Research
Research Center
Israel, despite its small size, has grown into a major player on the world science stage: According to an analysis in Science (7 February 1997 p. 793). Israel ranks second behind Switzerland in scientific papers per capita and third behind Switzerland and Sweden in citations per capita (7 May Science 1999 p. 894).
Herzog Hospital
Israel’s foremost center for geriatric and mental health care, Sarah Herzog Hospital combines exceptional medical care with outstanding research achievements. Herzog Hospital, established in 1895, treats the effects of advancing age and mental instability with the best medical technologies combined with professional expertise, compassion and care. With 340 beds, Herzog Hospital is the third largest hospital in Jerusalem.
For the past 30 years the Hospital has been at the forefront of biomedical and behavioral genetics research. Research done at Herzog Hospital is interdisciplinary, and combines a broad approach to studying complex behaviors, mental illness and aging, using techniques of molecular genetics and psychology
Current research projects include: Molecular Genetic Investigations of Schizophrenia, Bipolar Disorder and Autism; in neurological domains such as degenerative diseases including Alzheimer’s and Parkinson’s Diseases, stroke; ataxia; epilepsy and genetic studies of aging; Molecular Genetic Studies of Normal Personality and Schizophrenia; Molecular Genetic and Personality Aspects of Substance Abuse including Smoking; Psychological and Genetic Aspects of Eating Disorders, especially Anorexia Nervosa, and Mapping Genes to Attention Deficit Hyperactivity Disorder.
The Hospital’s doctors and scientists are widely published in a multitude of international scientific journals and books.
Goals
Problems of aging and mental health are an increasing burden in all societies. We believe that the scientific research is the best hope for resolving these problems in a satisfactory and human way. Herzog Hospital strives to be at the forefront of this battle.
In order to maintain the Hospital at the forefront of this scientific revolution in human genetics and disease, and to continue to contribute to the excellence of Israeli science, we are now embarking on an ambitious plan to strengthen the research infrastructure. A major goal is the building and furnishing of a new Research Center to continue to maintain its cutting edge biomedical research in Israel and in the world.
The Plan
The proposed Research Center will ultimately encompass an area of about 1000 square meters of laboratory space on one level. The recent construction of the Aaron Beare Research Laboratories has enabled the research staff to move into the first 250 meters of new, expanded space.
The Next Phase -The New Research Center
The second phase will be to construct the additional 750 square meters to complete the new Research Center. This will extend the capabilities of the laboratories to include, among other functions, basic aging research, neurophysiology, neuro-psychology, nutritional function and complex behavior/neurobiology and include part of the molecular genetics laboratories, and special tissue culture laboratory (biohazard clean areas).
Research Being Conducted or Planned at Herzog
Prof. Richard Ebstein’s research focuses primarily on the role of genes in abnormal human physiology and behavior. Special areas of interest are Alzheimer’s & Parkinson’s disease, stroke, mental illnesses, anti-social behaviors such as violence, substance abuse and sexual crimes including rape. Prof. Ebstein’s studies of normal and abnormal personality and particularly the discovery of the “Thrill Seeking Gene” made world wide headlines, including the front page of the NY TIMES and feature articles in TIME and NEWSWEEK. Not only is this gene important in explaining Thrill Seeking behavior in normal people but, as Prof. Ebstein has shown, it also contributes to heroin addiction (and other forms of substance abuse) and perhaps anti-social activities such as the recent shooting incidents in the United States.
Another area of interest for Prof. Ebstein and his research group is the genetics of schizophrenia and manic-depressive illness. In a Trilateral (Germany-Israel-Palestine) program that is sponsored by the German government, Arab Palestinian families are being recruited for genetic studies of schizophrenia.
In collaboration with Prof. Mona Soreq, Director of the Silberman Life Sciences Center at the Hebrew University, the genetic causes of stroke and dementia are being studied.
