Chronobiologic Factors in Experimental Stress Ulcer

The available literature on chronobiologic factors in experimental stress ulcer is extremely small and thematically limited. It focuses almost exclusively on circadian rhythms and, within that, on rhythms related to light-dark cycles, activity and body temperature. Among these, only differences in ulcer induction related to circadian activity patterns have been adequately demonstrated. Other circadian patterns and other temporal phase relationships might be profitably explored, including those related to postnatal development. It is also likely that the important relationships between biorhythms and stress ulcer are not limited to ulcer induction. Future studies should address chronobiologic factors in predisposition, severity of illness, the probability of recovery and response to various therapeutic interventions.     

月经周期对女性睡眠-觉醒和静息-活动的影响

目前有关月经周期对睡眠影响的研究结果并不一致,而对月经周期中昼夜睡眠-觉醒及静息-活动节律尚缺乏系统性的研究.本研究旨在观察正常育龄期女性月经周期中睡眠-觉醒及静息-活动昼夜节律的变化.我们采用静息-活动监测仪(actigraphy)和睡眠日志,调查了12个自然生活状态下健康育龄期妇女在月经周期不同阶段,即行经期、围排卵期、黄体早期及黄体晚期中睡眠与活动节律的变化.结果显示,睡眠-觉醒节律参数在四期之间无统计学显著差异;而静息-活动节律方面,所有受试女性静息-活动节律的平均日周期长度为(24.01±0.29)h,并且四期之间无显著性差异.行经期日间稳定系数(interdaily stability,IS)比黄体早期显著增加(P＜0.05).黄体早期日间活动开始时间明显较黄体晚期提前(P＜0.05);黄体早期的活动峰值时相比围排卵期显著提前(P＜0.05).月经周期可以影响静息-活动昼夜节律时相.而总体静息-活动数量与质量未发生显著变化;健康育龄期妇女在月经周期的各阶段中睡眠-觉醒节律亦无明显变异.     

Rest-activity circadian rhythm in breast cancer survivors at 5 years after the primary diagnosis

ABSTRACT

Rest-activity circadian rhythm (RAR) is a marker of the circadian timing system. Particular attention has been given to RAR characteristics in cancer diseases. Specifically, alterations of RAR parameters have been found, at different stages of clinical pathway, in breast cancer (BC) patients. No studies to date have analyzed RAR alterations in breast cancer survivors several years after the diagnosis. The aim of this study was to determine RAR by actigraphy in a population of BC survivors at 5 years after the primary diagnosis, and to compare their RAR characteristics with healthy controls. The study sample was 28 women: 15 BC survivors at 5 years from the primary diagnosis (BC-group) and 13 healthy controls (Ctrl-group), matched for age and body mass index. All participants have been monitored for 7 days by actigraphy to evaluate RAR. A statistically significant circadian rhythm (T = 24) was found in all 28 subjects (p < .001). The group analysis revealed a significant RAR both in BC- and Ctrl-group (p < .001). The acrophase was not different between the BC- and Ctrl-group (15:09 vs. 15:01 hr:min in BC- and Ctrl-group, respectively). In contrast, the MESOR (Midline Estimating Statistic of Rhythm) and the amplitude were lower in the BC-group with respect to the Ctrl-group. Indeed, the MESOR was 192.0 vs. 276.4 activity counts in BC- and Ctrl-group, respectively (p < .001), while the amplitude was 167.0 vs. 222.6 activity counts in BC- and Ctrl-group, respectively (p < .001). These results provide the first experimental evidence of alterations in RAR parameters in BC survivors at 5 years after the primary diagnosis. Larger studies with a prospective design are needed to assess the role of RAR in the quality of life and prognosis in BC survivors.     

吲哚美辛治疗口腔溃疡的动物实验研究

目的 探讨两种吲哚美辛制剂在口腔溃疡愈合中的作用.方法 大鼠右颊用铁钉烫烧造模,分为吲哚美辛凝胶给药组(YN)、复方苯佐卡因凝胶阳性对照组(NP)、吲哚美辛喷雾给药组(YP)、口腔炎喷雾阳性对照组(PP)、正常对照组(N)和阴性对照组(M).采用HE染色、组织学标准定量评价溃疡面再上皮化及肉芽组织形成情况,比色法检测溃...     

