Trastornos circadianos del sueño / Circadian Sleep Disorders

Resumen El sistema circadiano está sincronizado al ciclo luz-oscuridad que es generado por la rotación de la tierra, asegurando que la vigilia sea durante el día y que el sueño ocurra durante la noche. Sin embargo, el ritmo de sueño-vigilia puede estar desincronizado del ciclo luz-oscuridad o desincronizado de manera endógena, dando como resultado: insomnio, fatiga y bajo rendimiento en las actividades cotidianas. Mientras que los trastornos del sueño están clasificados por la Asociación Americana de Trastornos del Sueño como: disomnias intrínsecas, disomnias extrínsecas, parasomnias o trastornos del sueño médicos/psiquiátricos. Los trastornos circadianos del sueño se han categorizado por separado, en parte para reconocer que en la mayoría de los casos la etiología de los trastornos circadianos es una mezcla de factores internos y ambientales, o por un desajuste temporal entre ambos. Los síntomas generalmente son insomnio o hipersomnia, síntomas comunes en pacientes con trastornos circadianos del sueño, aunque hay otras causas a las que pueden atribuirse y que deben excluirse antes de realizar el diagnóstico de un trastorno circadiano del sueño. En el paciente sin otra patología del sueño, un registro diario de actividades, comidas, ejercicio, siestas y la hora de acostarse es una herramienta esencial para evaluar los trastornos circadianos del sueño. Estos registros deben mantenerse durante 2 semanas o más, ya que una perturbación debida a cambios de trabajo o viajes a través de zonas horarias puede tener efectos sobre el sueño y el estado de alerta durante el día, semanas después del evento.

Abstract The circadian system is synchronized to the light-dark cycle generated by the rotation of the earth, ensuring that wakefulness is during the day and sleep occurs at night. However, the sleep-wake rhythm may be out of sync with the light-dark cycle or endogenously out of sync, resulting in insomnia, fatigue, and poor performance in activities of daily living. Sleep disorders are classified by the American Sleep Disorders Association, as intrinsic dyssomnias, extrinsic dyssomnias, parasomnias, or medical/psychiatric sleep disorders. Circadian sleep disorders have been categorized separately to recognize that in most cases the etiology of circadian disturbances is a mix of internal and environmental factors or a temporary mismatch between the two. Symptoms are usually insomnia or hypersomnia, common symptoms in patients with circadian sleep disorders although other causes can be attributed and must be excluded before a diagnosis of a circadian sleep disorder is made. In the patient without other sleep pathology, a daily record of activities, meals, exercise, naps, and bedtime is an essential tool in assessing circadian sleep disorders. These records should be kept for 2 weeks or more, as a disturbance due to job changes or travel across time zones can have effects on sleep and daytime alertness weeks after the event.

Relação do cronotipo nos níveis de ansiedade e consumo Máximo de oxigênio em jovens / Relation between chronotype on anxiety levels and maximum oxygen consumption in young people

O presente estudo analisou a relação entre cronotipo, níveis de ansiedade, depressão e estresse, bem como níveis de condicionamento cardiorrespiratório em jovens. Métodos: Foi analisado um total de 36 participantes com idades entre 18 e 28 a nos, saudáveis e que atendessem ao cronotipo matutino e vespertino. Análises de nível de atividade física, consumo máximo de oxigênio, níveis de depressão, ansiedade e estresse foram realizadas com testes específicos. Em todos os cálculos foram utilizados um alfa de p<0.05 para análise estatística. Resultados: O nível de atividade física mostrou que a porcentagem dos matutinos suficientemente ativos foi de 58% comparado com 23.5% dos vespertinos. Mulheres com cronotipo vespertino apresentaram níveis menores de VO2máx quando comparados com as mulheres com cronotipo matutino (p=0.04). Os participantes vespertinos apresentaram níveis maiores de ansiedade (p=0.02) comparados com os matutinos e esses dados foram evidentes nos participantes do sexo feminino onde as mulheres do cronotipo vespertino apresentaram níveis maiores de ansiedade (p=0.03) comparados com mulheres de cronotipo matutino. Conclusão: Portanto, o estudo conclui que indivíduos do cronotipo vespertino apresentaram menores níveis de atividade física e maiores níveis de ansiedade evidenciados principalmente nas mulheres.(AU)

The present study analyzed a relationship between schedule, anxiety, depression and stress levels, as well as cardiorespiratory fitness levels in young people. Methods: A total of 36 healthy participants aged 18 to 28 years who met the criteria for chronotypes morning type and evening type were analyzed. Analyzes of physical activity level, maximal oxygen uptake, depression, anxiety and stress levels were performed. In all calculations, an alpha of p <0.05 was used for statistical analysis. Results: The level of physical activity was higher in morning types 58% compared to 23.5% of evening types. Women with evening chronotype had lower VO2max levels compared with women with a morning chronotype (p= 0.04). Evening types had higher anxiety levels (p= 0.02) compared to morning types and these data were evidenced in female participants with higher anxiety levels (p=0.03) compared to women with a morning chronotype. Conclusion: Therefore, the study concludes that young people with a evening chronotype exhibited lower levels of physical activity and higher anxiety levels, especially in women.(AU)

Sundown syndrome and symptoms of anxiety and depression in hospitalized elderly / Síndrome do pôr do sol e sintomas de ansiedade e depressão em idosos hospitalizados

ABSTRACT Sundown syndrome is characterized by the sudden appearance of neuropsychiatric symptoms such as agitation, confusion and anxiety in a chronologic fashion, usually during late afternoon or early evening. Objective: To evaluate the prevalence of sundown syndrome in university hospital wards and its relationship with anxiety/depression symptoms, cognitive decline, and clinical and demographic variables. Methods: We evaluated 70 patients admitted to the Lauro Wanderley University Hospital (HULW), João Pessoa-PB, Brazil. Data collection instruments were the Confusion Assessment Method (CAM), the Mini-Mental State Exam (MMSE) and the Hospital Anxiety and Depression Scale (HADS). Results: Mean patient age was 68.4±6.4 years, 55.7% were male, 67.1% were illiterate or had incomplete primary education. It was observed that 14.3% of patients had delirium, 15.7% had cognitive deficits, while 21.4% and 18.6% had anxious and depressive symptoms, respectively. The age of patients with delirium (71.9±8.7) was significantly higher than those without (67.8±5.8). At 95% confidence, there was a significant difference in the groups with and without delirium for the MMSE and HADS-D scales. Conclusion: We verified the occurrence of delirium compatible with the sundown syndrome and associated with depressive symptoms and cognitive deficit, with no apparent relationship with infectious processes or fever, number of drugs used, hospital stay or anxious symptomatology.

