Concordance between the In Vivo Content of Neurospecific Proteins (BDNF, NSE, VILIP-1, S100B) in the Hippocampus and Blood in Patients with Epilepsy.

The identification of reliable brain-specific biomarkers in periphery contributes to better understanding of normal neurophysiology and neuropsychiatric diseases. The neurospecific proteins BDNF, NSE, VILIP-1, and S100B play an important role in the pathogenesis of neuropsychiatric disorders, including epilepsy. This study aimed to assess the correspondence of the expression of BDNF, NSE, VILIP-1, and S100B in the blood (serum and peripheral blood mononuclear cells (PBMCs)) to the in vivo hippocampal levels of subjects with drug-resistant epilepsy who underwent neurosurgery (N = 44) using multiplex solid-phase analysis, ELISA, and immunohistochemical methods, as well as to analyze the correlations and associations of the blood and hippocampal levels of these proteins with clinical parameters. We first studied the concordance between in vivo brain and blood levels of BDNF, NSE, VILIP-1, and S100B in epileptic patients. A positive correlation for NSE between hippocampal and PBMC levels was revealed. NSE levels in PBMCs were also significantly correlated with average seizure duration. BDNF levels in PBMCs were associated with seizure frequency and hippocampal sclerosis. Thus, NSE and BDNF levels in PBMCs may have potential as clinically significant biomarkers. Significant correlations between the levels of the neurospecific proteins studied herein suggest interactions between BDNF, NSE, VILIP-1, and S100B in the pathophysiology of epilepsy.

Neurospecific Molecules Measured in Periphery in Humans: How Do They Correlate with the Brain Levels? A Systematic Review.

Human brain state is usually estimated by brain-specific substances in peripheral tissues, but, for most analytes, a concordance between their content in the brain and periphery is unclear. In this systematic review, we summarized the investigated correlations in humans. PubMed was searched up to June 2022. We included studies measuring the same endogenous neurospecific analytes in the central nervous system and periphery in the same subjects. Not eligible were studies of cerebrospinal fluid, with significant blood-brain barrier disruption, of molecules with well-established blood-periphery concordance or measured in brain tumors. Seventeen studies were eligible. Four studies did not report on correlation and four revealed no significant correlation. Four molecules were examined twice. For BDNF, there was no correlation in both studies. For phenylalanine, glutamine, and glutamate, results were contradictory. Strong correlations were found for free tryptophan (r = 0.97) and translocator protein (r = 0.90). Thus, only for three molecules was there some certainty. BDNF in plasma or serum does not reflect brain content, whereas free tryptophan (in plasma) and translocator protein (in blood cells) can serve as peripheral biomarkers. We expect a breakthrough in the field with advanced in vivo metabolomic analyses, neuroimaging techniques, and blood assays for exosomes of brain origin.

White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group.

Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Circadian reinforcement therapy in combination with electronic self-monitoring to facilitate a safe post-discharge period of patients with depression by stabilizing sleep: protocol of a randomized controlled trial.

BACKGROUND: The transition phase from inpatient to outpatient care for patients suffering from Major Depressive Disorder represents a vulnerable period associated with a risk of depression worsening and suicide. Our group has recently found that the sleep-wake cycle in discharged depressive patients became irregular and exhibited a drift towards later hours, associated with worsening of depression. In contrast, an advancement of sleep phase has earlier been shown to have an antidepressant effect. Thus, methods to prevent drift of the sleep-wake cycle may be promising interventions to prevent or reduce worsening of depression after discharge. METHODS: In this trial, we apply a new treatment intervention, named Circadian Reinforcement Therapy (CRT), to patients discharged from inpatient psychiatric wards. CRT consists of a specialized psychoeducation on the use of regular time signals (zeitgebers): daylight exposure, exercise, meals, and social contact. The aim is to supply stronger and correctly timed zeitgebers to the circadian system to prevent sleep drift and worsening of depression. The CRT is used in combination with an electronic self-monitoring system, the Monsenso Daybuilder System (MDB). By use of the MDB system, all patients self-monitor their sleep, depression level, and activity (from a Fitbit bracelet) daily. Participants can inspect all their data graphically on the MDB interface and will have clinician contact. The aim is to motivate patients to keep a stable sleep-wake cycle. In all, 130 patients referred to an outpatient service will be included. Depression rating is blinded. Patients will be randomized 1:1 to a Standard group or a CRT group. The intervention period is 4 weeks covering the transition phase from inpatient to outpatient care. The primary outcome is score change in interviewer rated levels of depression on the Hamilton Depression Rating Scale. A subset of patients will be assessed with salivary Dim Light Melatonin Onset (DLMO) as a validator of circadian timing. The trial was initiated in 2016 and will end in 2020. DISCUSSION: If the described intervention is beneficial it could be incorporated into usual care algorithms for depressed patients to facilitate a better and safer transition to outpatient treatment. TRIAL REGISTRATION: Posted prospectively at ClinicalTrials.gov at February 10, 2016 with identifier NCT02679768 .