Dynamics of core body temperature cycles in long-term measurements under real life conditions in women

Studies under real life conditions become more and more relevant in chronobiological and chronomedical research. The present study aims to analyze one of the most prominent biological rhythms: the core body temperature (CBT) rhythm in the real world outside the laboratory. CBT was recorded continuously in 37 healthy women (age between 21 and 44 years, median 29 years) with a newly developed intravaginal temperature sensor for up to 102 days. Sleep logs were available from 23 participants. To quantify the daily dynamics of each individual CBT-curve, novel measurement parameters are introduced which permit the quantification of the phase and shape of the CBT rhythms as well as their relation to the sleep–wake cycle. In addition to the classical phase markers (i.e. nadir and peak), the daily curves were segmented into quartiles by introducing the t25/t50/t75-values which can be used as phase and shape markers. At variance to previous studies, a conspicuous day-to-day variation was shown not only for the time point of the peak, but also for the time point of the nadir. However, the t-values, particularly the t75-value were relatively closely locked to external time and thus represent more reliable phase markers than the nadir. The (variable) time point of the nadir determined the period length, phase and shape of the subsequent CBT cycle. If a nadir occurred close to the wake-up time, the following cycle was considerably shorter than 24 hours, while a nadir distant from the wake-up time was followed by a longer cycle. Thus, the period lengths of the daily CBT cycles of each individual were characterized by an “expand/contract” rhythm. The analyses of the novel phase markers (t25/t50/t75) of the CBT curves allowed to identify “early” and “late” participants who may differ in their phase-response curves with regard to the entraining effect of light. In addition, the novel phase markers mirrored the different social entrainment conditions on weekends and workdays.     

The individual development of circadian temperature rhythm in infants

Abstract

The aim of this study was to explore the individual development of the circadian rhythm of human body temperature. Dailyperiodicchanges of body temperature were examined longitudinally in four infants from 3 to 18 months of age. At the 3rd month of life, the day‐night rhythm of the body temperature was obscure but at the 6th month it became moreevident. From the 12th month on, the circadian temperature rhythm with phase similar to that of the adult was discerned. However, the amplitude in circadian rhythm was significantly larger in children between 6 and 18 months of age than in the adult. These findings suggest that the adult type of circadian rhythm of human body temperature is established during the first year of life with regard to phase but not to amplitude.     

Rest-activity rhythm in breast cancer survivors: an update based on non-parametric indices

ABSTRACT

Recently we evaluated by actigraphy the rest-activity circadian rhythm (RAR) in breast cancer (BC) survivors at 5 years from primary diagnosis, as well as in a control group with similar age and body mass index (BMI). RAR, analyzed by Cosinor method, resulted significantly different in BC survivors compared to healthy subjects: BC survivors showed lower values of MESOR and Amplitude (A), while acrophase (φ) was similar in the two groups.

Now, using non-parametric methods we have detected Interdaily Stability (IS), Intradaily Variability (IV), nocturnal activity (L5), and daily activity (M10) on the same sample of previous study: 15 BC survivors at 5 years from the primary diagnosis (mean age = 56.7 ± 6.6 yrs; mean BMI = 24.5 ± 3.8 Kg/m²) and 13 healthy controls (mean age = 54.4 ± 7.2 yrs; mean BMI = 25.2 ± 2.8 Kg/m²).

The non-parametric indices showed that in BC-group IV was significantly higher than in Ctrl-group (0.86 vs. 0.65 a.u. in BC and Ctrl, respectively; p <.01), while L5 (11.27 vs. 34.41 a.c. in BC and Ctrl, respectively; p <.0001) and M10 (326.82 vs. 428.07 a.c. in BC and Ctrl, respectively; p <.01) were significantly lower compared to Ctrl-group.

The data suggest that BC patients need constant clinical assessment of RAR characteristics along the years following the primary diagnosis. The analysis of RAR in all its components, parametric and non-parametric, is important to detect alterations in the sleep-wake cycle and can be useful for developing new strategies for health protection, such as structured and tailored physical activity programs, to improve circadian activity level in order to raise the quality of life in BC survivors.     