RESUMO A síndrome de Sundown é caracterizada pelo aparecimento súbito de sintomas neuropsiquiátricos como agitação, confusão e ansiedade de forma cronológica, geralmente no final da tarde ou no início da noite. Objetivo: Avaliar a prevalência da síndrome do por do sol em enfermarias de um hospital universitário e sua relação com sintomatologia depressivo-ansiosa, déficit cognitivo e variáveis clínicas e demográficas. Métodos: Foram avaliados 70 pacientes admitidos nas enfermarias Hospital Universitário Lauro Wanderley (HULW), João Pessoa-PB, Brasil. Os instrumentos de coleta de dados foram a Escala de Avaliação de Quadros Confusionais (Confusion Assessment Method - CAM), o Mini-Exame do Estado Mental (MEEM) e a Escala Hospitalar de Ansiedade e Depressão (HADS). Resultados: A média de idade de 68,4±6,4 anos, 55,7% do sexo masculino, 67,1% não alfabetizados ou com instrução fundamental incompleta. Observou-se que 14,3% dos pacientes tinham delirium, 15,7% tinham déficit cognitivo, enquanto 21,4% e 18,6% apresentavam sintomas ansiosos e depressivos, respectivamente. A idade dos pacientes com delirium (71,9±8,7) foi significativamente maior que a dos que não apresentavam este quadro (67,8±5,8). Com 95% de confiança, há diferença significativa nos grupos com e sem delirium em relação das escalas do MEEM e do HADS-D. Conclusão: Verificamos a ocorrência de delirium compatível com a síndrome do pôr do sol e associado com sintomas depressivos e déficit cognitivo, sem relação aparente com processo infeccioso ou febre, número de medicamentos em uso, permanência hospitalar e sintomatologia ansiosa.

Mudança de fotoperíodo: proposta de modelo experimental / Change of photoperiod: proposal for an experimental model

Introduction: There are some physiological and behavioral variations related to seasonality, and light is the major synchronizer of these variations according to the seasonal functions in temperate latitudes. Thus, the objective of this study was to validate a methodology for photoperiod modification in Wistar rats byevaluating its interference in the biological rhythm. Methods: Three male adult Wistar rats (60 days) were exposed to 3 photoperiods of 17 days each, with different light/dark cycles (LD): LDPP/SDPP Animal, exposed to initial LD 16:30/07:30 (LDPP, long-day photoperiod) and final LD 07:30/16:30 (SDPP, short-day photoperiod); SDPP/LDPP Animal, exposed to initial LD 07:30/16:30 and final LD 16:30/07:30; and final LD 16:30/07:30; and CT Animal, under constant LD 12:00/12:00. LDPP/SDPP and SDPP/LDPP animals underwent an intermediate photoperiod between initial and final LD, in which light exposure was increased or reduced by 30 min each day until the photoperiods were inverted. All animals remained isolated during the study and had their core temperatures continuously measured by sensors implanted in the peritoneal cavity and their locomotive activity assessed by sensors attached to their cages. The data obtained were used to construct histograms. Results: LDPP/SDPP and SDPP/LDPP animals had a longer period of activity in the SDPP than in the LDPP. The temperature of the CT animal followed a rhythmic pattern. The rat strain used was sensitive to changes in photoperiod. Conclusions: The model proposed and validated in this study can be used in experiments that aim to assess the consequences of changes in light exposure.

Introdução: Existem variações fisiológicas e comportamentais relacionadas à sazonalidade, e a luz é o principal sincronizador destas variações de acordo com as funções sazonais em latitudes de climas temperados. Sendo assim, o objetivo deste estudo foi validar uma metodologia de modificação de fotoperíodo com ratos Wistar avaliando sua interferência no ritmo biológico. Métodos: Três ratos Wistar machos adultos (60 dias) foram expostos a 3 fotoperíodos de 17 dias cada, com diferentes ciclos claro/escuro (light/dark, LD): Animal CL/CC, exposto a LD inicial 16:30/07:30 (CL, claro longo) e LD final 07:30/16:30 (CC, claro curto); Animal CC/CL, exposto a LD inicial 07:30/16:30 e LD final 16:30/07:30; e Animal CT, sob LD constante 12:00/12:00. Os animais CL/CC e CC/CL passaram por um fotoperíodo intermediário entre o LD inicial e final, no qual a exposição à luz foi aumentada ou diminuída em 30 min a cada dia até que os fotoperíodos se invertessem. Todos os animais permaneceram isolados durante o estudo e tiveram suas temperaturas corporais continuamente aferidas por sensores implantados na cavidade peritoneal e suas atividades locomotoras medidas por sensores acoplados às suas caixas. Os dados obtidos foram utilizados para construção de histogramas. Resultados: Os animais CL/CC e CC/CL apresentaram maior período de atividade em CC do que em CL. A temperatura do animal CT seguiu um padrão rítmico. A linhagem utilizada apresentou sensibilidade à mudança de fotoperíodo. Conclusão: O modelo proposto e validado neste estudo pode ser usado em experimentos que tenham como objetivo avaliar as consequências das mudanças de exposição à luz.

Cronoterapia y psiquiatría: aspectos a considerar en la clínica / Chronotherapy and psychiatry: issues to consider clinic

Se ha demostrado que las funciones fisiológicas oscilan durante ciclos de 24 horas (circadianos), menos de 24 horas (ultradianos) y mayores de 24 horas (infradianos), lo que se denomina ritmos biológicos (cronobiología). El presente artículo hace énfasis en cómo los ritmos biológicos pueden incidir en la respuesta a los medicamentos y la terapéutica psiquiátrica (cronofarmacología, cronoterapia). Esta variable de estudio podría ofrecer nuevos márgenes en la eficacia y seguridad de los medicamentos y hacer su uso más racional.