Investigation of an Immediate Effect of Bright Light on Oxygen Consumption, Heart Rate, Cortisol, and α-Amylase in Seasonal Affective Disorder Subjects and Healthy Controls.

BACKGROUND: Body (fat) mass has been shown to decrease following bright light treatment for overweight women, irrespective of their seasonal (light) dependence. It is not known if this is due to an (immediate) increase of metabolism. METHODS: Ten women with seasonal affective disorder (SAD) and 10 non-SAD women matched by age, body mass index, and menopausal status participated in a laboratory study in the morning, twice within 1-5 days. During one session, bright light (4,300 lx) was presented for 30 min, and during the other session, red light (250 lx "placebo") was used. After an initial 15 min of sitting quietly in an experimental chamber, 10-min measurements were done before, at the end, and 15 min after light exposure; the subjects remained seated for 80 min in total. The measurements included 5-min oxyspirography (oxygen consumption, carbon dioxide emission, and heart rate), saliva sampling for the estimation of cortisol and α-amylase concentrations, and self-rating of mood, energy, and sleepiness. RESULTS: There was no light-specific effect on the measured variables, except that sleepiness was reduced more with bright light than with red light in the combined group. α-Amylase values were lower in the SAD patients than in the non-SAD controls. CONCLUSIONS: Morning artificial bright light, in comparison with dim red light, had no immediate effect on metabolism and resting sympathetic tone, though subjective sleepiness decreased more with bright light. SAD patients have low salivary α-amylase levels, indicating lower sympathetic tone.

Immediate effect of blue-enhanced light on reproductive hormones in women.

OBJECTIVE: Light is known to stimulate reproductive function in women. We here investigated the immediate effect of light on reproductive hormones, addressing the role of blue-sensitive (~480 nm) melanopsin-based photoreception mediating the non-visual effects of light. METHODS: Sixteen healthy women attended the Institute at ~07:25 (shortly after waking; sunglasses worn) twice in 2-3 days in April-May, within days 4-10 of their menstrual cycle. During one session, a broad-spectrum white-appearing light with a superimposed peak at 469 nm was presented against 5-10 lux background; during the other session, short-spectrum red light peaked at 651 nm with similar irradiance level (~7.0 W/m², corresponds to ~1200 lux) was used. Venous blood was taken at 0, 22 and 44 minutes of light exposure to measure concentrations of follicle-stimulating hormone (FSH), luteinising hormone (LH), prolactin, estradiol, progesterone and cortisol, and saliva was sampled to measure melatonin as a recognised indicator of the spectral-specific action of light. RESULTS: Melatonin values, as expected, were lower with white vs. red light (p=0.014), with the greatest difference at 22 minutes. Of the other hormones, only FSH concentrations differed significantly: they were mildly higher at white vs. red light (again, at 22 minutes; p=0.030; statistical analysis adjusted for menstrual cycle day and posture change [pre-sampling time seated]). CONCLUSION: Moderately bright blue-enhanced white light, compared to matched-by-irradiance red light, transiently (within 22 minutes) and mildly stimulated morning secretion of follicle-stimulating hormone in women in mid-to-late follicular phase of their menstrual cycle suggesting a direct functional link between the light and reproductive system.

