among chronic groups. In contrast, gene regulations strikingly converged in the abstinent groups and revealed unforeseen common adaptations within a novel huntingtin-centered molecular network previously unreported in addiction research. This study demonstrates that, regardless the drug, a specific set of transcriptional regulations develops in the abstinent brain, which possibly contributes to the negative affect characterizing protracted abstinence. This transcriptional signature may represent a hallmark of drug abstinence and a unitary adaptive molecular mechanism in substance abuse disorders.

Glucose-dependent insulinotropic peptide mitigates amyloid β-induced neurotoxicity independently of anti-inflammatory mechanisms

Alzheimer's disease (AD), a chronic degenerative and inflammatory brain disorder characterized by neuronal loss and dysfunction, is linked to accumulation of beta-amyloid (Aß) peptide. Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino-acid hormone, secreted from the enter endocrine K-cells, which has insulin-releasing and extra-pancreatic actions. GIP and its receptor (GIPR) present a widespread distribution in the mammalian brain, mainly in neurons and neuronal progenitor cells in the hippocampus, where they have been implicated with neuroplasticity, neuroprotection, neurogenesis and behavioral alterations. The present work was designed to determine the GIP effects on the synaptic deficit and inflammatory process induced by Aß1-40. The mice received injection of GIP (0.5 nmol/mice, i.c.v.) or vehicle 30 prior to the Aß1-40 (400 pmol/mice, i.c.v.) or PBS treatment. Fourteen days after the injection the animals were submitted to water maze paradigm, and the brains were removed to immunohistochemistry and PCR real time analysis. The intracerebroventricular (i.c.v.) injection of Aß1-40 (400 pmol) in mice resulted in a significant decline in spatial memory and synaptic loss, as demonstrated by water-maze paradigm and decline in hippocampal synaptophysin, respectively. Likewise, Aß1-40 led to an increase in iNOS (Fig. 1C), nNOS (Fig. 1D), TNF-a (Fig. 1A) and COX-2 (Fig. 1B) hippocampal expression. Interestingly, the treatment with GIP (0.5 nmol, icv) 30 min prior to the Aß1-40 treatment was able to prevented the cognitive impairment, the synaptophysin loss, the increase in iNOS and nNOS expression, but not TNF-a or COX-2 up-regulation (Fig. 1).

Acupuncture-related techniques for the treatment of opiate addiction: a case of translational medicine

Drug addiction is a chronic brain disorder characterized by withdrawal symptoms that occur during drug abstinence and a high tendency of relapse. Compared with the currently available pharmacological interventions, acupuncture therapy has the potential to help drug addicts stay away from drugs without major adverse side effects. It has taken decades of research to optimize the parameters of electrical acupoint stimulation for detoxification and for relapse prevention, as well as to establish a safe and easy procedure by which drug addicts can use it on themselves. The discovery that acupuncture can trigger the release of opioid substances from the brain in the 1970s provided the inspiration. Following this, basic research on animals made it possible to understand the mechanisms of action and establish the procedure for treating drug addictions. This article reviews the past, present, and foreseeable future regarding the use of acupuncture-related technique for the treatment of opiate addiction from the perspective of translational medicine.

Expression of the gene encoding the ghrelin receptor in rats selected for differential alcohol preference

The mechanisms involved in alcohol use disorder, a chronic relapsing brain disorder, are complex and involve various signalling systems in the brain. Recently, the orexigenic peptide ghrelin was shown to be required for alcohol-induced reward, an effect mediated via ghrelin receptors, GHS-R1A, at the level of the cholinergic-dopaminergic reward link. Moreover, ghrelin increases and GHR-R1A antagonists reduce moderate alcohol consumption in mice, and a single nucleotide polymorphism in the GHS-R1A gene has been associated with high alcohol consumption in humans. Therefore, GHS-R1A gene expression and alcohol intake were investigated in high, AA (Alko, Alcohol), versus low, ANA (Alko, Non-Alcohol), alcohol consuming rats as well as in Wistar rats. In the AA and ANA rats plasma ghrelin levels were also measured. GHS-R1A gene expression was increased in AA compared to ANA rats in nucleus accumbens, ventral tegmental area, amygdala, prefrontal cortex and hippocampus. A similar trend was observed in the ventral tegmental area of Wistar rats consuming high amounts of alcohol. Furthermore, the AA rats had significantly smaller reduction of plasma ghrelin levels over time, after several weeks of alcohol exposure, than had the ANA rats. The present study provides further evidence for that the ghrelin signalling system, in particular at the level of the mesocortocolimbic dopamine system, is involved in alcohol consumption, and thus possibly contributes to alcohol use disorder. Therefore the GHS-R1A may constitute a novel candidate for development of new treatment strategies for alcohol dependence.

