Brain Regions Activated during an Auditory Discrimination Task in Insomniac Postmenopausal Patients before and after Hormone Replacement Therapy: Low-Resolution Brain Electromagnetic Tomography Applied to Event-Related Potentials

Abstract

Electrical sources of auditory event-related potentials (ERPs) determined by means of low-resolution brain electromagnetic tomography (LORETA) in 48 unmedicated insomniac postmenopausal patients aged between 46 and 67 years were compared with those obtained in 48 age-matched normal female controls. Subsequently, the patients were included in a double-blind, placebo-controlled, comparative, randomized 3-arm trial phase – Climodien 2/3 [estradiol valerate (EV) 2 mg + the progestin dienogest 3 mg] was compared with EV 2 mg and placebo – followed by an open-label phase in which all of them received Climodien 2/2 (EV 2 mg + dienogest 2 mg). The double-blind and the open-label phase lasted 2 months. ERPs were recorded from 19 EEG leads in a two-tone oddball paradigm and electrical sources of standard N1 and P2 as well as target N2 and P300 components were estimated. In both patients and controls, LORETA revealed an activation of the superior temporal gyrus [auditory cortex, Brodmann areas (BA) 41, 42, 22] for all four components. For standard P2, an additional activation was observed medially parietally in the precuneus (BA 7, 5). For target N2, also a medial frontal source (BA 9, 10, 32) was identified. Finally, for the target P300 component – in addition to the aforementioned sources – activations in the prefrontal cortex (BA 9, 10, 46, 47), the inferior parietal cortex (supramarginal gyrus, BA 40, 39) and the posterior cingulum (BA 31) were found. Thus, patients and controls did not differ in the structural processes engaged in these fundamental aspects of information processing. However, patients demonstrated significantly reduced source strength – for standard ERP components predominantly in the temporal lobe and for target components predominantly in the frontal lobe, indicating reduced energetic resources available for perceptual and cognitive demands of the discrimination task. While, as compared with placebo, estrogen alone had only minor effects on ERP source strength, Climodien generally increased the impressed current density at the ERP peak latencies, predominantly in the temporal lobe, indicating an increased stimulus-induced cortical arousal in the primary and higher-order auditory cortex. Specifically, Climodien enhanced P300 source strength in the left middle temporal gyrus and in the left superior frontal gyrus, brain regions that on the one hand have been shown to be affected by hormone therapy in positron emission tomography and functional magnetic resonance neuroimaging studies and that on the other hand are among those critical for encoding and memory processes.

Guidelines for the Recording and Evaluation of Pharmaco-Sleep Studies in Man: The International Pharmaco-EEG Society (IPEG)

“…Most interesting from a methodological point of view is the finding that all 4 source localisation methods revealed similar results. The similar findings for the various inverse solutions and the physiologically meaningful results obtained from source localisation based not only on high-density but also on rather low-density EEG recordings [103,255,262] clearly justify the utilisation of these methods in pharmaco-sleep studies. However, it needs to be stressed that full details of the applied source localisation method with all its underlying assumptions (e.g.…”

“…Meanwhile LORETA has received considerable validation from studies combining it with other more established localisation methods, such as fMRI [251], structural MRI [252] and PET [253]. Further LORETA validation has been based on comparison with the localisation findings from implanted depth electrodes, in a number of studies in epilepsy [254] and on cognitive event-related potentials where the activated brain regions are known a priori [255]. One has to be aware that only cortical activities that make major contributions to the scalp-recorded EEG can be estimated by source localisation, and this means most of the deep active sources in the brain are not detectable.…”

Investigating the Effects of Estradiol or Estradiol/Progesterone Treatment on Mood, Depressive Symptoms, Menopausal Symptoms and Subjective Sleep Quality in Older Healthy Hysterectomized Women: A Questionnaire Study

“…Our study at least suggests that progesterone taken in the evening has no strong effects on subjective sleep quality in healthy older women. Results might have been different if subjects were included into the study based on sleep disturbances [47] . Ideally, such future studies would combine objective (sleep EEG) measures with more elaborated questionnaires like the Pittsburgh Sleep Quality Index [48] .…”

The other side of progestins: effects in the brain

“…In another study, insomniac postmenopausal women were tested with LORETA during a two-tone oddball paradigm (i.e., an auditory discrimination task). Data indicated that E2-V + DNG combination was able to increase the stimulus-induced cortical arousal in the primary and higher-order auditory cortex; an effect that was not achieved by E2-V treatment alone (Anderer et al 2004). Moreover, the combination of EE and NET acetate produced, during a spatial working memory task, a higher activation of prefrontal cortex compared with placebo (Smith et al 2006).…”