Abnormalities of dorsolateral prefrontal function in women with premenstrual dysphoric disorder: a multimodal neuroimaging study

Abstract

Objective: To investigate the neural substrate of premenstrual dysphoric disorder (PMDD), the authors used [15O]H2O positron emission tomography (PET) regional cerebral blood flow (rCBF) and blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal measurements during working memory in conjunction with a 6-month hormone manipulation protocol.

Method: PET and fMRI scans were obtained from women with prospectively confirmed PMDD and asymptomatic comparison subjects while they completed the n-back task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate, leuprolide plus estradiol, and leuprolide plus progesterone. Fifteen patients and 15 matched comparison subjects underwent PET imaging. Fourteen patients and 14 comparison subjects underwent fMRI. For each hormone condition, rCBF was measured with [15O]H2O PET, and BOLD signal was measured with fMRI, both during an n-back working memory paradigm. Global Assessment of Functioning Scale (GAF) scores and clinical characteristics were obtained for each patient before hormone manipulation, and symptoms were measured before and during the protocol.

Results: In both the PET and fMRI studies, a main effect of diagnosis was observed, with PMDD patients showing greater prefrontal activation than comparison subjects. In the patient group, the degree to which dorsolateral prefrontal cortex activation was abnormally increased correlated with several dimensions of disease: disability as indicated by GAF scores, age at symptom onset, duration of PMDD, and differences in pre- and postmenses PMDD symptoms.

Conclusions: Abnormal working memory activation in PMDD, specifically in the dorsolateral prefrontal cortex, is related to PMDD severity, symptoms, age at onset, and disease burden. These results support the clinical relevance of the findings and the proposal that dorsolateral prefrontal cortex dysfunction represents a substrate of risk for PMDD. The concordance of the fMRI and PET data attests to the neurobiological validity of the results.

FIGURE 1

Study Schematic and Timing of PET and fMRI Procedures in a Multimodal Neuroimaging Study of Premenstrual Dysphoric Disorder^{a a} All participants received injections of the gonadotropin-releasing hormone agonist leuprolide at a dosage of 3.75 mg i.m. every 4 weeks. Plasma follicle-stimulating hormone, luteinizing hormone, estradiol, and progesterone levels were measured at each study visit to confirm adequate gonadal suppression. After 3 months of unopposed leuprolide, all participants entered the hormonal add-back phase while continuing to receive monthly leuprolide injections. The women were randomly assigned to receive 5 weeks each of transdermal 17β-estradiol at a dosage of 0.1 mg per day or progesterone vaginal suppositories at a dosage of 200 mg b.i.d. in a double-blind, placebo-controlled crossover fashion with a 2-week washout period between the periods of hormone administration. In addition, during the fifth week of estradiol, all women received both estradiol and progesterone to induce menses. During the hormone add-back phases, women received both patches and suppositories each day (active or placebo, according to add-back phase) in order to blind the treatment team and participants to the hormone being replaced. Scanning windows are indicated by the yellow bars.

FIGURE 2

Between-Group Differences of PET and fMRI Activation in a Multimodal Neuroimaging Study of Premenstrual Dysphoric Disorder^{a a} Panel A shows the between-group differences in activation (2-back > 0-back) using PET and fMRI. Regions in which patients had greater activation than comparison subjects are shown in pink. Panel B shows the correlations between Global Assessment of Functioning Scale (GAF) scores and activation in patients using PET and fMRI. Regions in which these two measures were negatively correlated (the greater the overactivation, the more severe impairment indicated by GAF scores) are shown in blue. For all analyses: p<0.05, false discovery rate corrected; extent threshold=50.

FIGURE 3

Convergence of PET and fMRI Activation, Hormone Condition, Age, and Functioning in a Multimodal Neuroimaging Study of Premenstrual Dysphoric Disorder^{a a} In the top panels, PET and fMRI scan overlays illustrate the convergence between regions in which patients showed overactivation (pink) and regions in which their activations correlated with their Global Assessment of Functioning Scale (GAF) scores (light blue); overlap is indicated in dark blue; p<0.05, false discovery rate corrected, extent threshold=50. The graphs on the right depict data for each individual by hormonal condition for PET (panel A) average rCBF from a 4-mm sphere centered at coordinates x=36, y=54, and z=4 and for fMRI (panel B) average BOLD signal from a 4-mm sphere centered at coordinates x=44, y=42, and z=28. Circles enclose the maximal voxel in activation-GAF score correlation maps within the dorsolateral prefrontal cortex mask, from which extracted values are plotted for each hormone condition separately. In the bottom panels, PET and fMRI scan overlays illustrate the convergence between regions in which patients showed overactivation (pink) and regions in which their activations correlated with their age at onset (light blue); overlap is indicated in dark blue; p<0.05, false discovery rate corrected, extent threshold=50. The graphs on the right show data for each individual by hormonal condition for PET (panel C) average rCBF from a 4-mm sphere centered on coordinates x=48, y=40, and z=20 and for fMRI (panel D) average BOLD signal from a 4-mm sphere centered on coordinates x=46, y=42, and z=24. Circles enclose the maximal voxel in activation-age at onset correlation maps within the dorsolateral prefrontal cortex mask, from which extracted values are plotted for each hormone condition separately.