Twenty-four-hour variation of vestibular function in young and elderly adults

ABSTRACT

Animal and human studies demonstrate anatomical and functional links between the vestibular nuclei and the circadian timing system. This promotes the hypothesis of a circadian rhythm of vestibular function. The objective of this study was to evaluate the vestibular function through the vestibulo-ocular reflex using a rotatory chair at different times of the day to assess circadian rhythmicity of vestibular function. Two identical studies evaluating temporal variation of the vestibulo-ocular reflex (VOR) were performed, the first in young adults (age: 22.4 ± 1.5 y), and the second in older adults (70.7 ± 4.7 y). The slow phase velocity and time constant of the VOR were evaluated in six separate test sessions, i.e., 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00 h. In both studies, markers of circadian rhythmicity (temperature, fatigue, and sleepiness) displayed expected usual temporal variation. In young adults, the time constant of the VOR showed variation throughout the day (p < .005), being maximum 12:25 h (06:00 h test session) before the acrophase of temperature circadian rhythm. In older adults, the slow phase velocity and time constant also displayed temporal variation (p < .05). Maximum values were recorded at 10:35 h (06:00 h test session) before the acrophase of temperature circadian rhythm. The present study demonstrates that vestibular function is not constant throughout the day. The implication of the temporal variation in vestibular system in equilibrium potentially exposes the elderly, in particular, to differential risk during the 24 h of losing balance and falling.     

Daily rest-activity patterns in the bipolar phenotype: A controlled actigraphy study

This study assessed daily rest-activity patterns in euthymic, medication-naïve bipolar phenotype individuals. The Mood Disorder Questionnaire was used to identify 19 bipolar phenotype individuals and 21 controls. Participants wore an Actiwatch-L for 2 weeks to assess their sleep behaviour and circadian rest-activity rhythmicity. Bipolar phenotype individuals had increased movement during sleep, as assessed by the fragmentation index, greater activity levels during their least active 5?h (2 am–7 am), and lower circadian relative amplitude compared to controls. Higher activity levels during sleep affecting circadian amplitude in young adults with the bipolar phenotype may be associated with vulnerability for developing mood disorder.     

Worsening of rest-activity circadian rhythm and quality of life in female breast cancer patients along progression of chemotherapy cycles

Chemotherapy and its associated side effects can induce the disruption of circadian rest-activity rhythm and may have negative consequences on health-related quality of life (HRQoL) of cancer patients. In the current study, repeated-measures cross-sectional design was implemented to determine the status of circadian rest-activity rhythm and to assess the HRQoL of newly diagnosed female breast cancer patients those were planned to receive six cycles of chemotherapy. Rest activity and HRQoL were assessed in twenty-five patients during chemotherapy cycles 1st (C1), 3rd (C3), and 6th (C6) immediately after they reported to the outdoor ward of the Regional Cancer Center, Pt. J.N.M. Medical College, Dr. B.R. Ambedkar Memorial Hospital, Raipur, India. Wrist actigraphs for consecutive spans of 3–4 days were used to record the rest-activity rhythm, and its parameters were computed with the help of Cosinor Rhythmometry. Quality of life (QoL) parameters were assessed using EORTC QLQ-C30 and QLQ-BR23. Results revealed that average scores of all rhythm parameters, such as MESOR, amplitude, acrophase, rhythm quotient, circadian quotient, peak activity, dichotomy index, and autocorrelation coefficient; and all functional scales of QLQ-C30, such as physical, role, emotional, cognitive, and social, and global quality of life statistically significantly decreased with the increasing number of chemotherapy cycles (C1 to C3 and C6). Scores of symptom scales of QLQ-C30, such as fatigue, pain, dyspnoea, insomnia, appetite loss, and diarrhea increased significantly from C1 to C6. Among the QLQ-BR23 scales, scores of sexual functioning, sexual enjoyment, breast symptoms, and arm symptoms significantly decreased, whereas scores of systemic therapy side effects, and upset by hair loss significantly increased across the chemotherapy cycles. We conclude that rest-activity rhythm disrupted and HRQoL of breast cancer patients worsened along the increasing number of chemotherapy cycles. We suggest that along with the treatment protocol, level of disruption of these parameters should be assessed and managed with the proper interventions that prominently include timing of the chemotherapy administration. The latter is pivotal for maintenance of these parameters, which are likely to enhance the physiological ability of patients for better treatment responses and may improve the overall QoL and survival of the patients.     

