Prospectively screened women with PMDD showed a greater increase in cerebellar activity from the follicular phase to the symptomatic late luteal phase, compared with a group of asymptomatic control women. The effect was localized primarily to the midline vermis and fastigial cerebellar nuclei. These structures have been previously described as the “limbic” cerebellum (17
). Our finding is consistent with previous reports of elevated glucose metabolism in the midline cerebellum and vermis in unipolar and bipolar depressed patients (20
), and adds to the literature that indicates a role of the cerebellum in a wide range of behaviors involving emotion, pain, and executive functions (19
The cerebellum is rich in GABAA
receptors containing both δ and α subunits (24
), and GABAergic neurotransmission is thought to take part in the pathophysiology of PMDD and premenstrual syndrome (PMS) (1
). This is in part based on findings that genetically altered mice with disruption of the δ subunit exhibit more seizures and weaker behavioral responses to neuroactive steroids such as progesterone metabolites, as compared to wild type mice (28
). In the luteal phase, women with PMS/PMDD are less sensitive to the modulatory effects of neurosteroids and benzodiazepines (29
) suggesting that GABAA
receptor expression and function may change across the menstrual cycle (31
The neuroactive steroid, allopregnanolone, a ring A-reduced metabolite of progesterone, is produced in high concentrations by the ovary and brain during the luteal phase of the menstrual cycle (32
). Allopregnanolone and other pregnane-derived neuroactive steroids are potent allosteric modulators of GABAA
). Fluctuating levels of these progesterone-derived neuroactive steroids alter the composition and function of the GABAA
receptors and thereby may influence emotional and affective behaviors during the luteal phase (31
In fact, largely on the basis of animal studies, has it been proposed that women with PMDD have deficiencies in mechanisms regulating the cycling of GABAA
). Chronic treatment of rats with progesterone, at doses that model the exposure and withdrawal from progesterone that characterize the luteal phase, increases anxiogenic behavior and reduces sensitivity to the sedative effects of benzodiazepines. These effects parallel an increase in the α4 subunit of the GABAA
), which confers insensitivity to neurosteroids and co-localizes with the δ subunit of the GABAA
receptor, particularly in cerebellar granule cells (45
). It has also been proposed that a deficiency in mechanisms regulating cycling of δ GABAA
receptors may underlie the anxiety and decreased behavioral inhibition associated with PMDD (37
). Our finding of increased cerebellar activity from the follicular to the late luteal phase in women with PMDD may reflect an alteration in GABAA
receptor composition in the cerebellum, consistent with reports of diminished sensitivity to the inhibitory effects of neuroactive steroids during the late luteal phase in this disorder.
There was a significant difference in both PMDD and healthy control groups in progesterone levels between the follicular and late luteal phases, but there was no between phase difference in estradiol levels in either group. As the subjects were scanned between days 8 and 12 of the follicular phase before the mid-cycle rise in estradiol, the estradiol levels were similar in the follicular and luteal phases. The finding of a phase-related difference in progesterone but not in estradiol levels also supports the potential relationship between progesterone, likely via the progesterone metabolite ALLO, and glucose metabolism in the cerebellum.
In an fMRI study, women with PMDD had a premenstrual increase in amygdala activity and decrease in activation of the medial orbitorfrontal cortex when they were exposed to emotionally negative words during a go/no-go task (11
). Although our PET results did not show effects on glucose metabolism in the amygdala and frontal cortex, we did not perform a challenge study with emotionally negative stimuli. In addition, fMRI has the time resolution to show changes over a few seconds that would not be resolved by the FDG PET method, which integrates activity over a longer period (primarily the first 15 min after the radiotracer injection).
The participants in our study performed a simple auditory CPT to standardize their thoughts during the scans. It is possible that the task could affect glucose metabolism differently in PMDD than in control subjects. The CPT activates a complex network of brain structures, including the cingulate gyrus and other cortical regions (46
). Previous studies of healthy subjects during performance of similar auditory vigilance tasks have indicated lower glucose metabolism in the mid-cingulate cortex during task performance, as compared to a resting state (47
). There is no reason, however, to believe that the group difference in cerebellar activity related to menstrual phase was an artifact of the task.
The correlation of the increase in cerebellar activity from the follicular to late luteal phase, with parallel worsening of mood (p = 0.018), implicates cerebellar dysfunction as contributing to the symptomology of PMDD. The cerebellum does not show an abnormality in many imaging studies of subjects with affective or anxiety disorders (49
). However, various investigations have implicated the cerebellar vermis in affective processing (17
) and PMDD is a unique menstrual cycle –linked syndrome, not a subset of depressive disorder.
This study is limited by small sample size but one of its strengths is the inclusion of subjects with prospectively characterized PMDD who were well screened to exclude co-morbid psychiatric disorders. The follicular and late luteal phase timing of the scans was also carefully controlled. Further studies addressing cerebellar circuitry and investigating GABAA receptor biology in the cerebellum could deepen our knowledge of the pathogenesis of PMDD and might lead to new treatments for this debilitating disorder.