In collaboration, psychologists from the Ben-Gurion University of the Negev, the Center is pioneering studies of early childhood behavior to delineate the role of both genes and environment in contributing to early developmental aspects of temperament that lead to anti-social personality traits. Supported by a major grant from the U.S. National institute of Mental Health, the Dept is studying the role of genes in ,b>Attention Deficit Hyperactivity Disorder (ADHD). In a related collaborative project sponsored by the European Economic Community, the Dept is also conducting on the genetics of ADHD, with Prof. Joe Sergeant (Amsterdam, Netherlands) and Dr. Phillip Asherson (Institute of Psychiatry, London).
Prof. Ebstein in collaboration with Dr. Galila Agam and the Ben-Gurion University of the Negev have patented a diagnostic procedure for manic-depressive illness. Negotiations are currently underway to find a commercial partner to help us develop this facet of the Center’s research activities.
Anorexia Nervosa
Anorexia Nervosa (AN) is a serious disease with both psychiatric and biologic complications and which is most difficult to treat. Due to voluntary starvation, excessive physical exercise and various programs for weight reduction, these patients often reduce their body weight down to 70% of the desired level or even lower. At such level of weight loss, various cascades of deterioration take place both physically and mentally. It is not clear how patients (predominantly young girls) tolerate the serious effects of such voluntary starvation. One of the hallmarks of AN is denial of the problem and refusal to be treated. It often becomes chronic and has the highest mortality of all psychiatric disorders. Costs of hospitalization and medical care are substantial and there is little understanding of the etiology of anorexia and no effective drug therapy. Recent studies suggest that genes underlie a substantial portion of the liability
Research is being conducted on the personality and genetic factors contributing to anorexia nervosa. A large group of anorexic and non-clinical families have been recruited. The objectives of this anorexia research project are to understand the relationships between environment, genes, personality, behavior and recovery in women with AN, to provide targets for pharmacological treatment and to benefit clinical treatment and public health.
The Nutrition and Brain Function Laboratory
Directed by Dr. Shai Shoham, it focuses on how manipulation of nutrition can benefit brain function in a variety of medical problems including Parkinson’s and Alzheimer’s disease, stroke, epilepsy, ataxia and age-associated cognitive decline. His research is based on animal models of the above mentioned diseases since several questions about brain structure and function cannot be studied in human subjects. Dr. Shoham is one of the top experts on brain anatomy in Israel. Research projects currently underway in his laboratory are:
Neurodegenerative Diseases and Aging
The major neurodegenerative diseases associated with aging are Alzheimer’s and Parkinson’s disease. Stroke and epilepsy also are diseases that involve neurodegenerative processes. Oxidative stress and glial activation are ubiquitous in neurodegenerative diseases. The work focuses on understanding how these processes cause damage to the brain and disrupt normal behavior. One strategy focuses on attenuation of oxidative stress. One element of the research includes attenuation of oxidative stress via nutritional manipulations such as reducing dietary iron content and treatment with drugs that attenuate oxidative stress. A new project launched in the lab explores nutritional treatments in a strain of mice with accelerated aging – senescence accelerated mouse (SAM). Another strategy is to increase neurotrophic activity in brain.
Ataxia and Excercise
A project recently initiated by Dr. Shoham examines the effects of exercise on recovery in a model of neurodegeneration in the cerebellum of mice. As part of this project, mice models of cerebellum ataxia are being studied. Exercise has been shown to exert effects of brain that are attributed to increased neurotrophic activities. In all these projects, a major emphasis is on understanding the relation between changes at the neuroanatomical level and changes at the behavioral level.
Effects of stress on brain and behavior
Stress can affect the brain via several and complex pathways involving both hormones and neurotransmitters, and is believed to be partially responsible for several behavioral disorders. However, the great complexity of these pathways makes it difficult to sort out the mechanisms and how they are responsible for different types of behavioral abnormalities. In collaboration with Prof. Hermona Soreq from the Hebrew University, Dr. Shoham’s lab is characterizing the effect of one stress signal – increase in activity of the enzyme acetylcholinesterase on brain and behavior. Stereotypic behavior, namely repetitive and apparently purposeless patterns of motor behavior, make this transgenic mouse a potential model for a group of psychiatric disorders in which such behavior is displayed including Tourette, Autism, Schizophrenia and pervasive developmental disorder. Furthermore, relative resistance of this strain of mice to neurodeterioration in aging suggests that this variant of acetylcholinesterase may moderate stress-like aspects of aging. A major contribution from these projects is expected to be a better understanding of the neuroanatomical principles underlying the impact of emotional stress.
