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Basic research approaches include molecular biology, pharmacology, brain imaging, psychoneuroendocrinology, chronobiology and others. The Department is dedicated to forwarding our knowledge base in the biological and psychological underpinnings of these major disorders as well as developing new strategies for prevention and treatment.
The Stanford/VA Alzheimer's Center takes a multidisciplinary approach to studying this disease. Under the direction of Drs. Jerome Yesavage and Jared Tinklenberg, patients are followed longitudinally every six months. These examinations form the basis of research protocols directed by Drs. Adolf Pfefferbaum, Kelvin Lim, Paula Shear, Edith Sullivan, Vincent Zarcone, Dolores Gallagher-Thompson, Greer Murphy, Lawrence Eng, and Alan Schatzberg, respectively. The full study affords participating patients the opportunity to receive thorough examinations of multiple facets of physical and behavioral areas likely to be affected by Alzheimer's disease. These examinations systematically document general physical health, cognitive status, brain integrity, sleep abnormalities, psychosocial behavior, and neurochemical status.
A wide variability in the clinical manifestations and the clinical course of this illness becomes evident through multidisciplinary, longitudinal study. This center is working toward discovering the roots of these differences in hopes of enabling clinicians to predict prognoses and gain insight into the cause of AD. Dr. Yesavage and his colleagues are considering possible subtypes of AD as a potential explanation of these varying rates of decline. An alternative explanation invokes identification of additional factors which accelerate decline but are not related to the primary disease process. Dr. Yesavage and his colleagues are identifying ways to treat the components of these additional factors in order to slow the decline and give Alzheimer's patients a better quality of life.
In addition to the longitudinal cognitive study, Dr. Tinklenberg is currently finishing trials on the drug acetyl-L-carnitine and is beginning investigation of the drug Lazabemide this spring. Both of these drugs have been tested in Europe and show promising results in slowing the progress of memory loss associated with Alzheimer's disease. As part of the Stanford/VA Alzheimer's Center, Dr. Tinklenberg and his associates at the Palo Alto Veterans Affairs Medical Center operate one of nine diagnostic centers funded by the State of California to follow members of the elderly population who are suffering from memory loss. Dr. Tinklenberg is also interested in biological markers, such as a blood test, that would identify people who are at risk for Alzheimer's disease.
Psychiatrists Dr. Adolf Pfefferbaum and Dr. Kelvin Lim use magnetic resonance imaging to visualize the living brain and to quantify the volume of its many structures and various tissue types. This research group is developing state-of-the-art neuroimaging methods to assess brain abnormalities in the individual patient with Alzheimer's disease.
Neuropsychologists Dr. Edith Sullivan and Dr. Paula Shear use specialized tests to assess the many facets of cognitive, sensory, and motor abilities that are compromised by Alzheimer's disease. In conjunction with the neuroimaging studies, the neuropsychological investigations aim to identify the behavioral ramifications of the progressive brain abnormalities. The establishment of relationships between behavioral impairment and brain structural changes will provide patterns for those areas affected and not affected by Alzheimer's disease.
Dr. Vince Zarcone is investigating the common sundowning effect found in some patients with Alzheimer's disease. This syndrome is exemplified by increased confusion and agitation at night, as well as erratic sleeping patterns. Dr. Zarcone and his colleagues are investigating the cause of this dysfunction in hopes of researching cures or ways of managing this problem. Dr. Zarcone's research group is at the forefront of technical advances in researching circadian rhythms on patients with Alzheimer's disease.
Psychologist Dr. Dolores Gallagher-Thompson is studying care givers' psychosocial needs and developing model programs to treat depression, anger, and anxiety in care givers. Depression affects an estimated one-third of the people caring for patients with Alzheimer's disease. Dr. Gallagher's study also investigates the relationship of the development of depression and the sense of burden in care givers to specific types of medical and behavioral problems that arise during the course of the patient's disease.
Dr. Greer Murphy and his collaborator Dr. Lawrence Eng in the Stanford Department of Pathology are examining blood cells and cerebrospinal fluid from AD patients for amyloid proteins. Amyloid is the key pathologic change in the brain in AD. Mutations in the gene coding for this protein are known to cause AD in some families. Drs. Murphy and Eng have detected amyloid gene activity in blood cells of patients with AD, and are using molecular biology to determine whether abnormal activity of the amyloid gene might contribute to a more rapid decline in cognitive abilities. They are utilizing the powerful polymerase chain reaction biotechnology to facilitate measuring amyloid gene activity. This may lead to diagnostic or prognostic markers for AD that could be used by clinicians. Together, these Stanford University investigators are searching for ways to keep patients with Alzheimer's disease functioning outside of nursing homes, with the best quality of life, for as long as possible. The Stanford/VA Alzheimer's Center is examining many facets of AD to assemble a complete clinical understanding of this debilitating disease.
