Laura Palagini

The neurobiology, investigation, and treatment of chronic insomnia

Chronic insomnia is defined by difficulties in falling asleep, maintaining sleep, and early morning awakening, and is coupled with daytime consequences such as fatigue, attention deficits, and mood instability. These symptoms persist over a period of at least 3 months (Diagnostic and Statistical Manual 5 criteria). Chronic insomnia can be a symptom of many medical, neurological, and mental disorders. As a disorder, it incurs substantial health-care and occupational costs, and poses substantial risks for the development of cardiovascular and mental disorders, including cognitive deficits. Family and twin studies confirm that chronic insomnia can have a genetic component (heritability coefficients between 42% and 57%), whereas the investigation of autonomous and central nervous system parameters has identified hyperarousal as a final common pathway of the pathophysiology, implicating an imbalance of sleep-wake regulation consisting of either overactivity of the arousal systems, hypoactivity of the sleep-inducing systems, or both. Insomnia treatments include benzodiazepines, benzodiazepine-receptor agonists, and cognitive behavioural therapy. Treatments currently under investigation include transcranial magnetic or electrical brain stimulation, and novel methods to deliver psychological interventions.

Depression and systemic lupus erythematosus: a systematic review

Objective Systemic lupus erythematosus (SLE) is a chronic, relapsing–remitting autoimmune disorder that involves multiple organ systems including the central nervous system. Among the items included in the nomenclature for neuropsychiatric SLE, mood disorders have been identified. The aim of this paper is to review the clinical and psychobiological relationship between depression and SLE. Method We performed a systematic search of MEDLINE, EMBASE, PsychINFO, using MeSH headings and keywords for ‘depression’ and ‘SLE’. Results Seventeen studies reported depressive disorders, with prevalence rates in the range 17–75%. Three studies reported the most frequent symptoms, which may be represented by fatigue, weakness, somatic disorders and sleep disorders. Suicide ideation was much higher than in the general population. Nine studies analysed the relationship to SLE disease activity. The results of the available literature are contradictory. Psychobiological hypotheses have been considered in 13 studies. Among the psychobiological hypotheses which might underline the plausibility of their relationship, ‘psychosocial factors’ were the most frequently reported. Conclusions Differences in assessment techniques appear to be the main explanation for the variability in findings and important methodological limitations are present in the available literature to definitively point to the prevalence of depression, type of depression and most prevalent symptoms. To date, the relationship between depression and SLE disease activity also appears controversial. Methodological limitations are present in the available literature and it would be necessary to develop evidence-based guidelines to improve the diagnosis of depression in SLE. Identification of SLE-specific biomarkers of depression also has high priority.

The genetics of insomnia – Evidence for epigenetic mechanisms?

Sleep is a complex physiological process and still remains one of the great mysteries of science. Over the past 10 y, genetic research has provided a new avenue to address the regulation and function of sleep. Gene loci that contribute quantitatively to sleep characteristics and variability have already been identified. However, up to now, a genetic basis has been established only for a few sleep disorders. Little is yet known about the genetic background of insomnia, one of the most common sleep disorders. According to the conceptualisation of the 3P model of insomnia, predisposing, precipitating and perpetuating factors contribute to the development and maintenance of insomnia. Growing evidence from studies of predisposing factors suggests a certain degree of heritability for insomnia and for a reactivity of sleep patterns to stressful events, explaining the emergence of insomnia in response to stressful life events. While a genetic susceptibility may modulate the impact of stress on the brain, this finding does not provide us with a complete understanding of the capacity of stress to produce long-lasting perturbations of brain and behaviour. Epigenetic gene-environment interactions have been identified just recently and may provide a more complex understanding of the genetic control of sleep and its disorders. It was recently hypothesised that stress-response-related brain plasticity might be epigenetically controlled and, moreover, several epigenetic mechanisms have been assumed to be involved in the regulation of sleep. Hence, it might be postulated that insomnia may be influenced by an epigenetic control process of both sleep mechanisms and stress-response-related gene-environment interactions having an impact on brain plasticity. This paper reviews the evidence for the genetic basis of insomnia and recent theories about epigenetic mechanisms involved in both sleep regulation and brain-stress response, leading to the hypothesis of an involvement of epigenetic mechanisms in the development and maintenance of insomnia.

