Bipolar disorder is a recurrent illness with high morbidity for some patients. Episodes increase in frequency with time, and while a substantial number of patients with bipolar disorder respond well to treatment and live highly functional lives, approximately 10% to 15% of persons with the illness have been described as consistently having poor social outcome and poor response to treatment.
Further, persistent cognitive deficits have been reported in up to 30% of patients with bipolar disorder. These data suggest that for some patients with the disorder, the illness may not be benign, but may instead be associated with a deteriorative course. The factors that contribute to this poorer outcome group have not yet been elucidated.

The search for a neuroanatomic abnormality that may contribute to bipolar illness is an area of great interest. Both structural and functional changes in the brain are being studied with the hope that the data obtained will help us further understand bipolar illness. While the discoveries made thus far do not by themselves answer certain critical questions about the illness (e.g. why the onset of symptoms occurs at a certain age in life, why the illness is remitting in some persons and deteriorative in others), continuing study of these changes provides information that allows us to more selectively decide which questions to pursue and how best to do so.

Post Mortem Research in Affective Disorder (Bipolar Disorder)
Very few systematic post mortem studies involving affective disorder patients have been done. Until recently, most investigators doubted that an illness marked by episodic dysfunctional periods alternating with periods of almost total restitution of normal functioning could be associated with underlying structural deficits in the brain. However, of the very few studies that have been done, abnormalities in several brain regions have been observed.

COMPUTERIZED TOMOGRAPHY (CT)
In the last ten years structural brain changes have been demonstrated by CT in a subset of hospitalized affective disorder patients. Lateral ventricular enlargement or increased ventricular to brain ratios have been most commonly reported. An example is shown in this journal. Enlarged ventricles in particular have been a common finding seen in unipolar, bipolar and schizophrenic patients. The ventricles in the brain are the spaces where cerebrospinal fluid is stored. One explanation proposed for enlarged

ventricles is that the brain tissue which previously occupied this space has been somehow reduced. The tissue loss that might account for such a finding has not been explored using the CT method due to its relatively poor resolution.

MAGNETIC RESONANCE IMAGING (MRI)
Very few quantitative structural analyses using MRI have been reported to date. Further, the affective state of the patients at the time of the studies has been variable, making it difficult to assess if the finding is related to a particular mood state in the illness or is present even during euthymic periods. We and several other groups in the country have begun to use MRI to explore differences in brain structure, assessing in particular for reduced brain tissue that might account for enlarging ventricles. Very preliminary data suggest temporal lobe volume reduction in bipolar patients during well periods compared to normal controls. Other groups have reported changes in subcortical structures (small structures deep in the brain) in depressed patients compared to controls. The number of patients in most of these studies is small and larger studies are in progress.

Another abnormal finding in patients with bipolar disorder is the existence of “bright white spots” (hyperintense areas in the brain) on the MRI. Hyperintensities have been associated with a change in water content of brain tissue at the location of the hyperintensity. Although the cause of these areas of hyperintensities is not known for certain, the presence of these bright white spots is more common in patients with bipolar illness compared to controls. This finding suggests that there may be brain differences in patients with bipolar illness compared to normal controls.

COMBINING MRI STUDIES WITH NEUROPSYCHOLOGICAL TESTING
Our group is particularly interested in the possible impact of the frequency and intensity of a patient’s manic or depressive episodes on the patient’s brain structure (studied by MRI) and neuropsychological functioning (i.e. cognitive functioning and memory deficits as rated by neuropsychological testing). Unraveling these relationships could help to identify a subgroup of bipolar patients that may be more vulnerable to relapse or who may have
a more difficult course of illness.

It is possible, for example, that episodes of manias or depressions contribute to changes in brain structure in some bipolar patients. Findings may vary depending upon the particular symptoms experienced by the patient, and the particular type of illness the patient has in the spectrum of bipolar disorders. Such an investigation could yield important insights into the etiology of the disorders. Longitudinal studies are needed to determine the effects of illness episodes on brain structure. Unfortunately, there have been very few such studies in mood disorder patients. One longitudinal study using CT and having a mean follow up period of three years found that a group of patients with affective disorder had significant progression of ventricular enlargement in time compared to a schizophrenic and a normal comparison group.

There are few studies of cognitive function and memory deficits in bipolar patients in the euthymic state. Those that do exist suggest that a subgroup of bipolar patients may continue to have subtle deficits in the euthymic state that grow worse with time. The exact nature of the memory and cognitive impairments remains to be determined and a correlation of these impairments with changes in brain structure remains to be further demonstrated. Although robust findings between structure and neuropsychological function have been reported in schizophrenic patients, the relationship in bipolar patients has not been well explored. (as of 1995, when this paper was written - ed.)

CONCLUSION

Determining the relationships between episode frequency and number, and changes in brain structure and function is essential to understanding the etiology and course of bipolar disorder. To this end, our group is currently pursuing longitudinal studies to assess if 1) there are brain changes that occur in time with repeated episodes, and 2) if these repeated episodes and brain structural changes are associated with decrement in social or neuropsychological functioning.

LORI ALTSHULER, M.D. is an Assistant Clinical Professor of Psychiatry at UCLANPI and a member of the research service of the Brentwood Veterans Administration Medical Center.