Dr. Yakir Kaufman, the Director of the Department of Behavioral Neurology conducts research on behavioral changes in the elderly caused primarily as a result of dementia, Alzheimer’s and Parkinson’s Disease.
Lack of understanding of the relationship between psychogeriatrics, neurology and general medicine.
Sarah Herzog Hospital in Jerusalem is currently the only facility in Israel to combine neurological and behavioral approaches in treating the full range of geriatric illnesses.
Neurological diseases such as Alzheimer’s and Parkinson’s Diseases and dementia have a significant role in causing disability in the elderly. Of those aged over 65 with disabilities, almost half have neurological disorders that account for their infirmity, as do 90% of those who are totally disabled. Recent studies show that disability can either be prevented or the rate of its progression can be decelerated by early intervention, an accurate diagnosis, and comprehensive treatment. We believe that the existing clinical knowledge in neurology and its flanking medical specialties should enable much better all round diagnosis and treatment of the elderly.
In the elderly, a psychiatric syndrome (e.g. depressive behavior) is often the result of neurological and/or medical disease which affects the brain and is not just a psychiatric state. For example, a drug toxic effect on the brain might be quite frequent. Thus, a neurological/medical background of behavioral syndromes should be carefully looked for and is often not investigated.
The objectives of the research programs are:
• Ongoing evaluation and refinement of services provided by all three divisions.
• Development of new diagnostic and therapeutic strategies using a neurobehavioral approach.
• Continuation of research on clinical and brain-behavior that can be applied to both geriatric and non-geriatric populations.
• Expansion of current research on early indicators of Alzheimer’s Disease and other dementias.
• Clinical research of psychogeriatric syndromes and the influence of different therapeutic treatments on them.
Funding for the daily activities of the research department derive from a variety of public granting agencies including the Israeli Ministry of Health, the Israeli Center for Psychobiology, the Israeli Academy of Sciences, NARSAD-the National Alliance for Research on Schizophrenia and Depression, the U.S. National Institute of Mental Health, the German Research Foundation (DFG), and private donors.
Research is conducted by a multi-disciplinary team incorporating outside experts in the relevant fields. The new Research Center will obtain the most advanced equipment to enable our doctors and scientists to conduct the highest level of research.
Schizophrenia
Schizophrenia is a neurodevelopmental mental disorder whose etiology includes genetic and environmental factors. Because of its early onset, chronicity, and characteristic interference with education, employment, and socialization, this illness represents a tremendous human and economic burden to those who suffer from it, their families, and society as a whole. Despite historical pessimism about schizophrenia prognosis, studies performed during the last decade suggest that early identification and intervention can improve outcome. These findings have stimulated great interest for the idea that intervention at or even prior to the onset of the first illness episode might improve subsequent treatment response and long-term outcome.
One aspect of this increased emphasis is to highlight the potential damage associated with delays in treatment of early phases of psychotic illness. Recent data indicate that duration of untreated psychosis (DUP) in schizophrenia first episodes consistently predicts outcome independently of other variables and is not simply a proxy for other factors. As one of the few potentially malleable factors influencing outcome, DUP could prove to be a target for secondary preventive efforts in early psychosis. A related recently developed concept is the notion of even earlier pharmacological intervention during the prodromal phase of schizophrenia. This concept is based upon the hypothesis that genetic liability for schizophrenia could be manifest in brain dysfunction leading to psychiatric, neuropsychological, and psychosocial impairments even without or before the full illness manifestations. The clinical applicability of this paradigm is presently assessed and it entitles the development of improved criteria for detecting individuals at high risk for developing schizophrenia and of specific and ethically acceptable treatments for this stage of illness.