Brain but not serum BDNF levels are associated with structural alterations in the hippocampal regions in patients with drug-resistant mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy is the most common type of focal epilepsy, imposing a significant burden on the health care system worldwide. Approximately one-third of patients with this disease who do not adequately respond to pharmacotherapy are considered drug-resistant subjects. Despite having some clues of how such epileptic activity and resistance to therapy emerge, coming mainly from preclinical models, we still witness a scarcity of human data. To narrow this gap, in this study, we aimed to estimate the relationship between hippocampal and serum levels of brain-derived neurotrophic factor (BDNF), one of the main and most widely studied neurotrophins, and hippocampal subfield volumes in patients with drug-resistant mesial temporal epilepsy undergoing neurosurgical treatment. We found that hippocampal (but not serum) BDNF levels were negatively correlated with the contralateral volumes of the CA1 and CA4 subfields, presubiculum, subiculum, dentate gyrus, and molecular layer of the hippocampus. Taken together, these findings are generally in accordance with existing data, arguing for a proepileptic nature of BDNF effects in the hippocampus and related brain structures.

The habenular volume and PDE7A allelic polymorphism in major depressive disorder: preliminary findings.

OBJECTIVES: The habenula is a brain structure implicated in depression, yet with unknown molecular mechanisms. Several phosphodiesterases (PDEs) have been associated with a risk of depression. Although the role of PDE7A in the brain is unknown, it has enriched expression in the medial habenula, suggesting that it may play a role in depression. METHODS: We analysed: (1) habenula volume assessed by 3-T magnetic resonance imaging (MRI) in 84 patients with major depressive disorder (MDD) and 41 healthy controls; (2) frequencies of 10 single nucleotide polymorphisms (SNPs) in PDE7A gene in 235 patients and 41 controls; and (3) both indices in 80 patients and 27 controls. The analyses considered gender, age, body mass index and season of the MRI examination. RESULTS: The analysis did not reveal habenula volumetric changes in MDD patients regardless of PDE7A SNPs. However, in the combined group, the carriers of one or more mutations among 10 SNPs in the PDE7A gene had a lower volume of the left habenula (driven mainly by rs972362 and rs138599850 mutations) and consequently had the reduced habenular laterality index in comparison with individuals without PDE7A mutations. CONCLUSIONS: Our findings suggest the implication of the PDE7A gene into mechanisms determining the habenula structure.

Objective Measures of Immediate "Energizing" Effect of Light: Studies Review and Data Analysis.

While the energizing effect of light has been known since the early years of light therapy, its reliable detection using objective measures is still not well-established. This review aims to ascertain the immediate energizing effect of light and determine its best indicators. Sixty-four articles published before July 2022 were included in the review. The articles described 72 (sub-)studies performed in healthy individuals. Fourteen measures were analyzed. The analysis showed that light causes an energizing effect that can be best documented by measuring core (rectal) body temperature: the proportion of the studies revealing increasing, unchanging, and decreasing rectal temperature was 13/6/1. The second most suitable indicator was heart rate (10/22/1), which showed concordant changes with rectal temperature (a trend, seven mutual studies). There is no evidence from the reviewed articles that oxygen consumption, skin conductance, blood pressure, heart rate variability, non-rectal inner temperature (combined digestive, tympanic, and oral), skin temperature, or cortisol levels can provide light effect detection. Four other measures were found to be unsuitable as well but with less certainty due to the low number of studies (≤3): skin blood flow, noradrenaline, salivary alpha-amylase, and thyroid-stimulating hormone levels. On the other hand, light exposure had a noticeable effect on sympathetic nerve activity measured using microneurography; however, this measure can be accepted as a marker only tentatively as it was employed in a single study. The analysis took into account three factors-study limitation in design/analysis, use of light in day- or nighttime, and relative brightness of the light stimulus-that were found to significantly influence some of the analyzed variables. The review indicates that the energizing effect of light in humans can be reliably detected using rectal temperature and heart rate.

