THIRD INTERNATIONAL CONFERENCE 
ON BIPOLAR DISORDER

Recent Status Of Genetic Studies In Bipolar Disorder

Steven M. Paul, M.D.
Bibliography
Janice A. Egeland, Ph.D.
Edward I Ginns, M.D., Ph.D.

Abstract
Twin, family and adoption studies have provided strong evidence for an important genetic component in the susceptibility to develop bipolar affective disorder (BPAD). Unlike other common and genetically complex medical disorders (e.g., diabetes, obesity, Alzheimer ’s disease, hypertension) robust biological markers have not been identified for BPAD. Thus, genetic linkage studies have had to depend on categorical diagnoses. Genetic heterogeneity, phenocopies, genotyping errors and the complexities of performing/interpreting statistical analyses have undoubtedly contributed to the inconsistencies in the reported linkage studies for BPAD, as well as other genetically complex medical disorders. We will review some of the methodological challenges inherent in genetic linkage studies of BPAD and summarize the findings to date from different laboratories. Our own studies of BPAD in the Old Order Amish suggest the interaction of both susceptibility and protective alleles. Finally, we will briefly discuss the utility of more powerful approaches to gene mapping including the use of single nucleotide polymorphisms (SNPs) and multi-point allele sharing statistical methods to find genes underlying the susceptibility to develop BPAD.

Signaling Pathways and Gene Expression: Molecular Mechanisms Underlying Mood Stabilization in the Brain

Husseini J. Manji, M.D., F.R.C.P.
Bibliography

Slide Presentation

Abstract
It has become increasingly appreciated that the long term treatment of complex neuropsychiatric disorders likely involves the strategic regulation of gene expression in critical neuronal circuits. In this context, both lithium (Li) and valproate (VPA) increase the DNA-binding activity of the AP-1 family of transcription factors in cells of human neuronal origin in vitro, and in areas of rat brain ex vivo. Both agents also increase the expression of AP-1 driven reporter genes, as well as several endogenous genes known to be regulated by AP-1; the effects are markedly attenuated by site-directed mutagenesis of the AP-1 sites, suggesting that mood stabilizers regulate gene expression (in part) via their effects on AP-1. Both lithium and VPA exert major effects on MAP kinases and GSK-3b, effects which likely underlie their effects on AP-1. mRNA RT-PCR differential display has also been utilized to identify genes which are common long term targets for both lithium and VPA. Several novel candidates for the therapeutic actions of mood stabilizers have been identified, including an mRNA binding protein known to regulate mRNA stability; mood stabilizers may thus regulate multiple CNS genes in a concerted manner via their effects on this mRNA binding protein. We have also found a marked increase in the expression of a transcription factor (PEBP2b) and a marked increase in the levels of the neuroprotective protein bcl-2 (known to be transcriptionally regulated by PEBP2) in frontal cortex. These novel findings suggest that some of the long term beneficial effects of lithium and VPA may involve hitherto underappreciated neuroprotective effects.

Supported by Theodore and Vada Stanley Foundation and Joseph Young Sr. Awards

Regulation of Gene Expression in the CNS:  *FosB: A Molecular Mediator of Long-Term Neural Plasticity

Eric J. Nestler, M.D., Ph.D.
Bibliography

Abstract
The brain is capable of remarkable plasticity. Some changes, such as those underlying learning, memory, and recovery from mental illness, represent helpful adaptations, whereas other changes, such as those underlying the generation of a mental disorder or addiction, represent maladaptations. In either case, the stability of many such changes has suggested that regulation of neural gene expression may be involved. The first segment of the talk will review the signaling pathways in the brain that underlie the ability of external factors to regulate the expression of specific genes in the nervous system.

The second segment of the talk will focus on one particular transcription factor, *FosB, to illustrate the ways in which regulation of neural gene expression contributes to long-term plasticity in the brain. Transcription factors are proteins that bind to the regulatory region of specific genes and thereby increase or decrease the rate of transcription of those genes. *FosB is a member of the Fos family of transcription factors, which are induced rapidly and transiently in specific brain regions in response to many types of acute stimuli. However, in contrast to other Fos family members, biochemically modified isoforms of *FosB accumulate in a region-specific manner in brain uniquely in response to many types of chronic perturbations. Prominent among these are drugs of abuse, stress, and antidepressant drugs, which after repeated but not acute administration induce the *FosB isoforms in specific brain regions. Importantly, once induced, the *FosB isoforms persist in brain for relatively long periods of time due to their extraordinary stability. Mice lacking the fosB gene (which encodes *FosB) show abnormal biochemical and behavioral responses to chronic administration of psychotropic drugs, consistent with an important role for *FosB in mediating long-term adaptations in the brain (Hiroi et al., PNAS 94:10397-10402, 1997). More definitive evidence to support this hypothesis has recently been provided by analysis of inducible transgenic mice, wherein biochemical and behavioral changes, which mimic the chronic-treated state, are seen upon overexpression of *FosB in specific brain regions (see Chen et al., Mol Pharmacol 54:495-503, 1998).