Poor sleep quality and resistant hypertension

OBJECTIVES We aimed to determine the relationship between sleep quality and treatment-resistant hypertension (RH). METHODS In our cross-sectional cohort study, 270 consecutive essential hypertensive patients were recruited at the Outpatient Hypertension Unit, University of Pisa, Italy. The Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), and State-Trait Anxiety Inventory (STAI-Y2) were administered to all subjects. RH was defined as office blood pressure (BP) >140/90 mmHg with three or more antihypertensive drugs or controlled BP with four or more drugs. Poor sleep quality was defined as PSQI >5, depressive symptoms as BDI >10, and trait anxiety as STAI-Y2 >40. Patients with other sleep disorders were excluded. RESULTS Complete data were available for 222 patients (50.9% men; mean age, 56.6±12.5 y; RH, 14.9%). Poor sleep quality had a prevalence of 38.2% in the overall population. RH was associated with poor sleep quality, increased sleep latency and reduced sleep efficiency. No significant relationship was found between RH and short sleep duration or depressive symptoms and trait anxiety. Poor sleep quality was more prevalent in resistant vs nonresistant hypertensive women (70.6% vs 40.2%; P=.02) but not in resistant vs nonresistant men (43.8% vs 29.2%; P=.24). In women poor sleep quality was an independent predictor of RH, even after adjustment for cardiovascular and psychiatric comorbidities (odds ratio [OR], 5.3 [confidence interval {CI}, 1.1-27.6), explaining 4.7% of its variance. In men age, diabetes mellitus (DM), and obesity were the only variables associated with RH. CONCLUSIONS Poor sleep quality is significantly associated with resistance to treatment in hypertensive women, independent of cardiovascular and psychiatric confounders.

High internight reliability of computer-measured NREM delta, sigma, and beta: biological implications.

BACKGROUND Computer analysis of the sleep electroencephalogram (EEG) waveforms is widely employed, but there have been no systematic studies of its reliability. METHODS The most commonly used computer methods are power spectral analysis with the fast-Fourier transform (FFT) and period amplitude analysis (PAA) with zero cross or zero first derivative half-wave measurement. We applied all three computer methods to the digitized EEG of 16 normal subjects who underwent 5 consecutive nights of baseline (placebo) recording. We evaluated the internight reliability of three non-rapid eye movement (NREM) frequency bands of special importance to sleep research: delta (0.3-3 Hz), sigma (12-15 Hz), and beta (15-23 Hz). RESULTS Both FFT and the two methods of PAA gave excellent internight reliability for delta and sigma. Even a single night of recording correlated highly (r >.9) with the 5-night mean. Beta reliability was lower but still highly significant for both the PAA and the FFT measures. CONCLUSIONS Computer-analyzed sleep EEG data are highly reliable. Period amplitude methods demonstrate that wave incidence and period as well as amplitude are reliable, indicating that the reliability of composite measures (FFT power, PAA integrated amplitude) is not solely based on individual differences in EEG amplitude. The high internight stability of NREM delta indicates that it possesses traitlike characteristics and is relatively independent of day-to-day variations in state.

Sleep, dreaming, and mental health: A review of historical and neurobiological perspectives

Theories as to the function of sleep and dreaming and their relationship to emotions have been studied since the beginning of recorded history. Earliest historical records show the predominant view to be that dreams were considered divine in origin and only later did dream theory become linked with the functioning of the brain, perhaps most famously in psychoanalytic theory. The development of sleep laboratory techniques ushered in a new era of the dream study and their relationship to mental health. In this review we outline the history of theories about the genesis and function of dreams and sleep and their relationship to mental illness from ancient mythic and religious views to the first tentative scientific approaches to the ascendency of psychoanalysis and ultimately to the modern era of neuroscience.

Sleep disorders and systemic lupus erythematosus.

Objective Sleep disturbances are often seen in rheumatic diseases, including systemic lupus erythematosus (SLE). However, the prevalence of sleep disorders in SLE as well as the contributing factors to their occurrence remain poorly understood. The aim of this paper is to review the clinical and psychobiological data on the relationship between sleep disturbances and SLE. Method We performed a systematic search of MEDLINE, EMBASE and PsychINFO, using MeSH headings and keywords for “sleep disorders” and “SLE.” Results Nine studies reporting the relationship between sleep disorders and SLE were found. Prevalence rates of sleep disorders ranged between 55% and 85%; differences in assessment techniques appeared to be a major source of this variability. In the majority of the studies an association between sleep disorders and disease activity, pain and fatigue has been reported. Psychosocial variables, depression, steroid use, and the role that sleep disruption has on pain, inflammation and cytokines, have been hypothesized as possible psychobiological factors. Conclusions Sleep disorders appear to occur in more than half of patients with SLE and appear to be associated with disease activity. Pain and fatigue are also related to sleep disorders. Among the hypotheses on the possible mechanisms underlining the association between sleep disorders and SLE, psychosocial/psychological factors, especially depression, were the most frequently reported.