Menstrual cycles are influenced by sunshine.

INTRODUCTION: The study determined the effect of seasons and meteorological variables on ovarian-menstrual function. METHODS: Women (N=129) living in Novosibirsk (55°N), Russia, provided data on normal menstrual cycles for over 1 year between 1999 and 2008. Of these, 18 together with 20 other healthy women were investigated once in winter and once in summer in 2006-2009. The investigated variables included serum levels of follicle-stimulating hormone (FSH), luteinising hormone (LH) and prolactin on day ∼ 7 of the menstrual cycle, ovary follicle size (by ultrasound) on day ∼ 12 and ovulation occurrence on subsequent days. RESULTS: In summer vs. winter, there was a trend towards increased FSH secretion, significantly larger ovarian follicle size, higher frequency of ovulation (97% vs. 71%) and a shorter menstrual cycle (by 0.9 days). LH and prolactin levels did not change. In all seasons combined, increased sunshine (data derived from local meteorological records) 2-3 days before the presumed ovulation day (calculated from the mean menstrual cycle) led to a shorter cycle length. Air/perceived temperature, atmospheric pressure, moon phase/light were not significant predictors. CONCLUSIONS: Ovarian activity is greater in summer vs. winter in women living in a continental climate at temperate latitudes; sunshine is a factor that influences menstrual cycle.

Winter-summer difference in post-awakening salivary α-amylase and sleepiness depending on sleep and melatonin.

Winter and summer seasons are contrasted by light/dark conditions at temperate latitudes, and the negative influence of this contrast on circadian health is yet to be quantified. This field study (performed in Novosibirsk, 55°N, no daylight saving time transitions) aimed to compare post-awakening arousal state in summer and winter in subjects (N=45) on a fixed 5-workday schedule (waken up by alarm at either ∼6 am or ∼7 am). Their circadian status (by 24-h melatonin profiles) and sleep (by log data) have been previously reported. Salivary α-amylase levels (a biomarker of the sympathetic nervous system activity, or stress) and subjective sleepiness were measured immediately after awakening on Friday, at minute 0 (supine), 10, 20, and 30 (not supine). α-Amylase levels were found to be higher in winter, along with a blunted α-amylase awakening response (AAR; a decline from minute 0 to minute 10 value). Both effects were attributable mainly to the 7am group. Sleepiness levels also increased in winter, mainly due to the seasonally dependent subjects, and predictably associated with shorter, later sleep, and later melatonin circadian phase. The sleepiness and α-amylase changes did not correlate. The seasonal change in α-amylase was positively associated with the change in the amount of melatonin secreted, probably reflecting the parallelism in the noradrenergic neural control of both α-amylase and melatonin secretion. Together, higher post-awakening salivary α-amylase levels (indicating stress) and subjective sleepiness levels (indicating greater sleep need) in winter compared to summer point to a less healthy state in winter.

Effectiveness of Visual vs. Acoustic Closed-Loop Stimulation on EEG Power Density during NREM Sleep in Humans.

The aim of the study was to investigate whether visual stimuli have the same potency to increase electroencephalography (EEG) delta wave power density during non-rapid eye movement (NREM) sleep as do auditory stimuli that may be practical in the treatment of some sleep disturbances. Nine healthy subjects underwent two polysomnography sessions-adaptation and experimental-with EEG electrodes positioned at Fz-Cz. Individually adjusted auditory (pink noise) and visual (light-emitting diode (LED) red light) paired 50-ms signals were automatically presented via headphones/eye mask during NREM sleep, shortly (0.75-0.90 s) after the EEG wave descended below a preset amplitude threshold (closed-loop in-phase stimulation). The alternately repeated 30-s epochs with stimuli of a given modality (light, sound, or light and sound simultaneously) were preceded and followed by 30-s epochs without stimulation. The number of artifact-free 1.5-min cycles taken in the analysis was such that the cycles with stimuli of different modalities were matched by number of stimuli presented. Acoustic stimuli caused an increase (p < 0.01) of EEG power density in the frequency band 0.5-3.0 Hz (slow waves); the values reverted to baseline at post-stimuli epochs. Light stimuli did not influence EEG slow wave power density (p > 0.01) and did not add to the acoustic stimuli effects. Thus, dim red light presented in a closed-loop in-phase fashion did not influence EEG power density during nocturnal sleep.

