Francesca Regen

The relationship between REM sleep and memory consolidation in old age and effects of cholinergic medication

BACKGROUND Recent findings in young adults suggest that rapid eye movement (REM) sleep plays a role in procedural memory consolidation. The significance of REM sleep for memory consolidation in old age has not yet been investigated. METHODS Effects of REM sleep manipulation on declarative and procedural memory consolidation were investigated in 107 healthy older adults, ages 60-82 years. Rapid eye movement sleep deprivation was achieved by REM sleep awakenings and compared with non-REM sleep awakenings. Rapid eye movement sleep augmentation was realized physiologically by REM sleep rebound and pharmacologically by administering an acetylcholinesterase inhibitor in a double-blind, placebo-controlled design. Memory performance was tested by a paired associate list and a mirror tracing task at 9:30 pm and 7:30 am with sleep intervening between 11:00 pm and 7:00 am. RESULTS Although REM sleep deprivation led to a significant reduction in total and phasic REM sleep, memory consolidation remained unaffected. Both REM sleep augmentation groups showed a significant increase in phasic REM sleep, whereas only pharmacological cholinergic REM sleep manipulation exerted a significant positive effect on procedural memory consolidation. CONCLUSIONS Because only after cholinergic stimulation of phasic REM sleep procedural memory consolidation is improved, cholinergic activation seems to be a crucial component of REM sleep-related memory consolidation in old age.

Electroconvulsive therapy-induced brain plasticity determines therapeutic outcome in mood disorders

Significance Electroconvulsive therapy is controversial: How does a major electrical discharge over half the brain result in recovery in disorders such as refractory major depression and manic depression, which are apparently different diseases? We find local but not general brain anatomy changes following electroconvulsive therapy that are differently distributed in each disease, and the areas affected are those implicated as abnormal in each disorder. An interaction between electroconvulsive therapy and specific pathology appears to be responsible for the therapeutic effect. Our results have implications for other electrically based brain treatments, such as deep brain stimulation and transcranial magnetic stimulation. There remains much scientific, clinical, and ethical controversy concerning the use of electroconvulsive therapy (ECT) for psychiatric disorders stemming from a lack of information and knowledge about how such treatment might work, given its nonspecific and spatially unfocused nature. The mode of action of ECT has even been ascribed to a “barbaric” form of placebo effect. Here we show differential, highly specific, spatially distributed effects of ECT on regional brain structure in two populations: patients with unipolar or bipolar disorder. Unipolar and bipolar disorders respond differentially to ECT and the associated local brain-volume changes, which occur in areas previously associated with these diseases, correlate with symptom severity and the therapeutic effect. Our unique evidence shows that electrophysical therapeutic effects, although applied generally, take on regional significance through interactions with brain pathophysiology.

Reduced amygdala volume in newly admitted psychiatric in-patients with unipolar major depression

Structural neuroimaging studies investigating amygdala volumes in patients suffering from major depression have yielded variable results. Discrepant findings across studies may be attributable in part to heterogeneity with respect to antidepressant medication and to lack of adequate control for the effects of total brain volume and age. Here, 24 unipolar depressed in-patients newly admitted to a psychiatric unit and 14 healthy control participants matched for age, gender, and years of education underwent quantitative magnetic resonance imaging (MRI) toward the end of a one-week washout period. Saliva cortisol was measured at 08.00 and at 16.00h in patients during washout. Absolute amygdala volumes were significantly reduced in the patient group (by 13% in left amygdala and 12% in right amygdala). The effect of reduced amygdala volumes in patients remained significant after correction for brain volume (BV) and age. Furthermore, amygdala volume measurements in the patient sample showed a significant inverse relationship to the number of preceding depressive episodes. In patients, severity of disease (baseline HAMD scores) and baseline cortisol levels were not related to amygdala volume. This study of a sample of unmedicated depressed in-patients adds to the small, yet growing, body of evidence linking untreated major depression to reduced amygdala volume.

Mineralocorticoid Receptor Stimulation Improves Cognitive Function and Decreases Cortisol Secretion in Depressed Patients and Healthy Individuals

Memory and executive function are often impaired in patients with major depression, while cortisol secretion is increased. Mineralocorticoid receptors (MR) are abundantly expressed in the hippocampus and in the prefrontal cortex, brain areas critical for memory, executive function, and cortisol inhibition. Here, we investigated whether MR stimulation with fludrocortisone (1) improves memory and executive function and (2) decreases cortisol secretion in depressed patients and healthy individuals. Twenty-four depressed patients without medication and 24 age-, sex-, and education-matched healthy participants received fludrocortisone (0.4 mg) or placebo in a randomized, double-blind, within-subject cross-over design. We measured verbal memory, visuospatial memory, executive function, psychomotor speed, and salivary cortisol secretion during cognitive testing between 1400 and 1700 hours. For verbal memory and executive function, we found better performance after fludrocortisone compared with placebo across groups. No treatment effect on other cognitive domains emerged. Depressed patients performed worse than healthy individuals in psychomotor speed and executive function. No group effect or group × treatment interaction emerged on other cognitive domains. Fludrocortisone decreased cortisol secretion across groups and there was a significant correlation between cortisol inhibition and verbal memory performance. Our data suggest a crucial role of MR in verbal memory and executive function and demonstrate the possibility to improve cognition in depressed patients and healthy individuals through MR stimulation.