Mental activity after early afternoon nap awakenings in healthy subjects.

Despite the common misconception that rapid eye movement (REM) sleep is a unique correlate of dreaming, reports of mental activity can be elicited after awakenings from any stage of nocturnal sleep. We extended the investigation to naps and tried to explore the relationship between recall length and level of sleep stage and depth preceding the awakening. We hypothesized that dream report length would be related to arousal level. In 10 healthy young adults, sleep EEG and EOG were recorded for four non-consecutive early afternoon naps. Dream recalls were recorded following 10 s, 1 min, and 6 min of NREM Stage 2 and after 5 min of first REM period. We measured mental recall with total word count (TWC) method, sleep stages by using EEG visual scoring and Delta and Beta activity by period amplitude (PAA) and power spectral (PSA) analyses. All awakening conditions were followed by a dream report. TWC was significantly greater after REM than after 10 s and 1 min of NREM, and TWC did not differ among the NREM awakenings. Delta activity after REM was significantly lower compared to the NREM 6 and 1 min while Beta activity did not differ across the conditions. Assuming that arousal level decreased with increased NREM duration and increasing Delta EEG activity, the constant TWC across the three NREM awakenings indicates that arousal level cannot be the only factor affecting dream report length. Some other factor such as memory processing may explain the longer dream reports following REM sleep, or it may be that the EEG is an imperfect indicator of arousal level.

Poor sleep quality in systemic lupus erythematosus: does it depend on depressive symptoms?

Objectives Sleep disturbances are frequently observed in rheumatic diseases including systemic lupus erythematosus (SLE). This study aimed at evaluating the prevalence of insomnia, poor sleep quality and their determinants in a cohort of SLE patients. Methods Eighty-one consecutive SLE female patients were evaluated in a cross-sectional study. The Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), the Beck Depression Inventory (BDI) and the Self-rating Anxiety Scale (SAS) were administered. Patients with previous diagnosis of obstructive sleep apnea or restless legs syndrome were excluded. Fifty-three women with hypertension (without SLE) were enrolled as control group (H). Results In the SLE cohort poor sleep quality (65.4% vs 39.6%, p < 0.01) and difficulty in maintaining sleep and/or early morning awakening (65.4% vs 22.6%, p < 0.001), but not insomnia (33.3% vs 22.6%, p = ns), were more prevalent than in H. Depressive symptoms were present in 34.6% of SLE vs 13.2% H patients (p < 0.001) while state anxiety was more common in H patients (H 35.8% vs SLE 17.3%, p < 0.005). SLE was associated with a 2.5-times higher probability of presenting poor sleep quality in comparison to H (OR 2.5 [CI 1.21–5.16]). After adjusting for confounders, both depressive symptoms (OR 4.4, [1.4–14.3]) and use of immunosuppressive drugs (OR 4.3 [CI 1.3–14.8]) were significantly associated with poor sleep quality in SLE patients. Furthermore, poor sleep quality was not associated either with disease duration or activity. Conclusions In a cohort of SLE women, insomnia and poor sleep quality, especially difficulties in maintaining sleep, were common. Depressive symptoms might be responsible for the higher prevalence of poor sleep quality in SLE.

Independence of sleep EEG responses to GABAergic hypnotics: biological implications

GABAergic hypnotics are known to depress non-rapid eye movement delta and rapid eye movements and to stimulate non-rapid eye movement sigma (spindles) and beta EEG. This study addressed the question of whether the magnitudes of these effects are significantly correlated. Data were from a study in 16 normal subjects whose sleep was recorded for five nights under placebo and for three nights each under zolpidem (10 mg), triazolam (0.25 mg) and temazepam (30 mg). EEG was analyzed with both period-amplitude and power spectral (FFT) analysis. The magnitudes of the EEG and eye movement density responses were not significantly correlated for any of the three drugs. It is therefore unlikely that sleep responses to GABAergic drugs can be explained by the common cellular action (increased chloride conductance) of these drugs. We suggest that the sleep EEG responses are manifestations of complex (but consistent) interactions of excitation and inhibition in large brain systems although certain aspects of these responses (e.g. the different time courses of delta vs sigma and eye movement responses) may reflect molecular adaptations. A separate observation in this study was the strong traitlike characteristics of the sleep variables studied. These variables were highly correlated across nights of baseline sleep; in addition, individual differences in baseline sleep were significantly retained on the third night of temazepam administration.