Circadian variation in the acetylcholinesterase activity of specific rat brain areas

Abstract

Acetylcholinesterase (AChE) activity of the adenohypophysis, cerebellum, cerebral cortex, hypothalamus, amygdala, hippocampus, midbrain, pons, medulla oblongata and caudate nucleus was determined by a spectro‐photometric method in adult, male rats adapted toan LD 12:12cycle. Results of the study show that AChE activity is highest during the light phase and lowest during the dark phase of the cycle in all the brain areas studied except the adenohypophysis, cerebellum, hippocampus and hypothalamus. These findings expand earlier observations on the circadian variation in rat brain AChE activity and suggests a relationship with reported circadian variation in the acetylcholine levels of rat brain.     

Effect of continuous illumination of varying length on the reproductive rhythms in rats; after‐effects

Abstract

Permanent oestrus was induced in 24, 61 and 100% of 2‐months old Wistar rats under conditions of continuous light exposure (LL) for 1, 2 and 6 months, respectively. After cessation of 2 months LL, rhythmic fluctuations of oestrus activity were observed.

The weight of newborns produced by females under LL during pregnancy was increased by 7% as compared to controls (P < 0.05). LL before mating did not affect embryonic development.

20‐day old pups produced by females which were kept in LL for 1, 2 months and more were significantly heavier than controls by 5, 18 and 30%, respectively.

The stimulatory effect of LL for 1 and 2 months on pre‐ and postnatal development was maintained in the subsequent reproduction cycle, when these females were transferred to normal conditions of LD 14:10.     

The association between circadian rest-activity patterns and the behavioral and psychological symptoms depending on the cognitive status in Japanese nursing-home residents

ABSTRACT

Background: Limited information is available on the relationship between sleep disturbances during nighttime and the behavioral and psychological symptoms of dementia in older nursing-home residents. However, a few reports on the association between the circadian rest-activity rhythm and the behavioral and psychological symptoms of dementia in older residents have been published. The main objective of the present study was to examine the association among the circadian rest-activity rhythm, behavioral and psychological symptoms, and the cognitive function status among older individuals living in facilities. Method: The investigation was conducted from September 2017 to February 2018, and participants were recruited from five nursing homes in Akita prefecture, Japan, after obtaining patient agreement to participate in the study. To measure nonparametric circadian rest-activity parameters such as interdaily stability, intradaily variability, relative amplitude, mean of the least active 5-h period, and mean of the most active 10-h period, Actigraph devices were worn on the participants’ nondominant wrists continuously for seven days. The score or classification of the cognitive status and the severity of the behavioral and psychological symptoms of dementia (BPSD) were assessed using the clinical dementia rating (CDR) and the dementia behavior disturbance scale (DBD), respectively. The binomial logistic regression model was applied to clarify which kinds of circadian rest-activity parameters predicted the cognitive status in nursing home residents as well as the BPSD outcome. A multi-level model was also used to examine the association between the nonparametric rest-activity parameters and the BPSD outcome explained by the cognitive status among older individuals in facilities. Results: Seventy-seven participants (49 residents with dementia, and 28 residents without dementia) were included in this study. According to the binomial logistic regression analysis after adjusting for covariates, the classification of the cognitive status for older residents was associated with the DBD score (odds ratio, 1.22; 95% confidence interval [CI], 1.08, 1.38; p < 0.001), the IS (odds ratio, 0.01; 95% CI, 0.00, 1.00; p = 0.05) and the L5 (odds ratio, 0.99; 95% CI, 0.99, 1.00; p = 0.05). The results of a multi-level model also indicated that the IV at individual-level was significantly associated with the DBD score for nursing home residents, with the CDR score at cluster-level as an explanatory variable. As well, a significant association between the RA at individual level and the DBD score was observed in a multi-level model explained by the CDR score at cluster-level. Conclusion: Of these models, the multi-level model provided grounds for our proposal that the fragmentation or the amplitude of rest-activity parameters might be associated with the outcome of BPSD, considering the cognitive status of older individuals in different facilities. The findings offer practical insight into the prevention of BPSD and the improvement of rest-activity rhythms in rehabilitative care in nursing homes.     

