Functional Brain Imaging of Emotion-Perception in Late Life Depression

Sergio Paradiso, M.D., Ph.D.

The University of Iowa College of Medicine

Funded in June, 2006: $100000 for 3 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Is Late-Life Depression, in the Absence of Sadness, Associated with Sub-Clinical Ischemic Disease?

Investigators will use fMRI imaging in adults to explore the possibility that depression in elderly people that occurs in the absence of feeling sad is associated with small blood vessel disease in brain regions involved in perceiving emotion.  

Suicide is six times greater in elderly populations compared to younger populations, and depression is the major risk factor.  Depression in many older people has been found to occur without feelings of sadness, however, and this can obscure the diagnosis. The physiology of this situation is not known, but the Iowa researchers hypothesize that the brain’s ventral and medial frontal lobes, which are known to provide an awareness of emotion, have reduced functioning in late life depression that occurs without sadness.  Moreover, they hypothesize, the regions’ reduced functioning is related to sub-clinical ischemic cerebrovascular disease.  Ischemia results from an inadequate supply of blood, due to blocked arteries.

The investigators will test their hypotheses in three groups of twenty participants each: elderly people with depression and recognized feelings of sadness, elderly people found to have depression but without feeling sad, and healthy (non-depressed) control participants.  The investigators will use fMRI imaging to examine functioning in the ventral and medial frontal regions as participants are presented with emotional material.  MRI imaging will be used to quantify the amount of small blood vessel disease in these brain areas. If imaging reveals greater lesions in the white matter (communication cables) of these two brain regions in participants who are depressed but have less awareness of their emotions, the pilot data will be used to seek larger-scale funding to see if sub-clinical ischemia is related to depression in the absence of sadness.  

Significance:  This study may provide preliminary evidence of an association between small blood vessel disease in the brain and depression without sadness, and may ultimately lead to improved efforts to detect and treat undiagnosed depression in older people.

ABSTRACT

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Functional Brain Imaging of Emotion-Perception in Late Life Depression

Depression in late-life is strongly associated with personality changes, social withdrawal, and suicide. Tragically, most elderly suicide victims visit their primary care provider within a month prior to their death, but depression often goes unrecognized because in older people somatic and cognitive, but not emotional, symptoms are more common. Because of the elusive nature of this nondysphoric variant of late-life depression, objective methods of assessment, prevention, and better treatments are urgently needed. The goal of this project is to utilize state-of-the-art neuroimaging technology to clarify the underlying brain pathophysiology of nondysphoric late-life depression. This research will determine the extent to which impaired perception of emotional stimuli in older adults with nondysphoric depression is associated with dysfunctional brain activity in ventral and medial prefrontal regions, and the degree to which white matter ischemic disease predicts functioning in these regions.

The fast event-related fMRI paradigm in this proposal has been designed to allow tracking of the shape of the hemodynamic response curve, which has been shown to vary with age. Furthermore, BOLD fMRI will be complemented by using a multi-slice pulsed arterial spin labeling sequence (PASL). It is expected that ventral and medial frontal regions will show reduced BOLD response to emotional expressions in nondysphoric relative to dysphoric depression and age-matched non-depressed controls. Global, medial, and ventral white matter ischemic lesions (assessed using automated methods based on fluid attenuated inversion recovery MRI) will be greater in nondysphoric depression, compared to dysphoric depression and age-matched non-depressed controls. Furthermore, it is expected that white matter lesions will be associated with reduced activity in ventral and medial prefrontal cortex; this will be found for the BOLD- and the PASL-based sequences.

The results of this study may lead to novel pharmacological treatments of late-life depression involving drug therapies that target cerebrovascular function in conjunction with traditional antidepressants such as selective serotonin reuptake inhibitors, ultimately improving the lives of thousands of older individuals.

