Paul Thompson's Research Publications

Brain Images of Mental Illness

Invited Workshop, Proc. 14th Spring Brain Conference, Sedona, Arizona, March 12-15 2003.

Organized by: Thomas A. Woolsey MD

1Thomas A. Woolsey MD, 2Mark A. Mintun MD, 3Randy L. Gollub MD PhD, 4Paul M. Thompson PhD

1Dept. of Neurosurgery, Washington University School of Medicine, St. Louis, MO
2Department of Radiology, Washington University Medical Center, St. Louis, MO
3Psychiatric Neuroimaging, Massachusetts General Hospital, Boston, MA
4Laboratory of Neuro Imaging, UCLA School of Medicine, Los Angeles, CA


WORKSHOP ABSTRACTS


BRAIN IMAGES OF MENTAL ILLNESS

Thomas A Woolsey, M.D., Dept. of Neurosurgery, Washington University School of Medicine, 4566 Scott Avenue, St Louis, MO 63110

The early idea that psychiatric illness and/or drug altered states have a biological basis has recently been investigated and confirmed with a wide range of imaging strategies. The panel will present data illustrating this with emphasis on what lies ahead in the future.

Depressive illness(s) afflict a large portion of the population. Dr. Mintun will outline the bases now known for these afflictions and how abnormalities in brain structure and activity are related to the illnesses.

Significant changes in brain structure and function are now associated with schizophrenia. Dr. Thompson will summarize these data and discuss how the large database of human brain scans now being assembled at UCLA can be used to advance knowledge on this and other brain diseases.

Cocaine and other substances of abuse evoke different subjective states. Some of are correlated with activation and depression of different regions/systems in the brains of animals and man. Dr. Gollub will summarize the information to date and outline the needs and challenges for future investigation.


IMAGING STRUCTURE, FUNCTION AND PHARMACOLOGY IN MAJOR DEPRESSIVE DISORDER

Mark A. Mintun, M.D., Deptartment of Radiology, Washington University Medical Center, 510 S. Kingshighway Blvd., St. Louis, MO 63110

Major depressive disorder is a common, often severe, illness that typically includes feelings of sadness and guilt, anhedonia, psychomotor retardation, changes in sleep and appetite, and anxiety. Imaging research on the biological causes of these symptoms has focused on three major areas:

MRI has been used to identify abnormalities in depression involving the size of limbic and paralimbic structures, most notably the hippocampus.

Functional mapping using PET measures of metabolism or PET and functional MRI of blood flow, have been used to implicate abnormal processing in limbic circuits involving the hippocampus, amygdala, anterior cingulate and orbital cortex.

Finally, the success of serotonin reuptake inhibitors in the treatment of depression has been just one of the reasons for development of PET (and SPECT) radioligands capable of imaging serotonergic receptors in vivo. Changes in depression of the distribution of serotonin-2A (5-HT2A), 5-HT1A, and serotonin re-uptake site have each been reported.

The strengths and limitations of these imaging approaches must be considered when synthesizing the different findings. For example, the observation that depressed patients have smaller hippocampal volumes may reveal a predisposing factor to depression, a consequence of recurrent depressive episodes, or a combination. Abnormal activity in the pregenual region of the anterior cingulate may be an underlying abnormality of depression (a state feature), or be associated with the expression of the depressive symptoms (a trait feature). PET reports of reduced 5-HT2A and 5-HT1A receptors in limbic regions, particularly the hippocampus, might need to consider complications such as the pharmacological history of the patients and not merely whether the patients were free of medications at the time of the imaging. The approach to these questions by the investigators in the field of affective disease imaging research will be reviewed. Future work based on these findings and combining more powerful new techniques in functional imaging will be discussed.


BRAIN STRUCTURE CHANGES IN POPULATIONS, FAMILIES AND INDIVIDUALS WITH SCHIZOPHRENIA

Paul M. Thompson, PhD, Dept. of Neurology, UCLA Medical Center, 710 Westwood Plaza, Los Angeles, CA 90095-1761

Schizophrenia is a devastating psychiatric disorder that affects 1% of the population worldwide. Patients often suffer their first psychotic outbreak in their late teens or early twenties. Despite advances in neuroleptic drugs, many patients' symptoms remain refractory to treatment, with recurrent episodes of auditory and visual hallucinations, bizarre delusions, depression and social withdrawal that can last an entire lifetime. Neuroimaging studies now suggest that schizophrenia is a disorder of brain development, with anatomic abnormalities present at disease onset.

Teenagers with a severe, early onset form of schizophrenia also exhibit a dynamically spreading wave of cortical gray matter loss, detectable in sequential MRI scans. The tissue loss begins in a small region of the parietal cortex and moves forward to engulf frontal and temporal systems.

These deficits correlate with psychotic symptom severity, and may link with cortical dopamine or serotonin dysfunction. The shifting pattern of deficits is distinct from the neurodegeneration observed in the dementias, and may be an exaggeration or derailment of the neuronal remodeling that normally occurs in late teenage brain development. Computerized tracking of these cortical deficits will help understand how neuroleptic drugs decelerate or block the disease process.

Cortical deficits are also detectable in patients' first degree relatives, who are at greatly increased genetic risk for schizophrenia (10% lifetime risk).

In future, these dynamic and genetic brain maps may predict imminent onset of the disease, identifying pre-symptomatic brain changes in family members who are candidates for early interventions.


PROMISES AND OBSTACLES IN CREATING BRAIN IMAGES OF SUBSTANCE ABUSE

Randy L Gollub, M.D., Ph.D., Psychiatric Neuroimaging, Massachusetts General Hospital, East, 149 13th Street, Charlestown, MA 02129

Substance abuse is a complex disorder afflicting millions of people. Current methods to diagnose and treat substance abuse are limited. Therapeutic options have not advanced despite a tremendous advance in our understanding of the neurobiology underlying the behavioral effects of drugs of abuse. Substance abuse is unique in that it is one of the only psychiatric disorders for which there are credible animal models.

Early advances in our understanding of substance abuse came from work done using these animal models.

More recently cognitive neuroscientists have begun to make important contributions by devising behavioral paradigms to study normal and disordered emotion and appetitive drives in human subjects.

Functional and structural neuroimaging technologies are being used to investigate the neuroanatomic and neurochemical systems that are disordered in drug addicted individuals, both animal models and humans.

For example, cocaine evokes a subjective state described as euphoria that is hypothesized to be dependent on the release of dopamine from ventral tegmental nerve terminals into nucleus accumbens. Functional magnetic resonance imaging has demonstrated that this activation can be visualized in human cocaine addicted subjects in response to an acute challenge with cocaine. Moreover, positron emission tomography dopamine transporter binding studies have show that occupancy of striatal dopamine receptors correlates with euphoria. While these results and many others from investigators working in this field are encouraging because they are beginning to build the bridges between the animal and human systems, they are not yet having an impact on our ability to diagnose or treat the illness. Insight into the challenges inherent in the design of neuroimaging studies of mental illness and into the technical challenges in neuroimaging data acquisition and analysis, highlights the value of what has been accomplished to date. Further it sets the stage for important work that must be done before neuroimaging will fulfill the promise of its therapeutic potential.


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    Paul Thompson, Ph.D.
    Assistant Professor of Neurology
    4238 Reed Neurology
    UCLA School of Medicine
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    Westwood, Los Angeles CA 90095-1769, USA.

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