The cyanobacterium Oscillatoria brevis β-carotene extract modulates alterations of biochemical and hematological circadian patterns in stress-induced rat

Managing stress can prevent serious health problems. The present study aimed to evaluate the possible protective effect of β-carotene (βC), as a natural cyanobacterial product, against stress-induced alterations in biochemical and hematological circadian patterns. Male albino rats were subjected to chronic unpredictable stress (CUS) for 21 days. Rats were randomly divided into four groups (20 rats/group), viz. control, CUS exposed, βC-treated, and βC-treated + CUS-exposed groups. Before CUS exposure, Oscillatoria brevis βC extract was administered (10 mg/kg), intraperitoneally. Blood samples were collected at four Zeitgeber times (ZT: 3, 9, 15 and 21), 5 rats/time point, to monitor circadian profiles of aspartate transferase (AST), alanine transferase (ALT), total protein (TP), glucose (Glu), urea, creatinine, lactate dehydrogenase (LDH), creatinine kinase-MB (CK-MB), hemoglobin (Hb), hematocrite (HCV), red blood cell (RBCs), and white blood cell counts (WBCs). Results revealed that these parameters expressed circadian patterns. CUS exposure significantly (p < 0.05) increased AST, ALT, Glu, urea, creatinine, LDH, CK-MB, and HCV. On the other hand, it significantly decreased Hb, RBCs, and WBCs (p < 0.05). Furthermore, under CUS-exposure the peak time (acrophase) of circadian rhythms of all parameters was variably shifted. On the other hand, βC administration modulated these alternations, where data analysis confirmed a significant decrease in AST, ALT, Glu, urea, creatinine, LDH, CK-MB, and HCV, however, a significant increase in TP, Hb, RBCs, and WBCs (p < 0.05) was observed. Taken together, it can be concluded that βC administration caused restoration of acrophase and level of these parameters thus regulating their circadian rhythms in CUS-induced rats.     

同步遥测分析大鼠棕色脂肪产热与体温昼夜节律变化的时间关系

目的：同步遥测棕色脂肪组织（BAT）产热与体核温度昼夜律变化的时间曲线,分析二者昼夜节律变化的时间关系。方法：实验用成年雄性SD大鼠,在22℃环境温度下,明暗时间各12h,昼光时间为06：00h-18：00h,同步无线遥测体核温度（TC）、BAT温度（T队T）、腋窝温度（Tax）和动物活动的昼夜节律变化。结果：①在昼光中,TBAT较TC低0．67％,而在暗光中二者则相似。大鼠从昼光进入暗光时,TBAT升高的速率较TC升高速率快,开始上升的时间较TC提前8min;而从暗光进入昼光时,TBAT开始下降的时间则较TC提前4min。②Tax的昼夜节律幅度与TC相似,但无论动物在明光期或暗光期中,Tax均低于同步测量的TC。③从昼光期转入暗光期时,动物的行为活动出现增加反应先于TBAT和TC开始上升的时间。结论：实验结果证明,在暗光期中大鼠TC升高与BAT产热增加有关,说明BAT昼夜节律性产热的变化在维持体温昼夜生理节律中有重要的作用。     

Suprachiasmatic nucleus and circadian core temperature rhythm in the rat

Core temperature was telemetered from 26 singly-housed adult male inbred Fischer rats standardized in an ambient temperature of 24 ± 1°C, in light from 0600–1800 alternating with darkness (L:D 12:12), with food and water freely available. The rats were operated upon first for bilateral electrolytic lesioning of the suprachiasmatic nucleus (SCN) or by a sham-operation, which consisted of an inserted electrode which neither penetrated into the SCN area nor was activated to produce a lesion. Next, a temperature sensor was implanted intraperitoneally. The telemetered data obtained at 10-min intervals from each rat were analyzed by the least-squares fit of certain trial periods (cosinor methods). A circadian population rhythm persisted in the SCN-lesioned rats which sustained destruction of both SCN (P < 0.01). The amplitude of the circadian temperature rhythm was attenuated(P < 0.01) and the rhythm's acrophase advanced (P < 0.05) from mid-dark to a time near the transition from light to darkness. Unilateral lesions of the suprachiasmatic nuclei altered the circadain amplitude but not the phasing.     