Cognitive-Behavioral Therapy as Continuation Treatment to Sustain Response After Electroconvulsive Therapy in Depression: A Randomized Controlled Trial

BACKGROUND Although electroconvulsive therapy (ECT) is the most effective acute antidepressant intervention, sustained response rates are low. It has never been systematically assessed whether psychotherapy, continuation ECT, or antidepressant medication is the most efficacious intervention to maintain initial treatment response. METHODS In a prospective, randomized clinical trial, 90 inpatients with major depressive disorder (MDD) were treated with right unilateral ultra-brief acute ECT. Electroconvulsive therapy responders received 6 months guideline-based antidepressant medication (MED) and were randomly assigned to add-on therapy with cognitive-behavioral group therapy (CBT-arm), add-on therapy with ultra-brief pulse continuation electroconvulsive therapy (ECT-arm), or no add-on therapy (MED-arm). After the 6 months of continuation treatment, patients were followed-up for another 6 months. The primary outcome parameter was the proportion of patients who remained well after 12 months. RESULTS Of 90 MDD patients starting the acute phase, 70% responded and 47% remitted to acute ECT. After 6 months of continuation treatment, significant differences were observed in the three treatment arms with sustained response rates of 77% in the CBT-arm, 40% in the ECT-arm, and 44% in the MED-arm. After 12 months, these differences remained stable with sustained response rates of 65% in the CBT-arm, 28% in the ECT-arm, and 33% in the MED-arm. CONCLUSIONS These results suggest that ultra-brief pulse ECT as a continuation treatment correlates with low sustained response rates. However, the main finding implicates cognitive-behavioral group therapy in combination with antidepressants might be an effective continuation treatment to sustain response after successful ECT in MDD patients.

Manipulating REM sleep in older adults by selective REM sleep deprivation and physiological as well as pharmacological REM sleep augmentation methods.

Experimental approaches to manipulate REM sleep within the cognitive neuroscience of sleep are usually based on sleep deprivation paradigms and focus on younger adults. In the present study, a traditional selective REM sleep deprivation paradigm as well as two alternative manipulation paradigms targeting REM sleep augmentation were investigated in healthy older adults. The study sample consisted of 107 participants, male and female, between the ages of 60 and 82 years, who had been randomly assigned to five experimental groups. During the study night, a first group was deprived of REM sleep by selective REM sleep awakenings, while a second group was woken during stage 2 NREM sleep in matched frequency. Physiological REM sleep augmentation was realized by REM sleep rebound after selective REM sleep deprivation, pharmacological REM sleep augmentation by administering an acetylcholinesterase inhibitor in a double-blind, placebo-controlled design. Deprivation and augmentation paradigms manipulated REM sleep significantly, the former affecting more global measures such as REM sleep minutes and percentage, the latter more organizational aspects such as stage shifts to REM sleep, REM latency, REM density (only pharmacological augmentation) and phasic REM sleep duration. According to our findings, selective REM sleep deprivation seems to be an efficient method of REM sleep manipulation in healthy older adults. While physiological rebound-based and pharmacological cholinergic REM sleep augmentation methods both failed to affect global measures of REM sleep, their efficiency in manipulating organizational aspects of REM sleep extends the traditional scope of REM sleep manipulation methods within the cognitive neuroscience of sleep.

Association between pupillary unrest index and waking electroencephalogram activity in sleep-deprived healthy adults

OBJECTIVE In recent years there has been growing interest in the use of pupillography as an objective and time-saving method to assess the level of sleepiness. The aim of our study was to further elucidate the validity of pupillography by investigating the association of pupillometric variables with subjective sleepiness and waking electroencephalogram (EEG) activity. METHODS The level of sleepiness of 24 young healthy adults was evaluated during 40h of sustained wakefulness using pupillography and subjective ratings with the Stanford sleepiness scale and a visual analog scale (VAS). During the assessment of sleepiness by pupillography, waking EEG was simultaneously recorded and subjected to spectral analyses. As a pupillographic measure of sleepiness the pupillary unrest index (PUI) was calculated. RESULTS PUI, subjective sleepiness, and power in the δ, θ, α1, β1, and β3 frequency band exhibited significant variations over time. PUI showed a prominent circadian modulation under high homeostatic sleep pressure. At time points of maximum PUI indicating a high level of sleepiness, significant increases were found in subjective sleepiness as well as in δ, θ, α1, and β1 power. Moreover, PUI showed a significant, high intraindividual correlation with subjective sleepiness and with power in the δ, θ, and α1 frequency band. CONCLUSION The novel finding of a close association between pupillometric variables and distinct changes in waking EEG activity underscores the validity of pupillography as a time- and cost-efficient objective measure of sleepiness that could ease the diagnostic and therapeutic workup of patients who report excessive daytime sleepiness.