Impact of oral melatonin on the electroretinogram cone response.

BACKGROUND: In the eye, melatonin plays a role in promoting light sensitivity at night and modulating many aspects of circadian retinal physiology. It is also an inhibitor of retinal dopamine, which is a promoter of day vision through the cone system. Consequently, it is possible that oral melatonin (an inhibitor of retinal dopamine) taken to alleviate circadian disorders may affect cone functioning. Our aim was to assess the impact of melatonin on the cone response of the human retina using electroretinography (ERG). METHODS: Twelve healthy participants aged between 18 to 52 years old were submitted to a placebo-controlled, double-blind, crossover, and counterbalanced-order design. The subjects were tested on 2 sessions beginning first with a baseline ERG, followed by the administration of the placebo or melatonin condition and then, 30 min later, a second ERG to test the effect. RESULTS: Following oral melatonin administration, a significant decrease of about 8% of the cone maximal response was observed (mean 6.9 muV +/- SEM 2.0; P = 0.0065) along with a prolonged b-wave implicit time of 0.4 ms +/- 0.1, 50 minutes after ingestion. CONCLUSION: Oral melatonin appears to reach the eye through the circulation. When it is administered at a time of day when it is not usually present, melatonin appears to reduce input to retinal cones. We believe that the impact of melatonin on retinal function should be taken into consideration when used without supervision in chronic self-medication for sleep or circadian disorder treatment.

Summer-winter difference in 24-h melatonin rhythms in subjects on a 5-workdays schedule in Siberia without daylight saving time transitions.

The study aimed to quantify a seasonal change in circadian rhythms and its relationship to the social/sleep regimen in humans living in Novosibirsk (55°N), using the naturalistic situation that daylight saving time transitions have been abolished in Russia. Sixty-three volunteers entered the study, and 46 completed it. One group got up at ~6 a.m. and another at ~7 a.m. during their regular 5-workdays schedule. They collected 19 saliva samples at home over 24 h (including 2 samples during the night) on July 3-4, and December 18-19, 2015. Salivary melatonin was measured using radioimmunoassay; the times of evening onset and morning offset were objectively determined using the hockey-stick algorithm and served as circadian phase markers. Nearly all melatonin profiles were normal in summer (high nighttime and low daytime levels), whereas in winter, significantly more - 8 profiles - were abnormal (additional daytime peak, out-of-phase daytime secretion, or absence of secretion), of which 3 (plus 1 for other reasons) could not be included in the further analysis. The duration of melatonin secretion (somewhat less than 12 h) and amount of melatonin secreted did not differ between seasons. In winter compared to summer the melatonin rhythm, on average, significantly phase delayed by half-an-hour, with a tendency for greater inter-individual phase variability. The phase delay was attributable to those subjects who got up at ~7 a.m. (and who were longer sleepers). The melatonin rhythm reflected well the sleep timing difference between the two groups in summer, whereas in winter this coherence was lost. In summary, timing of the circadian system is strictly synchronised in summer by the long light: short dark photoperiod (with sleep as a constituent of the 7 h 10 min dark phase of the cycle), whereas in winter, with the long dark nights (17 h 12 min), an inter-individual phase desynchrony and even abnormal melatonin patterns emerge, despite a constant sleep/social regimen, suggesting that the winter season is unfavourable for circadian status.

A 6-day combined wake and light therapy trial for unipolar depression.