S100B Protein Stimulates Microglia Migration via RAGE-dependent Up-regulation of Chemokine Expression and Release

The Ca(2+)-binding protein of the EF-hand type, S100B, is abundantly expressed in and secreted by astrocytes, and release of S100B from damaged astrocytes occurs during the course of acute and chronic brain disorders. Thus, the concept has emerged that S100B might act an unconventional cytokine or a damage-associated molecular pattern protein playing a role in the pathophysiology of neurodegenerative disorders and inflammatory brain diseases. S100B proinflammatory effects require relatively high concentrations of the protein, whereas at physiological concentrations S100B exerts trophic effects on neurons. Most if not all of the extracellular (trophic and toxic) effects of S100B in the brain are mediated by the engagement of RAGE (receptor for advanced glycation end products). We show here that high S100B stimulates murine microglia migration in Boyden chambers via RAGE-dependent activation of Src kinase, Ras, PI3K, MEK/ERK1/2, RhoA/ROCK, Rac1/JNK/AP-1, Rac1/NF-κB, and, to a lesser extent, p38 MAPK. Recruitment of the adaptor protein, diaphanous-1, a member of the formin protein family, is also required for S100B/RAGE-induced migration of microglia. The S100B/RAGE-dependent activation of diaphanous-1/Rac1/JNK/AP-1, Ras/Rac1/NF-κB and Src/Ras/PI3K/RhoA/diaphanous-1 results in the up-regulation of expression of the chemokines, CCL3, CCL5, and CXCL12, whose release and activity are required for S100B to stimulate microglia migration. Lastly, RAGE engagement by S100B in microglia results in up-regulation of the chemokine receptors, CCR1 and CCR5. These results suggests that S100B might participate in the pathophysiology of brain inflammatory disorders via RAGE-dependent regulation of several inflammation-related events including activation and migration of microglia.

S30-01 - Stress reactivity in patients with drug dependence and personality disorders

Drug dependence is defined as a chronic relapsing brain disorder that is defined by a compulsion to seek and use drugs despite negative consequences. Drug-related cues and stress are known to be key factors for drug use. It has been argued that drug use could be seen as self-medication in patients with drug dependence and co-occurring personality disorders. However, the relevance of co-occurring personality disorders for stress reactivity after drug use is not clear.Thirty drug-dependent patients on stable opioid maintenance treatment with and without personality disorders were examined in a randomized placebo-controlled crossover study to investigate the effects of diacetylmorphine (DAM = heroin) on stress reactivity. They were compared with 20 healthy volunteers receiving saline. The drug-dependent patients administered either their individual prescribed DAM dose or saline. Afterwards they completed four emotional tasks while brain responses were measured with functional magnetic resonance imaging (fMRI). Before and after the fMRI investigation, adrenocorticotropic hormone (ACTH), cortisol, DAM blood levels, and psychological stress parameters, such as anxiety, anger, and craving were measured.The findings of DAM effects on stress reactivity in patients with drug dependence and co-occurring personality disorders will be reported and clinical implications regarding specific psychosocial interventions will be discussed.

The role of inflammation in epilepsy

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis.

Expression of the new P2Y-like receptor GPR17 during oligodendrocyte precursor cell maturation regulates sensitivity to ATP-induced death

The P2Y-like receptor GPR17 is expressed by adult neural progenitor cells, suggesting a role in lineage determination. Here, we characterized GPR17 expression and function in mouse cortical primary astrocytes/precursor cell cultures. GPR17 is expressed by a subpopulation of oligodendrocyte precursor cells (OPCs), but not by astrocytes. This expression pattern was also confirmed in vivo. In vitro, GPR17 expression was markedly influenced by culturing conditions. In the presence of growth factors (GFs), no significant GPR17 expression was found. When cultures were shifted to a differentiating medium, a dramatic, time-dependent increase in the number of highly branched GPR17-positive cells was observed. Under these conditions, GPR17 was induced in the totality of O4-positive immature oligodendrocytes. Instead, in cultures originally grown in the absence of GFs, GPR17 was already expressed in morphologically more mature OPCs. Shifting of these cultures to differentiating conditions induced GPR17 only in a subpopulation of O4-positive cells. Under both culture protocols, appearance of more mature CNPase- and MBP-positive cells was associated to a progressive loss of GPR17. GPR17 expression also sensitized cells to adenine nucleotide-induced cytotoxicity, whereas activation with uracil nucleotides promoted differentiation towards a more mature phenotype. We suggest that GFs may keep OPCs in a less differentiated stage by restraining GPR17 expression, and that, under permissive conditions, GPR17 contributes to OPCs differentiation. However, upon high extracellular adenine nucleotide concentrations, as during trauma and ischemia, GPR17 sensitizes cells to cytotoxicity. This double-edged sword role may be exploited to unveil new therapeutic approaches to acute and chronic brain disorders.