It has been shown that physiological functions oscillate during cycles of 24 hours (circadian), of less than 24 (ultradian) and larger than 24 hours (infradian). These are called biological rhythms (chronobiology). This article emphasizes on how biological rhythms may influence response to drugs and psychiatric treatment (chronopharmacology, chronotherapy). The study of this variable could offer new perspectives on efficacy and safety of drugs in order to pursue a more rational use of them.

Adaptação da escala brian para uso emcrianças e adolescentes: um estudopreliminar / Brian scale adaptation for use in childrenand adolescents: a preliminary study

Introdução: Alterações nos ritmos circadianos tem sido frequentemente observadas entre pacientes com Transtorno do Humor Bipolar (THB). No entanto, existem poucos instrumentos para medi-las e a maioria deles mede exclusivamente distúrbios do sono. A escala BRIAN, validada para adultos com THB, avalia a regularidade dos ritmos biológicos em quatro diferentes aspectos: sono, atividades, social e padrão de alimentação. O objetivo deste estudo-piloto foi adaptar a escala BRIAN para uma população de crianças e adolescentes (BRIAN-K) e avaliar se o novo instrumento é capaz de detectar diferenças entre pacientes e controles saudáveis. Métodos: Foram avaliados 20 pacientes com THB entre 8-16 anos e 32 controles pareados por sexo e idade. Os sujeitos foram avaliados por meio de entrevista clínica, K-SADS-PL e testagem cognitiva. A BRIAN-K foi aplicada em ambos os grupos. Resultados: O grupo de pacientes com THB apresentou escores mais altos de alterações em seus ritmos circadianos pelo escore total da BRIAN-K, quando comparados com o grupo controle (p=0,022). Particularmente, maior irregularidade foi observada no domínio “atividades” no grupo de pacientes (p=0,001). Nossos resultados também mostraram uma correlação positiva entre a idade de diagnóstico e o domínio “sono” da BRIAN-K (r=0,485; p=0,03). Conclusões: Estes dados preliminares sugerem que a versão BRIAN-K, recentemente adaptada para crianças e adolescentes, é capaz de discriminar pacientes com THB e controles. Futuros estudos com maior tamanho amostral são necessários para determinar a confiabilidade, a validade interna e externa do presente instrumento.

Background: Alterations in the circadian rhythms have been frequently observed in patients with Bipolar Disorder (BD). However, there are few instruments to measure these changes, and most of them only assess sleep disorders. The BRIAN scale validated for adults with BD, evaluates the regularity of the biological rhythms in four different aspects: sleep, activities, social rhythm, and eating pattern. The objective of this pilot study was to adapt the BRIAN scale to a sample of children and adolescents (BRIAN-K) and to evaluate if the new instrument is capable of detecting differences among patients and healthy controls. Methods: Twenty patients with BD, aged between 8 and 16 years, and 32 controls matched for gender and age were included. Participants were assessed using the clinical interview Schedule for Affective Disorders and Schizophrenia for School Aged Children (K-SADS-PL) and cognitive testing. The BRIAN-K was administered to both groups. Results: The group of patients with BD had higher scores of alterations in the circadian rhythms according to the BRIAN-K total score when compared to the control group (p=0.022). Particularly, more irregularity was found in the “activities”domain in the group of patients (p=0.001). Our results have also showed a positive correlation between the age at diagnosis and the “sleep” domain of the BRIAN-K(r=0.485; p=0.03). Conclusions: These preliminary data suggest that the BRIAN-K version, recently adapted for children and adolescents, can differentiate patients and controls. Future studies with a larger sample size are necessary to determine the reliability, as well as the internal and external validity of the present instrument.

Envejecimiento de un reloj (cronobiología de la vejez) / Ageing of a clock (cronobiology of old age)

El envejecimiento es el conjunto de modificaciones morfológicas y fisiológicas generadas como consecuencia de la acción del tiempo sobre los seres vivos. Entre estas modificaciones se debe de incluir la incapacidad de adaptación y de responder a los cambios medioambientales, por cada uno de los órganos, aparatos y sistemas. El envejecimiento de los organismos, y particularmente del hombre, es motivo de preocupación desde hace años debido a que nuestra expectativa de vida ha aumentado significativamente y este hecho ha acrecentado el número de habitantes con problemas de envejecimiento, que presentan procesos de deterioro paulatino de órganos y sus funciones asociadas. Muchas enfermedades, entre ellas ciertos tipos de demencia, enfermedades articulares, cardíacas y algunos tipos de cáncer, han sido asociados al proceso de envejecimiento. Uno de los trastornos más notorios en la senectud es la alteración del ritmo de sueño-vigilia, reflejo de un mal funcionamiento del reloj biológico y en consecuencia del sistema circadiano. En este escrito se abordan las bases fisiológicas de la desincronización interna que sufre el hombre en edad adulta así como sus consecuencias fisiológicas y algunas recomendaciones para coadyuvar al tratamiento de este trastorno.

Aging is the set of morphological and physiological changes generated by the action of time on living beings. These changes include the inability to adapt and respond to environmental challenges, by organs, apparatus and systems. Aging of organisms and particularly of man, has become a concern in recent years, because our life expectancy has increased significantly and this has increased the number of individual ailing from the effects of aging, which includes a series of processes of gradual deterioration of organs and their associated functions. Many diseases, such as dementia, joint disease, cardiovascular disease and some cancers have been associated with the aging process. One of the most notorious disorders in aged people is the alteration of the sleep-wake rhythm, a reflection of a malfunctioning biological clock and thus of the circadian system. This manuscript addresses the physiological basis and consequences of internal desynchronization suffered by aged people and numbers recommendations for the treatment of this disorder.