BACKGROUND: There are a dozen studies on double or triple chronotherapy in depression (sleep deprivation [wake therapy] + light therapy + sleep advance/stabilization). We investigated efficacy and feasibility of a modified triple chronotherapy protocol. METHODS: Thirty-five hospitalized patients with moderately severe non-seasonal depressive disorder, mostly free from antidepressants, underwent a 6-day protocol consisting of partial sleep deprivation late in the second half of the night (from 4:00 to 8:00) in a light therapy room (blue-enhanced white light increased hourly from 600→1300→2200→2800 lx) alternating with recovery nights with morning light treatment from 7:00 to 8:00. Patients were randomized to wear glasses with no filter (clear, N = 19) or filtering blue wavelength (orange-appearance, light intensity diminution by ∼70%, N = 16) during the treatments. Sleep was targeted to be shifted at least 1 h earlier. Depression was scored using HDRS-17 (Hamilton Depression Rating Scale) and BDI-II (Beck Depression Inventory-II) - before and after the 6-days treatment, HDRS-6-SR - daily, and visual analogue scales (VAS) for mood and energy - several times every day. RESULTS: Depression levels significantly declined following the first night and after 6-days treatment, with no difference between white and orange lights. Nevertheless, some superiority of white light emerged with respect to response rate (mood VAS), immediate effect during the 4-h treatment sessions (energy VAS), and expected treatment outcomes. All patients successfully advanced bedtime/wake-up (by 30-40 minutes) and resisted naps during daytime. LIMITATIONS: Relatively small sample size. CONCLUSIONS: The modified triple chronotherapy was well tolerated and improved depression. Light spectrum/intensity plays some role in the response.

Influence of timed nutrient diet on depression and light sensitivity in seasonal affective disorder.

Seasonal Affective Disorder (SAD) patients crave and eat more carbohydrates (CHO) in fall-winter when depressed, especially in the evenings, and feel energetic thereafter. Evening CHO-rich meals can phase delay circadian rhythms, and glucose increases retinal response to light. We studied timed CHO- or protein-rich (PROT) diet as a putative therapy for SAD. Unmedicated, DSM-IV-diagnosed depressed women with SAD (n=22, 19-63 yrs) in the follicular phase of the menstrual cycle (present in 19) were randomized to nine days of eating approximately 1600 kcal of either CHO before 12:00 h (n=9), CHO after 18:00 h (n=6), or PROT after 18:00 h (n=7); only water was allowed for the rest of the day. Measurements included the depression questionnaire SIGH-SAD (with 21-item Hamilton depression subscale), Eating Behavior Questionnaire (DEBQ), percentage fat (by bioimpedancemetry), clinical biochemistry (glucose, cholesterol, triglycerides, TSH, T4, cortisol), and electroretinogram (ERG). No differential effects of diet were found on any of the studied parameters (except DEBQ). Clinically, participants improved slightly; the 21-HDRS score (mean+/-SD) decreased from 19.6+/-6.4 to 14.4+/-7.4 (p=.004). Percent change correlated significantly with menstrual day at diet onset (mood improved the first week after menstruation onset), change in available sunshine (more sunlight, better mood), and initial percentage fat (fatter patients improved more). Scotopic ERG amplitude was diminished after treatment (p=.025, three groups combined), probably due to greater exposure to sunshine in 14/22 subjects (partial correlation analysis significant). Keeping in mind the limitations of this ambulatory study (i.e., inability to control outdoor light exposure, small number of participants, and briefness of intervention), it is suggested that the 25% clinical improvement (of the order of magnitude of placebo) is not related to nutrient diet or its timing, but rather to natural changes during the menstrual cycle, available sunshine, and ease of dieting for fatter patients.

SIRT1 Allele Frequencies in Depressed Patients of European Descent in Russia.

Depressive disorder (DD) is a widespread mental disorder. Although DD is to some extent inherited, the genes contributing to the risk of this disorder and its genetic mechanisms remain poorly understood. A recent large-scale genome-wide association Chinese study revealed a strong association between the SIRT1 gene variants and DD. The aim of this study was to analyze the occurrence of heterozygote carriers and search for rare SNP variants of the SIRT1 gene in a cohort of DD patients as compared with a cohort of randomly selected members of the Russian population. The complete coding sequences of the SIRT1 gene from 1024 DNA samples from the general Russian population and from 244 samples from patients with DD were analyzed using targeted sequencing. Four new genetic variants of the SIRT1 were discovered. While no significant differences in the allele frequencies were found between the DD patients and the general population, differences between the frequencies of homozygote carriers of specific alleles and occurrences of heterozygous were found to be significant for rs2236318 (P < 0.0001), and putatively, rs7896005 (P < 0.05), and rs36107781 (P < 0.05). The study found for the first time that two new SNPs (i.e., 10:69665829 and 10:69665971) along with recently reported ones (rs773025707 and rs34701705), are putatively associated with DD. The revealed DD-associated SIRT1 SNPs might confer susceptibility to this disorder in Russian population of European descent.