Heroin reduces startle and cortisol response in opioid-maintained heroin-dependent patients

Heroin dependence (HD) is a chronic relapsing brain disorder characterized by a compulsion to seek and use heroin. Stress is seen as a key factor for heroin use. Methadone maintenance and the prescription of pharmaceutical heroin [diacetylmorphine (DAM)] are established treatments for HD in several countries. The present study examined whether DAM-maintained patients and methadone-maintained patients differ from healthy controls in startle reflex and cortisol levels. Fifty-seven participants, 19 of each group matched for age, sex and smoking status, completed a startle session which included the presentation of 24 bursts of white noise while eye-blink responses to startling noises were recorded. Salivary cortisol was collected three times after awakening, before, during and after the startle session. DAM was administered before the experiment, while methadone was administered afterwards. Both heroin-dependent patient groups exhibited significantly smaller startle responses than healthy controls (P < 0.05). Whereas the cortisol levels after awakening did not differ across the three groups, the experimental cortisol levels were significantly lower in DAM-maintained patients, who received their opioid before the experiment, than in methadone-maintained patients and healthy controls (P < 0.0001). Opioid maintenance treatment for HD is associated with reduced startle responses. Acute DAM administration may suppress cortisol levels, and DAM maintenance treatment may represent an effective alternative to methadone in stress-sensitive, heroin-dependent patients.

Healthy aging and preclinical dementia: The United States–Israel Longitudinal Database Project

This article proposes the establishment of a United States–Israel Longitudinal Database for Healthy Aging and Preclinical Dementia as a prototype model for the eventual creation of an international database. It is envisioned that such a comprehensive international database, as a shared research resource, will provide the foundation for a systems approach to solve the dual public health problems of: (1) Early detection of individuals at an elevated risk of developing Alzheimer’s disease, and (2) Developing interventions to delay onset of, or prevent, chronic brain disorders later in life.

High cocaine dosage decreases neurogenesis in the hippocampus and impairs working memory

Drug addiction is a chronic brain disorder, characterized by the loss of the ability to control drug consumption. The neurobiology of addiction is traditionally thought to involve the mesocorticolimbic system of the brain. However, the hippocampus has received renewed interest for its potential role in addiction. Part of this attention is because of the fact that drugs of abuse are potent negative regulators of neurogenesis in the adult hippocampus and may as a result impair learning and memory. We investigated the effects of different dosages of contingent cocaine on cell proliferation and neurogenesis in the dentate gyrus of the hippocampus and on working memory during abstinence, using the water T-maze test, in adult rats. We found that cocaine, in addition to the changes it produces in the reward system, if taken in high doses, can attenuate the production and development of new neurons in the hippocampus, and reduce working memory.

Hypercholesterolemia in rats impairs the cholinergic system and leads to memory deficits

Alzheimer's disease (AD) is a chronic brain disorder characterized by cognitive impairment, cholinergic dysfunction, inflammation, tau and beta-amyloid pathology and vascular damage. Recent studies have shown, that high cholesterol levels are linked to the pathology of AD. The aim of our present work was to study the effects of hypercholesterolemia in adult rats. Five months after 5% cholesterol-enriched diet plasma cholesterol levels and total weight were significantly enhanced compared to controls. Spatial memory was studied in an 8-arm radial maze and cholesterol-treated rats showed an impaired learning and long-term memory. Hypercholesterolemia significantly reduced the number of cholinergic neurons in the basal nucleus of Meynert and decreased acetylcholine levels in the cortex. Nerve growth factor was only slightly enhanced in the cortex of cholesterol-treated animals. Levels of amyloid precursor protein, beta-amyloid(1–42), as well as tau and phospho-tau 181 were significantly enhanced in the cortex of cholesterol-fed rats. Hypercholesterolemia markedly increased several cerebral inflammatory markers and enhanced microglial CD11b-like immunoreactivity. Vascular density, stained by RECA-1 was not changed. However, cholesterol induced cortical microbleedings illustrated by intensive anti-rat IgG-positive spots in the cortex. In conclusion, our data demonstrate that hypercholesterolemia in rats caused memory impairment, cholinergic dysfunction, inflammation, enhanced cortical beta-amyloid and tau and microbleedings, all indications, which resemble an AD-like pathology.