PATRONES DE ALIMENTACIÓN, SUEÑO Y ACTIVIDAD REPRODUCTIVA EN JERBOS DE MONGOLIA (Meriones unguiculatus) / PATTERNS OF FEEDING, SLEEP AND REPRODUCTIVE BEHAVIOR IN MONGOLIAN GERBILS (Meriones unguiculatus)

Los jerbos de Mongolia son roedores utilizados como excelente modelo biológico. A pesar de esto, su clasificación como especie diurna, nocturna o crepuscular no ha sido clara. Los experimentos que se presentan en este artículo evaluaron patrones de alimentación, sueño-actividad y actividad reproductiva y copulativa en condiciones de luz/oscuridad 12:12 en Jerbos de Mongolia. Los resultados de los experimentos sugieren un patrón nocturno de comportamiento en estos roedores.

Mongolian Gerbils are often used as a biological model, but it remains unclear whether these rodents display nocturnal, diurnal, or crepuscular patterns of behavior. The experiments presented below studied patterns of sleep-activity, feeding, and reproductive behavior under 12:12 light dark cycles. All data from these experiments suggest a nocturnal pattern of behavior in these rodents.

La desincronización interna como promotora de enfermedad y problemas de conducta / Internal desynchrony as promotor of disease and behavioral disturbance

Life on our planet is ruled by a temporary structure that governs our activities, our days and our calendars. In order to cope with a daily changing environment, organisms have developed adaptive strategies by exhibiting daily behavioral and physiological changes. Biological rhythms are properties conserved in all the levels of organization, from unicellular to prokaryotes to upper plants and mammals. A biological rhythm is defined as the recurrence of a biological phenomenon in regular intervals of time. Biological rhythms in behaviour and physiology are controled by an internal clock which synchronizes its oscillations to external time cues that have the capacity to adjust the clock's mechanism and keep it coupled to external fluctuations. The suprachiasmatic nucleus (SCN) of the hypothalamus in mammals is the master circadian clock which is mainly entrained by the light-dark cycle. The SCN transmits time signals to the brain and then to the whole body and by means of its time signals the SCN keeps a temporal order in diverse oscillations of the body and adjusted to the light-dark cycle. The correct temporal order enables an individual to adequate functioning in harmony with the external cycles. Biological rhythms have a hereditary character, thus its expression is genetically determined. All animals, plants, and probably all organism show some type of physiological rhythmic variation (metabolic rate, production of heat, flowering, etc.) that allow for the adaptation to a rhythmic environment. Biological rhythms enable individuals to anticipate and to be prepared to the demands of the prominent cyclic environmental changes, which are necessary for survival. Also, biological rhythms promote showing maximum levels of a physiological variable at the right moment when the environment requires a maximal response. In humans, an example of circadian rhythms is the sleep-wake cycle; simultaneously, a series of physiological changes are exhibited, also with circadian characteristics (close to 24 hours). Circadian oscillations are observed in the liberation of luteinizant hormone, in plasma cortisol, leptin, insulin, glucose and growth hormone just to mentions some examples. The SCN controls circadian rhythmicity via projections to the autonomic system and by controlling the hypothalamus-adenohipofisis-adrenal axis. In this way, the SCN transmits phase and period to the peripheral oscillators to maintain an internal synchrony. Modern life favors situations that oppose the time signals in the environment and promote conflicting signals to the SCN and its effectors. The consequence is that circadian oscillators uncouple from the master clock and from the external cycles leading to oscillations out of synchrony with the environment, which is known as internal desynchronization. The consequence is that physiological variables reach their peak expression at wrong moments according to environmental demands leading then to deficient responses and to disease in the long run. Also, levels of attention, learning and memory reach peak expression at wrong moments of the day leading individuals to exhibit a deficient performance at school or work. The disturbed sleep patterns promote fatigue and irritability, which difficult social interaction. Internal desynchronization results from transmeridional traveling for which people pass multiple hourly regions. This results in an abrupt change in the time schedule and a syndrome known as <>. Frequent travelers complain about difficulties to adjust their sleep-wake cycle to the new schedule, thus resulting in fatigue, increased sleepiness and reduced attention. Jet lag results from a loss of synchrony among biological rhythms and among diverse functions, which remain out of phase with the day-night cycle. This <> is the cause of general discomfort, decrement in the physical and mental performance, as well as irritability and depression. Frequently, gastrointestinal disorders are a by-product of food consumption at an unusual schedule. The state of internal desynchrony is transitory and depends on the number of time zones that were crossed; thus, adaptation to a new external cycle can take from four to seven days. Another example of internal desynchrony is observed in individuals exposed to work shifts or to nocturnal work schedules (night work). In such conditions, circadian fluctuations in behavioral, hormonal and metabolic parameters are observed but their temporary relation with the external cycles is modified. The internal synchrony is thus affected by troubled environmental signs, out of phase with the daily activities of the individual; among them are the hours of food intake, the exposure to light during resting hours, the low temperature of the night, and the forced activity when homeostatic processes indicate a need to rest. This internal desynchrony leads to gastrointestinal disorders, disturbed metabolic fluctuations, disturbed cardiovascular functions, altered menstrual cycle, sleep disorders, sleepiness, increase of work accidents, etc. Internal desynchrony is especially due to the fact that circadian fluctuations are influenced by daily external cycles, but also by homeostatic factors, and can suffer from additional disturbance by sleep deprivation. Despite years of night work experience, incapacity to adapt to night work may persist. Only a minority of shift workers achieve spontaneous adjustment of the rhythms of core body temperature, melatonin, cortisol, thyroid stimulating hormone, or prolactin secretion to shifts by nocturnal work. Therefore shift and night workers develop a propensity to smoke, drink alcoholic beverages and use stimulant products. After five years of shift or night work, health problems appear with a higher incidence than in the general population. The growing social demand of shift work makes it necessary to decide on the characteristics and forms of shifts to carry out, and up to now organizing such working schedules remaing a serious problem. The improvement of health services has increased life expectancies and thus the general population is becoming old and people survive more years. Older people ail from health and behavioral problems including a deterioration of the biological rhythms. Main alterations consist of a loss of expression of the circadian functions or a decrease of the amplitude of the rhythms, and instability of synchronization mechanisms day by day. All in all, this implies a decreased capacity of the clock to adjust to the solar day. The decreased efficacy of the aging biological clock is evident in the fragmented sleep patterns and the disturbed sleep/wake rhythms, characterized by short sleep episodes during the day and decreased sleep during the night. Some studies suggest that the disturbed circadian rhythms may be the cause of diverse diseases associated with the elderly. In conclusion, during the last 100 years we have changed our lifestyle so radically that we lack already a physiological design to adapt so quickly to modernity. We can state that our body is designed for a world that does not exist. In this article we present a review of the main alterations of the biological rhythms generated by the transmeridional trips, shift-work and aging, their behavioral and physiological consequences that lead to disease and poor mental performance. We also discuss possible strategies that need to be explored and that may help people to improve their quality of life and to prevent internal desynchrony.