Shortening of the menstrual cycle following light therapy in seasonal affective disorder.

A significantly earlier onset of menstruation by 1.2 days, on average, was found following light therapy in 38 winter depressives; in two of them it could be classified as a minor side effect. There was no association between this shortening and depression improvement. A direct action of light on the hypothalamic-pituitary-gonadal axis is suggested.

Melatonin treatment of winter depression following total sleep deprivation: waking EEG and mood correlates.

Patients with winter depression (seasonal affective disorder (SAD)) commonly complain of sleepiness. Sleepiness can be objectively measured by spectral analysis of the waking electroencephalogram (EEG) in the 1-10 Hz band. The waking EEG was measured every 3 h in 16 female SAD patients and 13 age-matched control women throughout a total sleep deprivation of 30 h. Melatonin (or placebo) under double-blind conditions was administered subsequently (0.5 mg at 1700 h for 6 days), appropriately timed to phase advance circadian rhythms, followed by reassessment in the laboratory for 12 h. The increase in EEG power density in a narrow theta band (5-5.99 Hz, derivation Fz-Cz) during the 30 h protocol was significantly attenuated in patients compared with controls (difference between linear trends p=0.037). Sleepiness (p=0.092) and energy (p=0.045) self-ratings followed a similar pattern. Six patients improved after sleep deprivation (> or =50% reduction on SIGH-SAD(22) score). EEG power density dynamics was correlated with clinical response to sleep deprivation: the steeper the build-up (as in controls), the better the improvement (p<0.05). There was no differential effect of melatonin or placebo on any measure; both treatments stabilized the improvement. Overall, patients with winter depression manifest similar wake EEG characteristics as long sleepers or late chronotype with respect to an insufficient build-up of homeostatic sleep pressure. Sleep deprivation was an effective antidepressant treatment for some patients, but evening melatonin was not more efficacious than placebo in sustaining this antidepressant effect.

Is sleep per se a zeitgeber in humans?

It is not clear whether shifting of sleep per se, without a concomitant change in the light-dark cycle, can induce a phase shift of the human circadian pacemaker. Two 9-day protocols (crossover, counterbalanced order) were completed by 4 men and 6 women (20-34 years) after adherence to a 2330 to 0800 h sleep episode at home for 2 weeks. Following a modified baseline constant routine (CR) protocol on day 2, they remained under continuous near-darkness (< 0.2 lux, including sleep) for 6 days. Four isocaloric meals were equally distributed during scheduled wakefulness, and their timing was held constant. Subjects remained supine inbed from 2100 to 0800 h on all days; sleep was fixed from 2330 to 0800 h in the control condition and was gradually advanced 20 min per day during the sleep advance condition until a 2-h difference had been attained. On day 9, a 25 to 27 h CR protocol (approximately 0.1 lux) was carried out. Phase markers were the evening decline time of the core body temperature (CBT) rhythm and salivary melatonin onset (3 pg/ml threshhold). In the fixed sleep condition, the phase drift over 7 days ranged from +1.62 to -2.56 h (for both CBT and melatonin rhythms, which drifted in parallel). The drifts were consistently advanced in the sleep advance schedule by +0.66 +/- 0.23 (SEM) h for CBT (p = 0.02) and by 0.27 +/- 0.14 h for melatonin rhythms (p = 0.09). However, this advance was small to medium according to effect size. Sleep per se may feed back onto the circadian pacemaker, but it appears to be a weak zeitgeber in humans.