Research And Clinical Interests

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Decision-making and its dysfunction in individuals with psychiatric disorders

Decision-making is an important aspect of daily life. Moreover, dysfunctions of decision-making play a critical role in a number of neuropsychiatric disorders. Conceptually, decision-making can be divided both temporally and functionally into partially distinct processes: (1) the assessment and formation of preferences among possible options (2) the selection and execution of an action, and (3) the experience or evaluation of an outcome. During the first stage, individuals attribute value to the available options, and select one of them. During the second stage, individuals initiate, perform, and complete an action according to the preferences established during the first stage. To successfully complete this stage a range of action-related processes occurs, such as the sequencing of actions, the inhibition of competing actions, and the appropriate timing of actions. During stage three, individuals generate and process a signal, which is related to the difference between expected and experienced outcomes. The systems neuroscience framework based on distinct stages of decision-making can provide a roadmap to determine which component of decision-making is dysfunctional in psychiatric populations. This line of investigation can prove to be critical for the development and testing of new interventions aimed to improve decision-making and ensuing quality of life in impaired populations.

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dleland@ucsd.edu

Behavioral and brain activation patterns predicting individuals at risk for stimulant use and dependence

Stimulant (e.g. amphetamine and cocaine) dependence is an important public health problem with an estimated lifetime prevalence of 1-3%. The rate of use of any illicit drug increases during adolescence and peaks between 18 to 25 years of age, when approximately 20% of college students report some level of illicit drug use (other than marijuana) and approximately 10% report using stimulants over the past year. A high rate of stimulant use is especially alarming because epidemiological studies have shown that approximately one out of seven subjects who have tried stimulants progress to dependence. However, it is unclear whether individuals who initiate stimulant use differ from those who do not, and what factors contribute to the transition from use to dependence. Studying individuals who have used stimulants but do not have extended experience with them or suffer from significant adverse consequences associated with longer periods of substance use may provide an opportunity to examine what cognitive and affective characteristics may predispose individuals to transition from recreational use of the drug to abuse or dependence.

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wittmann@ucsd.edu

Behavioral and brain activation patterns predicting relapse of people with stimulant dependence

Methamphetamine and cocaine dependence are brain disorders characterized by repeated substance use and loss of control despite the presence of negative consequences. In particular, methamphetamine is an important and growing problem in the U.S. Although the prevalence of methamphetamine use among persons aged 12 and older did not change significantly between 2002 and 2004, the percentage of frequent users (individuals who had used methamphetamine within the past month) meeting criteria for stimulant dependence increased dramatically from 10.6 to 22.3 percent. In 2004, more than 1.6 million persons (0.6 percent of the U.S. population) met criteria for cocaine dependence. Tragically, there are no pharmacological treatments available for this devastating disease. A vital first step towards achieving this goal is discovering the neurobiological underpinnings of the disease. A central characteristic of substance dependence is the relapsing nature of the disorder. The return to drug use is a complex process that occurs within a year in more than 50% of people with stimulant dependence who seek treatment. A multitude of factors contribute to relapse, such as the environmental context, presence of substance cues, personal coping repertoire, and an escalation of craving after experience with the drug. The processes of relapse are thought to include cognitive behavioral, person-situation interactional, cognitive appraisal, and outcome expectation factors. However, neural system factors have been less well studied.

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ezwheele@hotmail.com

Functional magnetic resonance imaging as a tool to develop biomarkers for drug development

The most exciting new development over the past 10 years in the field of drug development has been the implementation of biomarkers to speed the development cycle. Biomarkers offer the possibility of obtaining indications whether novel drugs may have the predicted effect based on preclinical testing. Several biomarkers have been developed for examining treatment effects in Alzheimers disease, however, few biomarkers have yet been developed for psychiatric disorders. Functional neuroimaging provides a unique technique to inquire on a systems neuroscience level about the functioning of brain areas as they relate to many cognitive and affective processes. Moreover, functional magnetic resonance imaging (fMRI) is a relatively inexpensive, non-invasive, many times repeatable technique to obtain brain activation patterns on a second time scale. We found recently that Lorazepam significantly attenuated the BOLD-fMRI signal in a dose-dependent manner in bilateral amygdala and insula. Our data with a lorazepam, a standard anxiolytic, provide the first evidence of a dose-dependent change induced by an established therapeutic agent in brain regions known to be critical for the mediation of anxiety. This investigation may help to support the use of BOLD-fMRI with pharmacological probes to investigate the neural circuits underlying anxiety and to use fMRI as a tool in development of new anxiolytic agents.

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mstein@ucsd.edu

Behavioral and brain activation pattern alterations in individuals with anxiety disorders

Anxiety disorders are the most prevalent category of mental illness in the United States as well as in other countries. Anxiety disorders are associated with marked decrements in functioning and quality of life, and with increased risk for the subsequent onset of a range of mental disorders, including depressive and substance use disorders. For all these reasons – high prevalence, frequent associated morbidity and reduced quality of life, and increased risk for subsequent serious disorders – anxiety disorders are gaining recognition as a significant public health concern. Though prevention of anxiety disorders is a goal, efforts are currently directed at the mitigation of the impact of anxiety disorders through treatment. We are in the process of elucidating the basic anxiety circuitry, which involves the anterior insula and the amygdala. The anterior insular maintains glutamatergic connections to the basolateral amygdala, which are thought to act as a set-point modulator, resulting in in- or decreased association of salience of incoming stimuli. Moreover, the insular cortex sends excitatory efferents to midbrain nuclei and receives general arousal inputs via the locus coeruleus. Lastly, the medial prefrontal cortex (including the anterior cingulate) as well as well as the dorsolateral prefrontal cortex provides top-down modulation of this basic anxiety circuitry. These mechanisms are hypothesized to determine the phenomenology of the anxiety disorder. Each neural substrates is hypothesized to process a particular anxiety-relevant function, e.g. interoceptive processing takes place in the anterior insular, salience processing occurs in the amygdala, self-relevant processing in the medial prefrontal cortex and strategic excutive prcessing in the dorsolateral prefrontal cortex.