La vida se rige por una estructura temporal que gobierna nuestras horas, nuestros días y nuestros calendarios. Como parte de la adaptación a los ciclos de tiempo que impone el planeta, todo organismo presenta ritmos en su actividad y fisiología. Los ritmos biológicos son una propiedad conservada en todos los niveles de organización, desde organismos unicelulares procariontes hasta plantas superiores y mamíferos. De ellos, los más sólidos son aquellos asociados a los ciclos externos por la alternancia del día y la noche y por la alternancia de las estaciones del año. Los ritmos biológicos fisiológicos y conductuales son procesos dependientes de un reloj interno capaz de ajustar sus oscilaciones a claves de tiempo externas que lo mantienen sincronizado a estas fluctuaciones externas. El núcleo supraquiasmático del hipotálamo (NSQ) es en los mamíferos el principal reloj circadiano y se sincroniza principalmente por el ciclo luz-oscuridad. El NSQ transmite señales de tiempo al cerebro y de ahí al resto del organismo, y por medio de estas señales de tiempo mantiene un orden temporal en diversas funciones del cuerpo y las mantiene ajustadas al ciclo luz-oscuridad. El correcto orden temporal interno permite un adecuado funcionamiento del individuo en armonía con el medio externo y le permite exhibir respuestas adecuadas a un ambiente cambiante y predecible. El estilo de vida del hombre moderno propicia situaciones que llevan a alteraciones de nuestros ritmos biológicos que causan una desadaptación temporal, que a su vez redunda en daños a la salud, ya que afecta tanto la fisiología como la forma en que organizamos nuestra conducta. Un ejemplo de ello son los viajes a través de múltiples regiones horarias. Estos cambios de horario bruscos provocan un síndrome conocido como jet-lag, que consiste en un conflicto transitorio entre el tiempo <> y el tiempo <>, lo cual se denomina <>. El jet-lag se define como un conjunto de síntomas causados por una alteración del patrón de sueño, y de la expresión de ritmos biológicos fuera de fase entre sí y fuera de fase con el ciclo del día y la noche. Esta es la causa del malestar general, el deterioro del desempeño mental y físico, así como de la irritabilidad y depresión. Son frecuentes también las alteraciones gastrointestinales, resultado del consumo de alimento en un horario inusual. Otro ejemplo de alteraciones en los ritmos circadianos se observa en los trabajadores con turnos rotatorios o en turnos nocturnos. En estas condiciones se produce un conflicto entre las señales temporales asociadas al ciclo diurno y que transmite el reloj con las actividades y alimentos del trabajador en turnos. De este esquema de trabajo resulta una reducción de las horas de sueño y una alteración de los ritmos circadianos, que llevan a una desincronización interna. Ésta, al igual que en el caso del jet-lag, redunda en un deterioro de las funciones mentales y de la capacidad de atención y memorización, que se asocian a irritabilidad y problemas emocionales. Además, se observan consecuencias en la salud con incremento en la incidencia de malestares gastrointestinales, enfermedades cardiovasculares, obesidad y diabetes. La mejoría en los servicios de salud ha incrementado las expectativas de vida, lo que entonces enfrenta a la humanidad a una población que logra sobrevivir muchos años de su vejez con los cambios de conducta y salud propios de su edad, entre los que se incluye un deterioro de los ritmos biológicos. En este trabajo presentamos una revisión de las principales alteraciones de los ritmos biológicos generadas por los viajes transmeridionales, la vejez y el trabajo en turnos. También discutimos la relevancia de una buena adaptación de los ritmos biológicos y las consecuencias conductuales y fisiológicas que por su alteración llevan a la enfermedad y a un desempeño mental deficiente. También sugerimos estrategias que necesitan ser exploradas y que podrían ayudar prevenir la desincronización interna para mejorar la calidad de vida.

Melatonina, ritmos biológicos e sono: uma revisão da literatura / Melatonin, biological rhythms and sleep: a review of the literature

A melatonina, hormônio sintetizado pela glândula pineal, está envolvida em funções imunomodulatórias, antiinflamatórias, antitumorais, antioxidantes, e cronobióticas. Sua secreção ocorre à noite, estando relacionada com o sono, redução da temperatura corporal e outros eventos noturnos. Sua principal função em mamíferos é a de mediar sinais de escuridão, traduzindo informações sobre a duração da noite, com possíveis implicações no controle da ritmicidade circadiana e da sazonabilidade. Complexas vias neuroanatômicas conectando o núcleo supraquiasmático do hipotálamo à glândula pineal regulam sua secreção. Sua concentração plasmática é pequena, chegando a ser indetectável em alguns indivíduos, e mesmo doses exógenas mínimas administradas durante o dia são capazes de induzir o sono em indivíduos normais. Pode também melhorar a qualidade sono, ao promover uma sonolência que se assemelha ao padrão fisiológico, sem efeitos colaterais, diferentemente de diversas drogas hipnóticas, como os benzodiazepínicos. É por isso considerado promissor seu uso em tratamento de distúrbios de insônia.

Melatonin, hormone of the pineal gland, exhibits immunomodulatory properties, antiinflamatory actions, antitumor effects, antioxidative protection and chronobiotic modulation. The period of its secretion occurs at night, and is thereby associated with sleep, lowered core body temperature and other night time events. Its main function in mammals is to mediate dark signals, transducing information about the length of the night, with possible implications on circadian rhythm and seasonability controls. Complexes neuroanatomical pathways that connect the suprachiasmatic nucleus of the hypothalamus to the pineal gland control its secretion. Its plasmatic levels are small, undetectable in some individuals, and even minimal exogenous doses can induce sleep in healthy humans. It can also improve the quality of sleep, inducing a sleepiness state which resembles the natural sleep, without side effects, differently from the effects of the most hypnotics, such the benzodiazepines. Therefore, melatonin use is considered promising on treatment of sleep disorders, such insomnia.