In vivo neuroimaging techniques enable investigators concurrently to assess relationships among brain abnormalities, symptoms, and cognitive deficits. Neuroimaging assessments can also be repeated over the course of the illness to track changes in brain morphology and their association with behavioral features.
Dr. Pfefferbaum's neuroimaging work includes the study of healthy people of all ages, in order to establish age norms against which patients with mental disorders can be assessed. Using magnetic resonance imaging (MRI), he has demonstrated that over the life span the normal brain undergoes dramatic changes, first with increase of white and gray matter volumes during childhood development, and then with the gradual but inexorable loss of gray matter, beginning during early adulthood and increasingly dramatically after the age of 50.
Dr. Pfefferbaum and his colleagues are using MRI to study patients with schizophrenia, alcoholism and Alzheimer's disease. Group contrasts provide an important perspective on the pathophysiology of each disease. Patients with schizophrenia have a widespread increase in cerebrospinal fluid, which is primarily attributable to a loss of cortical gray matter. White matter is unaffected. In contrast, the widespread increase in cerebrospinal fluid in patients with histories of alcohol dependence is associated with loss of both white and gray matter. In schizophrenia, abnormalities are apparent even in young patients and are no more pronounced in patients up to age 45, suggesting a one-time, non-progressive disturbance. In alcoholics abnormality of white and gray matter is less apparent in younger patients, but becomes increasingly exaggerated compared to age norms in older patients. This may reflect the progressive nature of the disorder as well as the increasing vulnerability of the aging brain. Patients with Alzheimer's disease under the age of 65 show much greater loss of gray matter for their age than patients over the age of 65.
In addition to studying broad characteristics of brain morphology, Dr. Pfefferbaum and his colleagues are using MRI to examine specific brain structures, such as the hippocampus. The size of this structure will be important for performance on specific components of memory, not only in healthy adults, but also in patients with Alzheimer's disease, schizophrenia, alcoholism and Wernike Korsakoff syndrome, an uncommon brain disorder associated with malnutrition that occurs in chronic alcohol dependence.
Recent developments in magnetic resonance spectroscopy (MRS) now make it possible to expand in vivo imaging to assess not only broad morphological features, but to provide more detailed information about the concentration in brain tissue of various endogenous compounds, believed to reflect the viability of living neurons as well as certain other metabolic processes. In collaboration with investigators in the Department of Electrical Engineering, Drs. Pfefferbaum and Lim are developing approaches to apply these techniques to studies of patients with schizophrenia and Alzheimer's disease.
In complementary studies, Dr. Pfefferbaum has been using multi-lead scalp-recorded event-related potentials (ERPs), which provide a sensitive and specific tool for assessing sensory and cognitive deficits. Applications include recording potentials to paired stimuli to assess P50 non-suppression, a possible indicator of defective sensory gating, and recording later responses to cognitively meaningful stimuli to assess abnormalities in ability to direct and sustain attention, as well as to process cognitively meaningful stimuli. Multi-lead EEG recordings enables these deficits to be localized, with specific attention to the limbic and frontal brain areas, implicated in the pathophysiology of schizophrenia.
Stanford University Hospital recently established a new geropsychiatry program that offers state-of-the-art evaluations, diagnostic techniques, and treatments for patients. According to Dr. Javaid Sheikh, director of the program, psychiatric disorders of the elderly remain mostly undiagnosed and untreated, causing great pain and suffering in this population, and thus must be alleviated.
The most common psychiatric disorders of the elderly are anxiety; depression; and cognitive decline, which includes age-associated memory impairment, Alzheimer's disease, and other forms of dementia. Dr. Sheikh and his colleagues offer cognitive therapy as well as medication for the disorders they treat. They are also conducting research on these conditions and investigating new possibilities for treatment, as well as training residents in geriatric psychiatry.
One of Dr. Sheikh's research studies focuses on panic attacks. He and his colleagues are carrying out a study of two drugs that have proven useful with younger patients on people 55 and older. Panic attacks often grow worse with time, and some people go on to develop multiple fears, including fear of driving, shopping in large malls, going to the cinema, and in extreme cases, they may refuse to leave their homes. This condition can cause extreme disability but has never been studied in older people.