This evolving work supports the view that *FosB functions as a type of "molecular switch" that gradually converts acute responses into relatively stable adaptations that contribute to long-term neural and behavioral plasticity. These studies also provide a template on which other transcription factors that mediate long-term plasticity in the brain can be identified.

Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging

Perry Renshaw, M.D.
Bibliography

Slide Presentation

Abstract
Magnetic resonance methods currently in use for the assessment of human subjects include magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and functional magnetic resonance imaging (fMRI). MRI provides detailed information regarding brain anatomy and is widely used to characterize neuropathological conditions in clinical practice. MRS allows the detection of signals from certain drugs, including lithium, and from a limited number of endogenous neurochemicals. fMRI refers to a family of methods for obtaining brain images which are sensitive to changes in cerebral metabolism with spatial resolution on the order of a few millimeters and temporal resolution of a few seconds.

MRI, MRS, and fMRI rely on the same basic principles and, at least for human studies, generally use the same hardware. Although the technology is evolving rapidly, there are currently more than 1,000 installed 1.5 T MR scanners in the United States which are capable of performing some or all of these methods. Thus, this technology is widely disseminated and available to investigators at a number of clinical research sites. This presentation will describe the basic principles of MRI, MRS, and fMRI. With this information as background, separate talks in this session by Drs. Moore and Yurgelun-Todd will discuss recent MRS and fMRI research findings which have provided new insights into the pathophysiology of bipolar disorder.

Current Status of MR Studies in Bipolar Disorder

Gregory J. Moore, Ph.D.
Bibliography

Slide Presentation

Abstract
Recent studies utilizing advanced magnetic resonance techniques have provided important new insights into the neuropathophysiology of bipolar affective disorder (BD) and its effective treatment. High resolution structural imaging studies using three dimensional volumetric magnetic resonance imaging (MRI) combined with advanced computer segmentation techniques allow for quantitative assessment of the volume of specific brain structures. Studies using these techniques have recently documented abnormalities in very specific regions of the frontal cortex and the temporal lobe in subjects with BD. Strikingly, these in vivo findings have been validated by post-mortem analyses in brains of BD subjects. In addition to the structural imaging studies, in vivo investigation of regional brain neurochemistry in BD is now possible utilizing magnetic resonance spectroscopy (MRS). Several studies utilizing MRS have shown regional neurochemical abnormalities in BD patients. Recent reports utilizing quantitative proton MRS to study brain neurochemistry longitudinally have shown that lithium treatment modulates regional brain myo-inositol and choline levels in BD subjects. The hypothesis is under investigation that the acute modulation of these important neurochemicals may be predictive of ultimate treatment response. Importantly these structural and neurochemical studies are beginning to elucidate the circuitry and biochemical pathways involved in BD and its treatment, information which is key to the development of novel and more effective therapeutic strategies for this devastating illness.

fMRI Studies of Affect Recognition in Healthy Adolescents and Adults with Bipolar Disorder

Deborah Yurgelun-Todd, Ph.D.
Bibliography

Abstract
Abnormalities of the limbic system, including difficulties with visual and verbal affective processing, have been reported to be present in bipolar patients. The ability to correctly discriminate emotion in facial expression is an essential component of successful social behavior. Individuals with bipolar disorder demonstrate difficulty with emotional discrimination and labeling, as well as inappropriate and incongruent affective responses. It has been hypothesized that disturbances in affect may represent distinct etiologic factors for psychiatric illness, further underscoring the importance of understanding affective response, recognition, and modulation in patients. The neural mechanisms mediating affective processes and their relationship to the pathophysiology of bipolar disorder remain to be clarified. Recent advances in neuroimaging techniques have made possible the non-invasive examination of specific brain regions during cortical challenge paradigms. We collected fMRI data and conventional magnetic resonance images in order to measure changes in regional cerebral activation during paradigms requiring recognition of facial expression in patients with bipolar disorder and healthy adult and adolescent subjects.

Prior to the scan, subjects were instructed to view the stimuli and the identify facial expression presented. Scanning was performed on a 1.5 Tesla scanner which had been retrofitted with a whole body echo planar coil, using a head coil. During each task condition, a series of 50 sequential images were obtained. Functional images were collected every three seconds using a gradient echo pulse sequence (TE = 40 msec, flip angle = 75 deg). To visualize signal changes, we used a task-activation paradigm which alternated between resting and stimulated states. Measures of signal intensity were derived by averaging the signal measured in all pixels in each ROI for each time point during the task activation period. The findings from this study indicate age related patterns of limbic activation. The data suggest that in non-psychiatric subjects, there are neurodevelopmental changes in frontal and amygdalar activation associated with affect recognition. In adult patients with bipolar disorder, signal intensity changes imply a dysregulation between prefrontal cortex and the amygdala during affect recognition. These findings are consistent with the hypothesis that bipolar disorder may be associated with an altered pattern of limbic development. These findings extend our understanding of neurophysiologic changes associated with affective illness and add further support to the premise that one role of the amygdala during development is to recognize facial expression and, through experience, learn to assign affect to facial expression.

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