Surgery – Diagnostic testing – Eye or testing by visual stimulus
Reexamination Certificate
2001-03-19
2003-10-07
Hindenburg, Max F. (Department: 3748)
Surgery
Diagnostic testing
Eye or testing by visual stimulus
Reexamination Certificate
active
06629935
ABSTRACT:
FIELD OF THE INVENTION
THIS INVENTION relates generally to mood disorders. In particular, the present invention is concerned with a method and apparatus for diagnosis of a mood disorder, particularly unipolar and/or bipolar mood disorder, or predisposition therefor. The invention also relates to a process of using the diagnostic method to prevent mood disorders, to identify therapeutic compounds for alleviation of mood disorders, and to identify genetic markers associated with such disorders.
BACKGROUND ART
A variety of mood disorders exist which compromise to varying degrees the social integration and quality of life of affected individuals. The major forms of mood disorder include bipolar disorder (manic depression) and unipolar disorders (major depression and unipolar mania). Other mood disorders include dysthymic disorder, cyclothymic disorder, seasonal affective disorder and substance-induced mood disorder.
Bipolar disorder is a common condition with a lifetime prevalence of 1.2% to 1.6% (Weissman et al. 1988
, Psych. Med
. 18:141-153; Kessler et al. 1994
, Arch. Gen. Psych
. 51:8-19). It is characterised by recurrent episodes of mania and depression with symptomatic recovery between episodes.
The pathophysiology of bipolar disorder remains poorly understood despite considerable research (Goodwin et al. 1998
, Arch. Gen. Psych
. 55:23-25). Although it is strongly heritable, the genetics are complex, with less than full concordance in monozygotic twins (Mitchell et al. 1993
, Aust
. &
New Zeal. J. Psych
. 27:560-580). At least four different susceptibility loci have been identified (Adams et al. 1998
, Am. J. Hum. Genet
. 62:10841091). A trait-dependent biological marker would assist genetic linkage studies (which are dependent upon the identification of the clinical phenotype) and would potentially lead to an understanding of the underlying molecular defect in bipolar disorder.
In unipolar depression, there are recurrent episodes of depression with symptomatic recovery, but there are no episodes of mania. In unipolar mania there are recurrent episodes of mania but no episodes of depression. Like bipolar disorder, the pathophysiology and specific genetic defects underlying unipolar disorders remain poorly understood.
Current techniques for diagnosing mood disorders rely entirely on subjective interpretation of a patient's condition based on clinical interview. However, apart from being relatively time-consuming, the subjective nature of this technique in interpreting a psychiatric profile does not provide consistently accurate determinations of clinical phenotype. Consequently, misdiagnosis of mood disorders may occur which can thereby affect the prescribed pharmacological and non-pharmacological therapy.
In the 1930s, Hunt and Guilford (1933
, J. Abnormal and Social Psychology
28:443-452) found that hospitalised manic-depressive patients displayed slow alternation rates when viewing an ambiguous figure (ie. Wheatstone cube) compared to normal controls. The mean passive viewing number of alternations per minute was 4.25 for manic-depressives and 18.06 for normal controls. A strong implication from this study is that such slower alternation rates may be the result of clinical progression. Moreover, the data from this study support the use of this test to confirm the presence of manic-depressive illness in hospitalised individuals with a life history of illness at least as long as that for the individuals in the study.
SUMMARY OF THE INVENTION
The present invention arises from the unexpected discovery of differential rates of binocular rivalry between subjects with mood disorders (particularly unipolar and bipolar mood disorders), and non-clinical controls. In this respect, it was found that euthymic subjects affected by these mood disorders have a statistically significant slower rate of rivalry compared to non-clinical control. Surprisingly, the inventors also discovered that slow rates of binocular rivalry are present in some relatives of subjects with mood disorders. These findings suggest that slow binocular rivalry alternation rate is an alternative phenotypic expression of the bipolar and/or unipolar genotype and is not the result of one or more clinical episodes.
The inventors have also found from unilateral caloric, and transcranial magnetic, stimulation during binocular rivalry (as hereinafter described) that binocular rivalry is likely to be an interhemispheric switching phenomenon, ie. the perceptual alternations relate to alternating activation of the left and right hemispheres of the brain. Thus, the inventors consider that slow binocular rivalry is likely to correspond to slow rate of interhemispheric switching. The inventors have also shown that unilateral caloric stimulation also alters the perceptual alternations of the Necker cube, thus supporting interhemispheric switching as the neural mechanism of ambiguous figures. The similarly abnormal (slow) alternation rates in binocular rivalry and the Necker cube in subjects with bipolar disorder suggest that these perceptual phenomena share a common neural mechanism. The similar effects of caloric stimulation on binocular rivalry and Necker cube alternations suggest that this common neural mechanism is interhemispheric switching.
Accordingly, the inventors have devised a method of diagnosing mood disorders or predisposition therefor based on the above candidate trait-dependent biological marker. The current method therefore may also have utility in genetic linkage studies for the identification of the molecular defect(s) underlying these disorders, and for the identification of compounds which may alleviate such disorders. Other aspects of the invention will become apparent from the following description.
Thus, in one aspect, the invention broadly resides in a method for diagnosis of a mood disorder or predisposition therefor in a test subject, said method including the steps of:
(a) determining an interhemispheric switch rate of the test subject, wherein the test subject has not been diagnosed previously with the mood disorder; and
(b) comparing the switch rate with a corresponding reference switch rate to diagnose presence or absence of the mood disorder or predisposition therefor.
Suitably, the test subject has had less than two episodes of the disorder or is asymptomatic.
Preferably, the interhemispheric switch rate is determined by measuring a rate of perceptual rivalry in the test subject.
The rate of perceptual rivalry may be determined by measuring a rate of reversal of perspective for ambiguous optical stimuli.
Preferably, the rate of perceptual rivalry is determined by measuring a rate of binocular rivalry.
Alternatively, the interhemispheric switch rate may be determined by measuring a rate of the nasal cycle.
Suitably, the rate of perceptual rivalry is measured by:
(a) displaying at least one image to the test subject, wherein the at least one image invokes perceptual alternation;
(b) signalling respective incidences of perceptual alternation in the test subject during a predetermined period to provide a number of signals; and
(c) dividing the number of signals by the predetermined period to provide the rate of perceptual rivalry.
Preferably, the method is characterised in that said signalling is effected by the test subject or by a suitable detection means.
Preferably, the method is further characterised by the step of processing each of the signals relating to interhemispheric alternation to convert these signals into digitised signals, and storing the digitised signals for subsequent use.
Suitably, presence of the mood disorder is diagnosed, or a predisposition therefor is suggested, when the interhemispheric switch rate of the subject is equal to a corresponding reference switch rate associated with the mood disorder or predisposition therefor. In contrast, absence of the mood disorder may be diagnosed, or predisposition therefor discounted, if the above criteria are not satisfied and/or when the interhemispheric switch rate of the subject is equal to a corresponding reference switch rate
Miller Steven Mark
Pettigrew John Douglas
Hindenburg Max F.
Oppenheimer Wolff & Donnelly LLP
Szmal Brian
The University of Queensland
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