The role of circadian rhythm on the pharmacokinetic of methotrexate in streptozotocin-induced diabetes mellitus rats

Chronopharmacokinetic studies have been conducted both in animals and humans. Anticancer agents are of great interest due to their narrow therapeutic range and large pharmacokinetic variability. It was reported that the pharmacokinetics of MTX showed a circadian rhythm in rats and humans. Since diabetes-induced physiological changes can affect pharmacokinetics of drugs, it was reported that MTX blood concentration in diabetic rats was higher than that of the control groups. The present study was designed to elucidate whether these diabetes-induced changes in pharmacokinetics occurred during the day and thus administered MTX at four different times in streptozotocin-induced diabetes mellitus (SIDM) rats. Blood samples were drawn at 5, 15, 30, and 60 min after IV infusion of MTX in both the SIDM and control groups. Control and SIDM Area under the concentration - time curve (AUC) values showed a significant circadian rhythm with a peak located in mid-dark phase at 14:00. Clearance values were significantly low at 14:00 in the diabetic group when compared to other periods and the control group. The MTX AUC was increased when treatment with dexamethasone was given to suppress the endogenous production of corticosterone in both control and SIDM rats. These results suggest that the extent of MTX pharmacokinetics varies with the time of day in the SIDM rats and these variations might be related to changes in corticosterone concentrations.     

Influence of circadian disruption on neurotransmitter levels,physiological indexes,and behaviour in rats

Brain monoamines – such as noradrenaline (NA), dopamine (DA) and serotonin (5-HT) – regulate several important physiological functions, including the circadian rhythm. The purpose of this study was to examine changes in NA, DA and 5-HT levels in various brain regions and their effect on core body temperature (T_c), heart rate (HR) and locomotor activity (Act) in rats following exposure to an artificial light/dark (LD) cycle. For this, male Wistar rats were housed at an ambient temperature (T_a) of 23?°C and 50% relative humidity with free access to food and water. Rats were exposed to either natural (12?h:12?h) or artificial (6?h:6?h) LD cycles for 1 month, after which each brain region was immediately extracted and homogenized to quantify the amounts of NA, DA and 5-HT by high-performance liquid chromatography. Behavioural changes were also monitored by the ambulatory activity test (AAT). Notably, we found that artificial LD cycles disrupted the physiological circadian rhythms of T_c, HR and Act. Although the 5-HT levels of rats with a disrupted circadian rhythm decreased in cell bodies (dorsal and median raphe nuclei) and projection areas (frontal cortex, caudate putamen, preoptic area and suprachiasmatic nucleus) relative to the control group, NA levels increased both in the cell body (locus coeruleus) and projection area (paraventricular hypothalamus). No significant changes were found with respect to DA. Moreover, circadian rhythm-disrupted rats also showed anxious behaviours in AAT. Collectively, the results of this study suggest that the serotonergic and noradrenergic systems, but not the dopaminergic system, are affected by artificial LD cycles in brain regions that control several neural and physiological functions, including the regulation of physiological circadian rhythms, stress responses and behaviour.     

Endogenous clock gene expression in the suprachiasmatic nuclei of previsual newborn rabbits is entrained by nursing

The rabbit is particularly suitable for investigating the development of mammalian circadian function. Blind at birth, the pups are only visited by the mother to be nursed once every 24 h for about 3 min and so can be studied largely without maternal interference. They anticipate the mother's visit with increased behavioral arousal and with a rise in body temperature, both of which represent endogenous circadian rhythms. We now report that in newborn pups the suprachiasmatic nuclei of the hypothalamus (SCN; the main circadian pacemaker in mammals) show endogenous 24‐h rhythmicity in the expression of the clock genes Per1, Per2, and Bmal1. Pups nursed from postnatal days 1 to 7 and fasted to day 9 showed the same rhythms of clock gene expression as normally nursed controls. We also report that these rhythms are entrained by nursing. Pups killed on postnatal days 3–4 showed the same rhythms in gene expression as pups in the previous experiment, whereas littermates subsequently nursed from postnatal days 4 to 7 with nursing delayed 6 h showed a corresponding shift in the diurnal pattern of clock gene expression. Consistent with this, two groups of pups implanted with telemetric thermal sensors and nursed 6 h apart had daily patterns in body temperature synchronized with the two different nursing times. We conclude that the expression of clock genes associated with the newborn rabbit's circadian system is entrained by nonphotic cues accompanying nursing, the exact nature of which now needs to be clarified. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2009