Inhibition of retinoic acid catabolism by minocycline: evidence for a novel mode of action?

Retinoic acid (RA) represents an essential and highly potent endogenous retinoid with pronounced anti‐inflammatory properties and potent anti‐acne activity, and has recently been suggested to share a common anti‐inflammatory mode of action with tetracycline antibiotics. We hypothesized that tetracyclines may directly interfere with RA homeostasis via inhibition of its local cytochrome P450 (CYP450)‐mediated degradation, an essential component of tightly regulated skin RA homeostasis. To test this hypothesis, we performed controlled in vitro RA metabolism assays using rat skin microsomes and measured RA levels in a RA‐synthesizing human keratinocyte cell line, both in the presence and in the absence of minocycline, a tetracycline popular in acne treatment. Interestingly, minocycline potently blocked RA degradation in rat skin microsomes, and strikingly enhanced RA levels in RA‐synthesizing cell cultures, in a dose‐dependent manner. These findings indicate a potential role for CYP‐450‐mediated RA metabolism in minocyclines pleiotropic mode of action and anti‐acne efficacy and could account for the overlap between minocycline and RA‐induced effects at the level of their molecular mode of action, but also clinically at the level of the rare side effect of pseudotumor cerebri, which is observed for both, RA and minocycline treatment.

Striking Growth-inhibitory Effects of Minocycline on Human Prostate Cancer Cell Lines

OBJECTIVE To elucidate a hypothetical link between retinoic acid (RA) signaling and minocycline for targeting prostate carcinoma (PCA). RA signaling has been implicated in growth-inhibition of malignant PCA, and intracellular RA homeostasis has been investigated as a potential therapeutic target. Minocycline is a tetracycline antibiotic with pleiotropic actions in many tissues and reaches comparably high levels in human prostate tissue. Interestingly, minocycline exhibits the rare side effect of a pseudotumor cerebri, which is otherwise known to occur from vitamin A intoxication or in retinoid therapy. Therefore, we hypothesized minocycline to putatively interact with intracellular RA homeostasis in PCA. METHODS Using LN-CAP, DU-145, and PC-3 cell lines, effects of minocycline on microsomal RA metabolism and on cell growth were assessed in vitro. RESULTS Minocycline was identified to potently inhibit cell growth, at concentrations within the range of tissue levels readily reached under standard therapeutic conditions. In vitro inhibition experiments revealed inhibition of RA breakdown, yet only at comparably high concentrations of minocycline. Using all trans-RA, RA metabolism inhibitor liarozole, and different retinoid receptor antagonists, the putative RA-dependent effects of minocycline were further evaluated and confirmed to be independent of RA signaling. CONCLUSION Our findings add to the growing body of evidence for the many pleiotropic actions of minocycline. In view of the striking effects of minocycline on cell growth in PCA cell lines in vitro and its relatively safe side effect profile, the use of minocycline for targeting PCA should be timely clinically evaluated.

Do tetracyclines and erythromycin exert anti-acne effects by inhibition of P450-mediated degradation of retinoic acid?

For decades, retinoic acid (RA) is known as the most potent therapeutic option in the therapy of acne and altered homeostasis of endogenous retinoids has been discussed in the context of acne pathogenesis. Besides retinoids, antibiotics such as tetracyclines or erythromycin are well established in acne pharmacotherapy. Accumulating evidence points towards common molecular pathways being targeted by both RA and anti‐acne antibiotics; however, a precise ‘common denominator’ connecting these chemically diverse anti‐acne agents has not yet been identified. Interestingly, tetracyclines are associated with the occurrence of pseudotumor cerebri, a rare neurological side effect otherwise associated with retinoid intoxication or RA exposure. This association at the clinical level suggests an interaction between tetracyclines and endogenous RA signalling. As erythromycin does not cross the blood brain barrier, CNS side effects are not to be expected, yet not precluding a possible local interaction of erythromycin with endogenous RA metabolism in the skin. We hypothesize tetracyclines and erythromycin to locally inhibit endogenous RA metabolism in the skin and thus mimic therapeutic action of RA. This readily testable hypothesis suggests inhibition of endogenous RA metabolism and amplification of endogenous RA signalling as a mechanism underlying the biochemical actions of antibiotics in acne therapy. Elucidation of such interactions may ultimately enhance our understanding of acne therapy and pathogenesis and may yield a sound, scientific basis for hypothesis‐driven development of novel therapeutic compounds.