Sincronización no-luminosa: ¿otro tipo de sincronización? Primera parte

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SUMMARY One of the most important functions in which the circadian system participates is to assess that the behavioural and physiological variables adjust appropriately to daily events in the environment, a process referred to as entrainment. Since in the nature the food disposition and predators' activity also are cyclical, the temporary relation between the circadian rhythm and periodic environmental signals maximizes the survival of each species in its temporary niche. Thus, through this mechanism, the organisms adapt to their environment through circadian system which entrain the organism activities to different external signals. In nature environments the predominance of photic entrainment like primary zeitgeber of the biological clock (suprachiasmatic nucleus) is a clear adaptation to the earthly life; nevertheless other biological advantages can be conferred to an individual if the circadian system also is sensible to other environmental signals that they provide from the external time. In such way, the light is not the only synchronizer affecting the biological clock. Other stimuli like the temperature and locomotor activity induced by novel stimuli and certain drugs are also able to entrain the biological clock. These signals have been described like non-photic stimuli. The general effects of the non-photic signals are able to generate phase response and entrain a free running rhythm, only during the subjective day, time in which the biological clock is sensible to these signals which are able to generate phase advances. These phase response are of great magnitude, even of greater magnitude than the induced ones by a light signal. The non-photic signals are also able to induce residual effects (after-effects) on entrainment process, thereby generating changes in the endogenous period, therefore affecting the phase angle in a cycle L:O and promoting the development of locomotor activity rhythm splitting. Furthermore, the light entrainment has been characterized in a wide variety of diurnal and nocturnal species. While, the non-photic entrainment only appears in nocturnal rodents. Being the hamster's biological clock one of that responds to the greater number of biological non-photic signals such as the acute exposition to sexual odors, social interactions, as well as by simple injection of saline solution, all of these non-photic signals are able to induce phase advances of the locomotor activity rhythm in free running when they are applied onto the subjective day. The entrainment to a non-photic stimulus is also observed in humans. Among the non-photic stimuli we can have the pharmacological treatments, social stimuli, stress, food restriction and communication between mother and product in the foetal and neonatal life. These later stimuli are of a particular importance to optimize the circadian function and sensitize the newborn to external environment. Thus the non-photic stimuli could be categorized like behavioural or pharmacological stimuli. These manipulations involve an increase in the locomotor activity, excitation or states able to phase resetting the circadian clock and peripheral oscillators in different species. The non-photic stimuli can affect to the biological clock through an afferent projection from the SCN that translate the non-photic information and is able to induce phase responses. Additionally, non-photic stimuli could also affect the biological clock through the action of a peripheral oscillator, which is sensitive to this type of signals. These peripheral oscillators translate the non-photic information and it communicates with the SCN, through synaptic and no-synaptic mechanisms. With regard to the physiological mechanisms involved on this process, there has been suggested to participate four neurotransmitter systems in the circadian system: a) the serotonergic system originating from the raphe nucleus, b) the NPY system from the leaflet intergeniculate (IGL), c) the GABAergic system, which it is present in most of the neurons of the SCN and IGL (the afferent projections of the raphe and the IGL nucleus make synapse with GABAergic neurons in the SCN) and 4) finally a neural system involving dopamine and melatonin signals, which have been importantly implicated in the brain in the foetal and neonatal live. In comparison to the cascade of intracellular signals caused by glutamatergic stimulation associated to photic entrainment, which excites to the SCN cells, the transmitters implicated in the nonphotic entrainment typically inhibit the SCN neurons. For example the melatonin's main action on the SCN neurons is inhibiting adenylyl cyclase and the translation of related signals driven by the AMPc, such inhibition of activity of the protein kinase depended of AMPc (PKA), which give rise to a decreased phospho- rylation of the transcription factor CREB. In this way, the phase responses induced by non-photic stimuli are not associate with the phosphorylation of the transcription factor (CREB) associated to responsive DNA-elements to binding AMPciclic or with the transcription of early expression genes in the SCN, events of metabothrophic signalling pathway of the photic entrainment. The phase responses generated by the non-photic signals occur during the subjective day, time in which the spontaneous expression of clock genes is high in diurnal and nocturnal animals. A reason why the phase resetting of biological clock to non-photic signals can be generated by a fast suppression in the expression levels of the genes clock. The decrease of Per1 and Per2 messenger RNA's expression levels in the SCN generated by non-photic stimuli occurs during a half of the subjective day, not during the subjective night, which suggests that these genes may participate in the phase resetting of biological clock during the subjective day. The interactions between phase response induced by the light and those induced by non-photic stimuli have been described previously. When a photic stimulus is applied after a non-photic signal during subjective day, with the purpose of studying the interaction between photic stimuli and non-photic stimuli, the photic stimulus blocks or attenuates the phase advances generated in response to different non-photic stimuli applied, such as the forced locomotor activity, sleep privation, NPY administration, or serotonergic agonists (8-OH-DPAT) administration. If the genes clock responds to the non-photic stimuli, then the lack of some of them will have to generate alterations in the response to non-photic signals. In the Clock mutant mice, the biological clock responses to the non-photic signals applied during the subjective day generate phase responses in opposed direction from those generated by intact subjects. This latter suggests that different genes clock participate in the generation of the phase response to a non-photic stimulus. The non-photic entrainment of the circadian system has a biological and/or social importance in several contexts. In the early products life, the communication of circadian information from the mother is important in regulating the biological clock of the foetus or newborn before they are sensitive to light. Under circumstances where the social and work routines are altered, by changes of constant "work turn" (shift work), the biological clock receives photic and non-photic signals which generate a dysfunction and poor work efficiency. The absence of non-photic signals followed by a social abstinence can induce alterations in the mental health (depression). The sleep disorder, experimented blind subject can arise from a lost of the social entrainment, therefore a decrease in the efficiency of the clock mechanism. Thus latter alterations of the clock, it could be possible to develop new forms of pharmacological and behavioural treatments.