The symptomatology of schizophrenia and related disorders includes positive psychotic symptoms (e.g. delusions and hallucinations), negative symptoms (e.g. impaired social skills, apathy, blunted affect, poor rapport), and widespread cognitive impairments affecting attention, memory, and learning capacities. Presently available medications are effective against positive symptoms, but they do not significantly improve negative symptoms and cognitive deficits. Moreover, their use implies patient exposure to a variety of side effects, including motor, Parkinson’s disease-like symptoms, and metabolic side effects (e.g. obesity, blood sugar level elevation) that characterize second-generation antipsychotic drugs such as olanzapine (Zyprexa) and clozapine (Leponex).
During the last decade, our group has contributed extensively to the development and establishment of a novel class of medications to be used in psychotic disorders such as schizophrenia, and in illnesses such as autism, posttraumatic stress disorder, and Parkinson’s disease (1-7). This class of medications affects brain neurotransmission mediated at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, and is designated as “glycine site agonists” of the NMDA receptor (substances that enhance the activity of the NMDA receptor.)” Typical representatives of these medications are glycine, D-serine, and sarcosine, which are natural amino acids that are present in the human body and thus have the advantage of being practically devoid of significant side effects. By now, studies performed by our and other research groups have demonstrated that these compounds have the capacity to significantly alleviate negative symptoms and cognitive deficits in schizophrenia subjects (1-5).
Research Projects on Psychiatry
1. Psychiatry
2. Nutrition and Brain Function in Psychiatry and Geriatrics including Alzheimer’s and Parkinson’s Disease
Psychiatry
• Neuropsychological evaluation of attention and concentration deficits in schizophrenia
• The development of new methods of diagnosis and classification of schizophrenia with special focus on negative symptoms and cognitive deficits
• Studies of the role of genetic polymorphism in schizophrenia using novel family study methods
• The assessment of correlations between clinical status and serum levels of long-acting antipsychotic compounds
• Assessment of serum free radicals levels and their role in the pathogenesis of schizophrenia and tardive dyskinesia ( movement disorder induced by psychiatric drugs)
• The role of central nervous system excitaory amino acids (EAAs) neurotransmission in the pathophysiology of schizophrenia and related psychiatric syndromes
• Investigations of the safety and efficacy of the NMDA receptor modulators glycine and d-cycloserine as potential new treatments in schizophrenia and related psychiatric syndromes
• Assessment of the correlation between NMDA receptor polymorphism and treatment response to glycine and d-cycloserine
• Efficacy and safety of novel atypical antipsychotics (i.e. clozapine, risperidone, olanzepine, iloperidone).
• A new biofeedback modality for the treatment of Attention Deficit Disorder (ADD)
• Cognitive Processing without Awareness in Hypnosis, Electrophysiological Manifestations.
• The effects of family attitudes upon the course of illness of schizophrenic patients.
Nutrition and Brain Function in Psychiatry and Geriatrics including Alzheimer’s and Parkinson’s Disease
• Animal models of schizophrenia and tardive dyskinesia based upon the PCP/NMDA
hypothesis of schizophrenia and the glutamatergic hypothesis of tardive dyskinesia
• The role of EAAs in the etiology of brain damage
• The assessment of glycine and d-cycloserine-induced morphological changes in rat brain.
• Effects of nutritional iron deficiency on hippocampal development in relation to cognitive behavior in rats
• Manipulations of endogenous iron and neurotoxicity induced by excitatory amino acids in rat brain.
• Combination of diet restriction and antioxidant drugs for protection from Parkinson’s disease
• High dose glycine nutrition affects glial cell morphology in rat hippocampus and cerebellum
• Diet Restriction Increases Enkephalin-and Dynorphin-like Immunoreactivity in Rat Brain and Attenuates Long-term Retention of Passive Avoidance