HYPOTHESIS

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Hypothesis:
Depression in late-life is strongly associated with personality changes, social withdrawal, and suicide. Most elderly suicide victims visit their primary care provider within a month prior to their death, but depression often goes unrecognized. In older persons, the presenting complaints are often only somatic and cognitive, and not emotional. Many individuals with subsyndromal depression experience nondysphoric depression (e.g., absence of reported sadness, loss of pleasure), making depression without sadness difficult to detect and an often severe mental health condition. Because of the elusive nature of this disorder, improved methods of assessment, prevention, and treatment are needed. While the mechanisms of nondysphoric depression are not known, structural neuroimaging studies suggest a connection between late-life depression and ischemic cerebrovascular lesions. Based on the role ventral and medial frontal lobe play in self-awareness of emotional states, we propose that nondysphoric depression is associated with greater white matter lesions in ventral and medial frontal regions. In addition, because white matter lesions (irrespective of their location) impair frontal lobe function, the relationship between overall white matter ischemic lesions and the hemodynamic response in the ventral and medial frontal lobe in nondysphoric depression will be examined.

Goals:
1. To examine the functional neuroanatomy of nondysphoric late-life depression using affective probes and fMRI.
2. To examine the regional and global density of white matter lesions in nondysphoric depression with automated methods using fluid-attenuated inversion recovery (FLAIR) MRI.
3. To examine the extent to which ischemic disease of the cerebral microvasculature, measured as global white matter ischemic lesions, influences the hemodynamic response function in ventral and medial frontal lobe regions in nondysphoric depression.

Methods:
Sixty older adults will be studied. In a semi-structured interview, patients with dysphoric and non-dysphoric depression must endorse an appropriate subset of the DMS-IV criteria for depression.  Controls will be included based on negative screening for these criteria.

Functional and structural neuroimaging will be conducted.  A fast event-related fMRI paradigm has been designed to allow tracking of the shape of the hemodynamic response curve, which has been shown to be sensitive to aging and a putative marker for arteriolar narrowing and stiffening.

To achieve our first goal, an emotion recognition task has been developed using faintly morphed emotional facial expressions.  Morphed images allow testing perception of faint levels of emotion more routinely encountered in everyday life.

To achieve our second goal, an automated method will be used to measure severity of white matter ischemic lesions.  This automated method will provide an objective and quantitative assessment of white matter lesions.

To achieve our third goal, the degree to which global white matter ischemic burden predicts BOLD and ASL responses in the ventral and medial prefrontal regions will be examined.

SELECTED PUBLICATIONS

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Narushima K., Paradiso S., Moser D.J., Jorge R., and Robinson R.G. Effect of antidepressant therapy on executive function after stroke. Br J Psychiatry. 2007 Mar;190:260-5.

Vaidya J.G., Paradiso S., Andreasen N.C., Johnson D.L., Boles Ponto L.L., and Hichwa R.D. Correlation between extraversion and regional cerebral blood flow in response to olfactory stimuli. Am J Psychiatry. 2007 Feb;164(2):339-41.

Robinson R.G., Paradiso S., Moser D.J., Mizrahi R., Fiedorowicz J.G., and Kouzoukas D.E. Neuropsychological correlates of normal variation in emotional response to visual stimuli. J Nerv Ment Dis. 2007 Feb;195(2):112-8.

Bigelow N.O., Paradiso S., Adolphs R., Moser D.J., Arndt S., Heberlein A., Nopoulos P., and Andreasen N.C. Perception of socially relevant stimuli in schizophrenia. Schizophr Res. 2006 Apr;83(2-3):257-67.

Paradiso S., Andreasen N.C. , Crespo-Facorro B., O'Leary D.S., and Hichwa R.D. Emotion in unmedicated patients with schizophrenia evaluated with Positron Emission Tomography. Am J Psychiatry. 2003 Oct;160(10):1775-83.

Crespo-Facorro B., Paradiso S., Andreasen N.C., O'Leary D.S., and Hichwa R.D. Neural mechanisms of anhedonia in schizophrenia: a PET study of response to unpleasant and pleasant odors. JAMA. 2001 Jul 25;286(4):427-35.