Enmascaramiento. Un tipo de sincronización. Primera parte

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Abstract: Organisms adapt their temporary niche with two complementary mechanisms. The first mechanism is referred to as entrainment of the endogenous biological clock, which circumscribes temporarily the activity of the subject into day or night. The second mechanism is defined as masking, and this refers to an alternative route which does not involve the activity of the pacemaker. It involves, instead, a sharp response of the animal during light-time, inhibiting or enhancing the expression of locomotor activities in nocturnal or diurnal species, respectively. Masking describes the direct and immediate effects on the expression of any biological rhythm induced by the season-dependent signals present in the environment. Moreover, this masking mechanism appears to complement the biological clock entrainment, which is used by organismsto adapt to their specific nocturnal or diurnal niche. Several constraints arise when trying to study the biological clock entrainment or the light-associated oscillators system. Theseare due to the fact that the zeitgeber influences the biological clock and affects the output response of the circadian clock. According to the aforementioned description, it appears the masking effects occur as a natural event and result from an inevitable consequence to the season-dependent life of living organisms. Circadian rhythms do not only reflect the physiological output responses of the biological clocks as their activities also result from a mixture of responses arising either from the masking effects and/or from the entrainment mechanisms driving the timing of the biological clock within the animal. Although conspicuous differences do exist between maskingand entrained- rhythms, both rhythms follow a similar timecourse. Nevertheless, the transition between light and darkness (environmental change) under the masking rhythm results in abrupt changes in the animal behavior activity (i.e, from a resting to an ambulatory activity or viceversa). In contrast, when the environment acts as a zeitgeber under the biological clock entrainment, the behavioural transition of the animal appears to be less abrupt and, therefore, the environment factors affecting the biological rhythms never match. Based on different chronobiological studies in animals, several authors have described different forms of masking mechanisms used by the brain, and classified according to the light-induced decrease or increase locomotor activity responses: a) Positive Masking refers to the increase or decrease of locomotor activity response in a diurnal or nocturnal animal, respectively, as a result of the increase in lighting; b) Negative Masking refers to the decrease of locomotor activity responses as a result of decrease in lighting in a diurnal animal, or an increase in lighting in a nocturnal animal; c) Paradoxical Positive Masking refers either to the increase locomotor activity responses of a nocturnal animal exposed to increase lighting or an increase in locomotor activity responses in a diurnal animal after lighting decreases; d) Paradoxical Negative Masking refers to the decrease of locomotor activity responses in a nocturnal animal when lighting is decreased, or to the decrease of locomotor activity responses in a diurnal animal when lighting is increased. In addition to the aforementioned classification of different masking mechanisms on the behavioral locomotor activity responses in both diurnal and nocturnal animals, other authors classify different forms of masking, based on the neural mechanisms that generate the masking effects. Authors defined the occurence of different forms of masking effects when enviromental factors (i.e, light, darkness) produce direct or indirect effects on the cyrcadian rhythm in an animal. Thus, a) Type I masking occurs when the environment produces a direct effect on the circadian rhythm output; b) Type II masking occurs when behavioral changes in the animal affect other physiological brainrhythms, for instance, an increase or decrease of behavioral locomotor activity may affect the temperature rhythm of an organism, enhancing the expression of an altered activity on the biological clock; c) Type III masking occurs when physiological or biochemical changes alter the neural output of the biological clock that conveys the time-related information of the biological rhythm; for instance, physiological or pathological conditions have been shown to affect the functional activity of specific neural pathways and their membrane receptors involved in the regulation of the body temperature. Such situations appear to modify the phase of the body temperature rhythm with the phase of the biological clock, which both rhythms appear to match under basal conditions. The sensibility limits necessary to generate the inhibition of the synthesis and release of melatonine, in rats and hamster, suggest the involvement of the rods, the predominant photoreceptor in the rodent retina. Nevertheless, studies the mutant mice rd/rd (the mutation rd generates the total loss of photoreceptors type rods and a considerable loss of photoreceptors type cones) presented an inhibition in the synthesis and release of the melatonine and locomotor activity induced by the light. This suggests that the photoreceptors type cones and rods are not necessary to mediate the effects of the light on the locomotor activity and that the light masking depends on another type of contained photoreceptor in the retina. Some studies report the loss of the rhythmycity in drinking, locomotion or sleep-wakefulness, not only when the animals are kept in light constant, also when the animals are kept under lightdarkness cycles (L:D). Other studies that involve to mutant mice of the two genescryptocromos, which they are arrhythmic in constant conditions; they show a SCN functional diminished, light pulses applied in the subjective night do not generate alterations in the inhibition of the locomotor activity induced by the light. This suggests the loss of the masking responses induced by light. Certainly, these results point to a loss or attenuation of the masking by the SCN lesion. On the other hand, other works showing a persistence of the masking pd drinking and locomotor activity in L:D conditions after the SCN lesions. The lesions of other structures of the rodent visual system alter the light masking. It is more a significant increase of the masking in subjects with IGL lesion is observed. Subsequently, it was reported that the masking induced by the light was more significant in mice that were submitted to an NGLd lesions, which suggests that the increase in the masking to the light observed after the IGL lesions are probably due to an incidental damage of the NGLd. It also has been reported that the light masking increase after the visual cortex lesions in hamster and mice. The mutant mice clock shows brilliant light pulses: between 100 to 1600 lux they induce a complete suppression of the locomotor activity (negative masking). On the other hand, dim light pulses induce an increment of the basal levels of the locomotor activity (positive masking) in a similar way to that of the normal subjects. The participation of other genes clock in the regulation of the light-masking has not been specific. The masking is not a limited phenomenon to conditions of laboratory. There are few examples of the direct effects of light on the temporary organization of the behavior in wildlife. An impressive case is the owl primate (Aotus lemurinus griseimembra), which shows a pattern of locomotor activity that depends on the lunar cycle. This primate is nocturnal, but its activity increases (positive masking) when the luminescence is found between 0.1 and 0.5 lux, the luminescence generated precisely by the brightness of the moon. Intensities of light lower to this diminish the locomotor activity (negative masking) of the subject. The masking mechanism is an important process in the adaptation of an organism to its environment as it confers this the capacity to respond quickly to a sudden change in environmental conditions. Since the functional point of view the masking contributes to an increment in the amplitude of a entrainment rhythm, promotes direct responses to geophysical variables that the organism selects that they optimize its evolution and its adaptation to its temporary niche, all this contributes to an increase in the probability of survival of the subject to its environment.

