Does amygdalar perfusion correlate with antidepressant response to partial sleep deprivation in major depression?

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Abstract

This study used functional MRI (fMRI) to clarify the sites of brain activity associated with the antidepressant effects of sleep deprivation (SD). We hypothesized: (1) baseline perfusion in right and left amygdalae will be greater in responders than in nonresponders; (2) following partial sleep deprivation (PSD), perfusion in responders' right and left amygdalae would decrease. Seventeen unmedicated outpatients with current major depression and eight controls received perfusion-weighted fMRI and structural MRI at baseline and following 1 night of late-night PSD. Baseline bilateral amygdalar perfusion was greater in responders than nonresponders. Clusters involving both amygdalae decreased from baseline to PSD specifically in responders. Right amygdalar perfusion diverged with PSD, increasing in nonresponders and decreasing in responders. These novel amygdalar findings are consistent with the overarousal hypothesis of SD as well as other functional imaging studies showing increased baseline amygdalar activity in depression and decreased amygdalar activity with remission or antidepressant medications.

Introduction

One night of total sleep deprivation (TSD) or partial sleep deprivation (PSD) produces temporary remission in 40–60% of patients with major depression (Wu and Bunney, 1990). Yet mechanisms of the antidepressant effects of sleep deprivation (SD), and explanations of why some individuals respond while others do not, remain unclear. Previous positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies of SD report at least one area in which responders and nonresponders differ significantly at baseline, along with differential response patterns to SD in responders and nonresponders. In most cases, areas of differing baseline activity or unique change in responders were reported in ventral anterior cingulate, basal orbital, or medial frontal areas (Ebert et al., 1991, Ebert et al., 1994, Wu et al., 1992, Wu et al., 1999, Volk et al., 1992). Similar PET findings in these areas have been linked with clinical response to antidepressant medications (Buchsbaum et al., 1997, Mayberg, 1997).

More recent work has employed functional magnetic resonance imaging (fMRI) to examine these effects with superior spatial resolution (Clark et al., 2001, Clark et al., submitted for publication). We recently (Clark et al., submitted for publication) used fMRI to clarify the exact medial frontal sites of brain activity associated with the antidepressant effects of SD in both region of interest (ROI) and voxelwise analyses. Using an arterial spin labeling (ASL) based fMRI method, we found greater baseline left ventral anterior cingulate (LVAC) perfusion in responders than nonresponders and a reduction of LVAC perfusion with PSD specific to the responder group. To test the anatomic specificity of these findings, we a priori divided the anterior cingulate and medial frontal cortex into dorsal, rostral, and ventral ROIs for each hemisphere, using ROIs derived from the Talairach daemon.

The “overarousal” hypothesis postulates that depression is associated with a pathological increase in physiologic arousal and that SD works by “de-arousing” depressed patients, or at least those who respond clinically. Aside from behavioral observations (Szuba et al., 1991), subjective reports of increased energy level (Van Den Burg et al., 1992), and neuroendocrine studies documenting increased hypothalamic–pituitary–adrenal (HPA) axis activity (Roy-Byrne et al., 1984), the main evidence for this theory comes from polysomnographic and functional neuroimaging data. Sleep abnormalities in depression, consistent with depressed patients' reports of disturbed and nonrestorative sleep, include prolonged sleep latency, reduced total sleep time and sleep efficiency, and decreased slow wave (“deep”) sleep as well as increased REM sleep (Benca et al., 1992, Benca, 1996). Depressed patients have also been reported to exhibit increased nocturnal core temperature, especially those who respond to SD (Elsenga and van den Hoofdakker, 1988).

Functional brain-imaging data have shown elevated baseline limbic activity in depressed patients in wakefulness and sleep, with decreases in limbic activity in association with SD or other antidepressant treatments. Generally, reports of altered baseline limbic function in SD responders have focused primarily on medial frontal areas, including our own findings in the left ventral anterior cingulate area. Elevated baseline levels of limbic activity in depressed patients, whether in SD studies (Ebert et al., 1991, Ebert et al., 1994, Wu et al., 1992) or other paradigms (Bench et al., 1992, Mayberg et al., 1997), are consistent with the concept of increased physiologic arousal. The overarousal hypothesis is also consistent with decreases in limbic activity in association with TSD (Ebert et al., 1991, Ebert et al., 1994, Wu et al., 1992), PSD (Clark et al., submitted for publication) or other antidepressant treatments (Scott et al., 1994, Buchsbaum et al., 1997).

The present study investigates the role of the amygdala in response to PSD in depressed individuals. Little has been reported about amygdalar function in connection with the antidepressant response to SD (Ebert et al., 1991, Wu and Gillin, 1992), and in our previous study we focused on the prefrontal cortex. However, increasing evidence suggests an important role for the amygdala in major depression (Whalen et al., 2002). Elevated resting baseline glucose metabolism has been reported in patients with major depression (Abercrombie et al., 1998, Drevets et al., 2002b). Treatment with antidepressant medications has been reported to modify affective response (Sheline et al., 2001, Davidson et al., 2003, Fu et al., 2004) and resting amygdalar activity (Drevets et al., 2002a) in major depression. Based on these observations, as well as the overarousal hypothesis, we predicted increased baseline perfusion in both the left and right amygdalae among PSD responders with major depression. We also hypothesized that perfusion in responders' right and left amygdalae would decrease with SD.

Section snippets

Subjects

Seventeen unmedicated outpatients with current major depression and eight controls received perfusion-weighted fMRI and structural MRI at baseline and following 1 night of late-night PSD. To enter the study, depressed subjects (ages 18–55) had to meet full diagnostic criteria for current DSM-IV major depressive disorder (unipolar) and to have a baseline 17-item Hamilton Depression Rating Scale (HDRS-17) score of 16 or greater. Control subjects had no psychiatric disorders and were matched

Results

Seventeen patients (male/female 5/12; 42.8 ± 9.5 years) and eight controls (male/female 4/4; 35.0 ± 9.5 years) participated in the study. Patients and controls did not differ significantly on demographic measures. Responders (n = 5) and nonresponders (n = 12) did not differ on age, gender, or ethnicity. However, responders had significantly more years of education than nonresponders (t = 10.6, df = 1, P = 0.000, between-groups t-test, 2-tailed). Interestingly, all five of the responders reported 16 years of

Discussion

Our most important findings from this study include greater baseline amygdalar perfusion in responders than nonresponders and differential amygdalar perfusion changes with SD between responders and nonresponders. Increased baseline perfusion in responders was apparent bilaterally in ROI analysis on between-group t-tests; however, only the stronger right amygdala difference was evident on voxelwise analysis. The MANOVA indicated that the larger perfusion values for the responders were maintained

Acknowledgments

This work was supported by 5 K08 MH01642, M01RR00827, and the VISN 22 Mental Illness, Research, Education and Clinical Center. We thank Lesley Wetherell, Anna Demodena, and Dexter Walpole for their help in conducting this study.

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