Work in the laboratory has contributed to a number of advances in the treatment of behavioral disorders. Scientists have gained a better understanding of the role of infant eating and activity patterns on subsequent weight, and developed cognitive/behavioral treatments for eating and anxiety disorders. Stanford scientists have identified the risk factors for eating disorders and designed a curricula to reduce the risk factors. They have also developed cost-effective methods for cardiovascular risk reduction and prevention, particularly smoking cessation.
Dr. Agras currently directs a National Institute of Mental Health multisite study evaluating the most effective cognitive/behavioral and interpersonal therapies for bulimia nervosa.
Dr. Agras's colleague, Dr. C. Barr Taylor, is developing methods of treating anxiety disorders, which are common and often disabling problems. His research in this area has helped develop very effective pharmacologic and psychological interventions for panic disorder (agoraphobia), social fears, and simple phobias. Current studies are examining mechanisms of change, evaluating new medications, and extending the principles derived from treating panic disorder to other anxiety problems.
Stanford psychiatrists Dr. C. Barr Taylor and Dr. Chris Hayward, psychologist Joel Killen, and their colleagues from pediatrics and the Stanford Center for Research in Disease Prevention are identifying behaviors and attitudes during adolescence that could result in eating disorders and anxiety disorders later in life. Over the past four years, the team has developed and taught a healthy weight regulation curriculum to sixth- and seventh-grade girls in selected schools in Santa Clara County. Preliminary findings have pointed to a significant increase in knowledge maintained over a four-month period, a decrease in those with tendencies toward purging, and a considerable drop in weight concerns.
Dr. Regina Casper, an international authority on eating and depressive disorders, recently joined the Stanford faculty from the University of Chicago. According to Dr. Casper, anorexia nervosa is a heterogeneous disorder with a restricting and a bulimic type. Anorexia nervosa is both a psychological disease that goes hand-in-hand with a devastatingly poor self-image, and a physical disorder associated with hyperactivity despite severe weight loss and a disturbed body image. Another cause of the disorder is a need for independence and control in the patient's life. Treatment for anorexia nervosa often requires nutritional management and an exploration of the reasons for the patient's personal involvement in the starvation process.
Stanford physicians are making great strides in the understanding and treatment of anxiety and eating isorders. They hope to expand the educational components of their laboratory by beginning a postdoctoral research training program in eating and anxiety disorders and developing curricula for school-based prevention of eating and anxiety disorders. Future plans include the establishment of an assessment center for monitoring long-term outcomes of eating and anxiety disorders.
Research emphasis is placed on the biophychosocial underpinnings and pharmacological treatment of mood disorders. Research is under way on the role of the Hypothalamic-Pituitary-Adrenal (HPA) axis, the stress system, in the pathogenesis or expression of depressive syndromes or symptoms. Studies are being conducted in human subjects as well as in rats (with Dr. Dona Wong) and in primates (with Dr. Seymour Levine). Particular emphasis is on molecular biological studies on the effects of HPA axis on dopamine metabolism.
A number of drug treatment trials are under way. The Mood Disorders Program is participating in a large national study on the use of two alternative antidepressant agents to treat patients with chronic depression. Other studies on new investigational antidepressants, not otherwise available, have also been launched. A study on the use of divalproex sodium in mania is also underway.
Stanford physicians in the clinic are investigating medical treatments for OCD, including drugs such as fluvoxamine and intravenous clomipramine. Studies are also under way to identify ways to predict those patients who will respond to which medications and how to measure patients' improvement. A study comparing behavioral and drug treatments for trichotillomania (hair pulling) is currently in progress.
In one project, Dr. Ciaranello and Dr. Dona Wong, a molecular biologist on the psychiatry faculty, have been searching for a genetic cause for infantile autism. They are working to develop molecular probesÑspecific sequences of single-stranded DNA, which are used to seek out complementary sequences in other single strandsÑto detect abnormalities in autistic children. Genetic tests, they expect, will eventually be able to detect the disorder prenatally or at birth. Dr. Ciaranello and his research team are also working with the National Institute of Mental Health to look for a genetic marker in manic-depressive illness in children of parents who have the disease.
Using the tools of molecular genetics, researchers have localized the genes responsible for several inherited diseases to a certain chromosome, and sometimes to an exact location on a chromosome. At least three genes that may be responsible for manic-depressive illness have been proposed, yet not all familial cases of the disease can be accounted for by these three sections of chromosomes. For children, early diagnosis of mental disease is critical. A genetic marker could help clinicians give appropriate diagnoses and begin interventions while the young brain is still developing and adaptable.