Sincronización luminosa. Conceptos básicos. Primera parte

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Abstract The periodic fluctuations in diverse physiological parameters are a general property of all organisms. Furthermore, when these fluctuations occur to intervals regulates these are considered as «biological rhythms¼. The biological rhythms are generated by an endogenous mechanism of the organism. The biological rhythms appear in wide interval in frequencies of oscillation, which go from a cycle by millisecond to a cycle per year. Additionally, the geophysical environment is characterized by the existence of cycles deriving from movements of the earth and the moon with regard to sun. These environmental or geophysical cycles are the days, tides, lunar phases and seasons of the year. When the frequency of a biological rhythm approaches that of an environmental cycle, the prefix "circa" is used to refer to it. Likewise, 24-hour biological rhythms are designated as circadian rhythms. The circadian rhythms represent one of the most ubiquitous adaptive characteristics of the organism. In mammals, they represent an important process through which events of the internal milieu are organized in an appropriate temporary sequence, thus enhancing a maximum adaptation to external milieu. This characteristic allows organisms to predict and to be prepared for changes in the geophysical environment associated with the day and the night. To carry out this adaptive role, the circadian rhythms require the biological system having the capacity to measure the biological time. Thus, the circadian rhythm should be generated endogenously, adjusting the geographical time. Moreover, under usual environmental conditions, the period of the oscillator is adjusted to the period of the environmental cycle. The endogenous origin of the biological rhythms is based on the fact that, in temporary environmental signs isolation conditions, the biological rhythm persists with a light but significant variation in the value of the period of oscillation. The afore mentioned considerations suggest that the rhythm observed does not depend on cyclic geophysical phenomena. Thus, the rhythm maintained under constant conditions reflects an internal organism's process. This essential ability of the organism to maintain circadian rhythms, even in the absence of periodic environmental cues, is known as rhythm in spontaneous oscillation or free-running. Nevertheless, the organism is never isolated from temporary signals and it keeps a narrow temporary relation with the environmental cues by which the phase and the period of the overt rhythm can be adjusted to the phase and period of the environmental cyclic changes. This process is called «entrainment¼. It is considered that the three fundamental properties of circadian rhythms are the persisting free-running rhythm, the temperature compensation and the entrainment. Literally, the word entrainment means «to get aboard a train¼ (from the French word entramen «to carry along¼). In this context, the entrainment of a biological clock is generated through a controllers stimuli train with a specific period, which induces a biological clock with a different endogenous period from 24 hours to be adjusted for the period of the periodic environmental cycle. The entrainment of the biological clock provides to internal milieu of a reckoned of the external time. This process can occur for a modulation of the period and/or of the phase of the biological rhythm, that is, the endogenous period of the biological rhythm is adjusted to the period of the zeitgeber with a relation phase stable (or phase angle) between the zeitgeber and the oscillation entrained. Studies where subjects were submitted to a rigorous temporary isolation indicated that only certain environmental variables are capable of acting as temporary signals for the circadian system. In 1951, Aschoff coined the word «Zeitgeber¼ from the German «given of time¼, which describes an environmental cycle capable of affecting the period and the phase of a biological clock. In nature, multiple environmental cues oscillate under a daily cycle, including light, darkness, temperature, humidity, availability of food and social signals. Some of these factors may act as zeitgebers of the biological clock, but the most consistent and predictable environmental signal is the 24-hour cycle of light-darkness (L:O) (photic entrainment). Nevertheless, organisms can be entrained for other stimuli (non-photic entrainment) such as temperature, electromagnetic fields, environmental pressure, sound, availability of food and social signals. Researchers have developed two theoretical models to explain the mechanism(s) by which the circadian clock is entrained to an environmental cycle: the discreet model (non-parametric or phasic) and the continuous model (parametric or tonic). The model of continuous entrainment is based on the observation that the period in free running (POE) to depend of the intensity light and suggests that the light has a continuous action on the biological clock to entrain it to a cycle light-darkness (L:O). The mechanism suggested for this is the acceleration and deceleration of the POE (angular velocity), due to daily changes in the intensity of the light, these permit to circadian pacemaker is continuously adjusted along the environmental cycle. The discreet model has been the most utilized model to explain the entrainment to environmental cycles. The basic premise of this model is that the circadian pacemaker entrained this in equilibrium with the cycle light: darkness (L:D), which consists of brief pulses of light (zeitgeber). When a brief pulse of light falls in a specific phase of the biological clock, this produces an phase response equal to the difference between the POE and the period of the cycle entrained. The day-night cycles generated by the rotation of the earth around its axis influence the life of the organism to a large extension. Many organisms coordinate their activities to these cycles. Some of them are diurnal, while other ones nocturnal. Moreover other animals escape from the daily periodic environment and they organize their life in constant environments as in the depth of the ocean or in natural caverns. It is not clear how and because biological clocks with a period of approximately 24 hours evolved in cyclic environments of exactly 24 hours. A possible explanation is that the cycles L:D provide an optimum stability for their expression. There has been as were that the cycle L:D is the first environmental signal behind the emergency and maintenance of the circadian clocks. A large number of cell functions are affected by the light, and is being speculated that the original organisms could have restricted some of their outstanding metabolic processes at night, thus avoiding the adverse effects of the light. In fact, some organisms adjust several of their sensitive cell processes to the light. For example, there is an augmented replication of the DNA, at night to avoid the exposition to deleterious ultraviolet radiation. Thus it is possible to propose a hypothesis of how the circadian clocks could evolve at phylogenetically level: the ancient organisms generated a temporary program, where sensitive processes to the light were temporarily restricted to avoid the damage induced by the sunlight; these temporary programs turned out to be advantageous and thus they were selected through evolution of species.