For more information, please contact:

alan@ucsd.edu

Behavioral and brain activation pattern alterations in individuals exposed to combat (Operation Enduring Freedom / Operation Iraqi Freedom)

Several studies have now shown that military personnel deployed to Iraq and Afghanistan frequently use mental health clinics (31% and 19% of returnees, respectively). Often, these visits are for treatment of posttraumatic stress disorder (PTSD) following combat-related experiences in the field. Our recently established neuroimaging unit of the VA San Diego Center of Excellence looks to provide unique clinical and research advancements for this at need population. Neural system models based on functional neuroimaging research for mental health disorders provide insights into testable biologically based hypothesis. The research focus of the neuroimaging unit is on the expression of stress and resiliency in Operation Iraq Freedom (OIF) and Operation Enduring Freedom (OEF) personnel. This investigation focuses on PTSD and related comorbidities and is based on the models developed in other anxiety and PTSD populations. Working with post-deployment military personnel gives an opportunity to aide current veterans and to better understand the effects of recently acquired combat-related PTSD.

For more information, please contact:

stapert@ucsd.edu

The effect of alcohol on the brain systems underlying cognitive and emotional processing

A low level of response to alcohol is a genetically influenced factor that contributes to the development of alcohol use disorders (AUD). Individuals who require higher doses of alcohol to achieve a given effect (i.e., have a low level of response at a given blood alcohol concentration or BAC) are more likely to develop AUDs than those who react more intensely to ethanol’s effects, as shown by 10- and 15-year follow-ups. This trait is seen in 40% of sons and daughters of alcoholics but less than 10% of controls. Little is known about the neural mechanisms that underlie individual differences in the level of response to alcohol. Using functional neuroimaging, one can begin to identify how brain systems contribute to individual differences in level of response to alcohol. This research program is aimed to examine the effect of a standardized alcohol challenge on behavioral performance and neural activation during a cognitive and emotional processing tasks, and the determine the relationship between the level of response to alcohol and behavioral performance or neural activation patterns.

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aminassian@ucsd.edu

Measurement of locomotor behavior in humans to determine the effects of treatment in individuals with bipolar disorder

Inhibition, i.e. the ability to withhold or attenuate an action or a thought, is of central importance in the regulation of behavior. Inhibitory deficits are key features of the mania of Bipolar Disorder (BD) and provide a behavioral target for translational research. The primary focus of this translational project is to assess three domains of inhibition in manic BD patients and in animal models based on pharmacological challenges and gene engineering technology. The assessment of inhibitory failures in manic BD patients will enable the validation of animal models that can predict novel treatments of BD and help identify the neural substrates underlying BD. In particular, motor hyperactivity, i.e. inability to inhibit ongoing actions, upon exposure to a relatively novel environment can be assessed by ambulatory monitoring devices to characterize motor activity with a high degree of spatial and temporal resolution.

For more information, please contact:

Jim.Fiedler@va.gov

Telemental Health – decreasing barriers to access psychiatric care

Veterans with mental health issues traditionally pose complex treatment issues. The goal of the Telemental Health program is to increase mental health access and services to Veterans while maintaining a high level of patient satisfaction. We have uniformly had very satisfied patients and providers. While we have primarily assisted with access to general mental health, there are several mental health specialty programs that are currently only offered at one VA site and we are looking to make these available at other distant sites to further improve patient access.

For more information, please contact:

Jim.Fiedler@va.gov

Anger Management – using a comprehensive educational, cognitive behavioral and mindfulness approach to reduce anger

Anger is a completely normal, usually healthy, human emotion. From time to time we all experience this very powerful feeling. Some of the common causes of anger include frustration, hurt, annoyance, disappointment, harassment and threats. It is helpful to realize that anger can be our friend or foe, depending on how we express it. But when anger gets out of control and turns destructive, it can lead to problems—problems at work, in your personal relationships, and in the overall quality of your life. And it can make you feel as though you're at the mercy of an unpredictable and powerful emotion. The precise prevalence of anger related problems is unknown, however, in a large epidemiological study, about 15% of individuals reported extremely high hostility scores. A range of factors ranging from social to genetic has been found to significantly affect the prevalence of anger. There is a strong connection between observed aggressive parenting and subsequent aggressive parenting in the offspring generation, which seems to suggest that anger/aggression is passed on via parenting styles from one generation to the next. Anger is an important emotion that has profound health consequences and is based on a complexly organized neural circuitry. Although anger plays an increasingly important role in our daily experience, surprisingly few studies have been carried out to systematically determine which treatment approaches are most effective. A key element in the search for an “effective” treatment for anger is the establishment of the motivation for change in the patient.