Dr. Moos has found that parental depression may be a significant risk factor for children. Recent studies have shown that children of depressed parents had more emotional and behavioral symptoms than did children of nondepressed parents. Working with the Stanford University Arthritis Center and the Pediatric Rheumatology Clinic at Lucile Salter Packard Children's Hospital, Dr. Moos has found that severely ill children with juvenile rheumatic diseases experience more psychological problems and miss more days of school than do mildly ill patients. Parental depression, family stressors, and lack of family cohesion were also associated with psychosocial dysfunction among patients and their siblings. Dr. Moos hopes that he can develop more effective interventions to help improve adaptation and ease the adjustment process for patients and their families.
In other research, Dr. King has been studying specific neurotransmitters: dopamine, norepinephrine, and serotonin. After measuring these chemicals in up to 100 individuals, Dr. King has observed that there may be a seasonal variance in their levels. For example, dopamine and norepinephrine levels seem to be higher in the winter than in the spring. According to Dr. King, this may account for the more anxious and introverted feelings many individuals experience during the winter. Dr. King has also been exploring the role of dopamine in craving behavior in substance abuse patients.
Dr. Spiegel also is well known for his elucidation of the biology of hypnosis. His laboratory has shown that changes in perception induced with hypnosis are accompanied by measurable changes in brain electrical activity, using a technique which records event-related potentials. He has determined that a specific neurotransmitter, dopamine, is involved in hypnotic response, and that hypnotized subjects can consciously control activity in their gastrointestinal tract. In addition, Dr. Spiegel has been working on clinical trials of the effects of hypnosis in psychotherapy for phobias, smoking, and post-traumatic stress disorders. His studies of trauma have demonstrated severe dissociative symptoms in the immediate aftermath of natural disasters, which has led to the inclusion of a new diagnostic category, Acute Stress Disorder, in the fourth edition of the American Psychiatric Association's Diagnostic and Statistical Manual.
Several Stanford psychiatrists and psychologists specialize in the disorder and see patients in clinical practice at the Stanford University Clinic and the Stanford-associated National Center for PTSD at the VA Medical Center.
Research conducted at the VA Clinic has shown that the disorder affects the brain and body. People with PTSD may have reduced levels of endorphins, the body's natural opiates that help block pain. As a result, researchers have found patients' reaction to pain altered. Researchers have also reported differences in the hypothalamic-pituitary-adrenal systems and the sympathetic nervous systems of PTSD patients. When stimulated, the sympathetic nervous system can speed heart and respiratory rates, increase blood flow to skeletal muscles and induce sweating and other reactions the body undergoes when faced with an emergency.
Stanford investigators are researching structural alterations of the brain and their functional significance in patients with schizophrenia at Stanford's Mental Health Clinical Research Center (MHCRC), which is based at the Palo Alto Veterans Affairs Medical Center. Dr. Adolf Pfefferbaum, director of the center, and other Stanford investigators use structural neuroimaging to explore the altered physical characteristics of the brain; functional neuroimaging to study reduced levels of blood flow and glucose metabolism; experimental neuropsychology to investigate areas of preservation and loss in specific cognitive, motor, and sensory abilities; and electrophysiology to examine indicators of impaired sensory and cognitive processing and processes underlying disrupted sleep patterns.
These studies help psychiatrists find whether structural defects and dysfunction are localized to specific brain areas and behavioral abilities, or whether they are widely distributed. Studies at the Center are designed to allow physicians to investigate the role of factors such as aging, gender, age of symptom onset, and length of illness in the brain abnormalities observed. Some of the brain abnormalities and symptoms seen in patients with schizophrenia are also seen in patients with other psychiatric and neurological disorders, such as complex partial epilepsy and psychotic depression. In order to better understand the specific characteristics of schizophrenia, patients with these other illnesses are also being studied at the MHCRC. The program also includes several studies on investigational antipsychotic agents.
A multidisciplinary team of 20 scientists and 40 research assistants carry out approximately 100 different, ongoing basic research experiments that can be applied to a wide variety of human illnesses and problems. These projects guide research on 50 or more specific sleep illnesses. Dysfunction in the process of wakefulness, sleep, and biological timing has been strongly implicated in mental illnesses, including manic depressive psychosis, endogenous depression, schizophrenia, as well as cognitive disorders. Some of the research programs in the center include:
Another project focuses on life stressors and coping among healthy and high-risk groups. Center researchers are developing new procedures to assess life stressors, social resources, and coping responses, studying the influence of psychiatric disorders such as alcohol abuse and depression on family members of patients.