Behavioral interventions to eliminate fear responses

Fear memory underlies anxiety-related disorders, including posttraumatic stress disorder(PTSD). PTSD is a fear-based disorder,characterized by difficulties in extinguishing the learned fear response and maintaining extinction. Currently, the first-line treatment for PTSD is exposure therapy, which forms an extinction memory to compete with the original fear memory. However,the extinguished fear often returns under numerous circumstances, suggesting that novel methods are needed to eliminate fear memory or facilitate extinction memory. This review discusses research that targeted extinction and reconsolidation to manipulate fear memory. Recent studies indicate that sleep is an active state that can regulate memory processes. We also discuss the influence of sleep on fear memory. For each manipulation, we briefly summarize the neural mechanisms that have been identified in human studies. Finally, we highlight potential limitations and future directions in the field to better translate existing interventions to clinical settings.     

Disturbances of sleep and wakefulness associated with the use of antihypertensive agents

Sleep disturbances are frequently associated with the use of antihypertensive drugs. They are observed mainly during the administration of drugs that affect central adrenergic mechanisms. Beta-adrenoceptor antagonists which readily penetrate into the brain (propranolol, pindolol) increase wakefulness and/or decrease REM sleep. Alpha 2-adrenoceptor agonists (clonidine, guanfacine) markedly reduce the duration of REM sleep. The catecholamine depleting agent reserpine increases REM sleep during single or repeated-dose administration, while the MAOI phenelzine shows opposite effects. The 5-HT2 antagonist ritanserin, which is chemically related to the antihypertensive agent ketanserin, increases slow wave sleep while REM sleep is decreased. Sleep disturbances have not been reported during the administration of calcium entry antagonists. However, they seem to modify the effects of hypnotics and CNS stimulants. There are no formal studies on the effects of angiotensin converting enzyme inhibitors and vasodilators on sleep in man.     

Selected Neurophysiological,Psychological, and Behavioral Influences on Subjective Sleep Quality in Nurses: A Structure Equation Model

Few studies have examined relationships among neurophysiological, psychological, and behavioral factors with regard to their effects on sleep quality. We used a structure equation model to investigate behavioral and psychological factors that influence neurophysiological regulation of sleep in shift workers. Using a cross-sectional study design, we tested the model with a sample of 338 female nurses working rotating shifts at an urban regional hospital. The Morningness-Eveningness Questionnaire (MEQ) and short-form Menstrual Distress Questionnaire (MDQ) were used to measure neurophysiological factors involved in morningness-eveningness and menstrual distress. The Sleep Hygiene Awareness and Practice Scale (SHAPS) and Profile of Mood States Short Form (POMS-SF) were completed to measure behavioral factors of sleep hygiene practices and psychological factors of mood states. In addition, the Pittsburgh Sleep Quality Index (PSQI) measured participant''s self-reported sleep quality. The results revealed that sleep hygiene practices and mood states mediated the effects of morningness-eveningness and menstrual distress on sleep quality. Our findings provide support for developing interventions to enhance sleep hygiene and maintain positive mood states to reduce the influence of neurophysiological factors on sleep quality among shift workers.     

Rem sleep,early experience,and the development of reproductive strategies

We hypothesize that rapid eye movement or REM sleep evolved, in part, to mediate sexual/reproductive behaviors and strategies. Because development of sexual and mating strategies depends crucially on early attachment experiences, we further hypothesize that REM functions to mediate attachment processes early in life. Evidence for these hypotheses comes from (1) the correlation of REM variables with both attachment and sexual/reproductive variables; (2) attachment-related and sex-related hormonal release during REM; (3) selective activation during REM of brain sites implicated in attachment and sexual processes; (4) effects of maternal deprivation on REM; (5) effects of REM deprivation on sexual behaviors; and (6) the REM-associated sexual excitation. To explain why we find associations among REM sleep, attachment, and adult reproductive strategies, we rely on recent extensions of parent-offspring conflict theory. Using data from recent findings on genomic imprinting, Haig (2000) and others suggest that paternally expressed genes are selected to promote growth of the developing fetus/child at the expense of the mother, while maternally expressed genes counter these effects. Because developmental REM facilitates attachment-related outcomes in the child, developmental REM may be regulated by paternally expressed genes. In that case, REM may have evolved to support the “aims” of paternal genes at the expense of maternal genes. Patrick McNamara, Ph.D., is an assistant professor of neurology at Boston University School of Medicine and a member of the Department of Neurology at the Boston VA Medical Center. He specializes in study of catecholaminergic mechanisms of cognitive disorders in Parkinson’s and related disorders. He has a long-standing interest in anthropological and evolutionary approaches to medicine and to human cognition. His recent book Mind and Variability applied Darwinian models to problems of memory and identity. He is currently writing a book on the evolutionary psychology of sleep and dreams. Sanford Auerbach, M.D., is an associate professor of neurology and psychiatry at Boston University School of Medicine and medical director of the Neurophysiology Laboratories at the Boston Medical Center. He is a behavioral neurologist and a board-certified sleep specialist. He is also director of the Sleep Disorders Center at Boston Medical Center. He has been associated with the NIH-sponsored Sleep Heart Health Study and other sleep-related research. He has been a member of the executive committee of the Sleep Section of the American Academy of Neurology and a past chair of the Neurology section of the American Sleep Disorders Association. Jayme Dowdall is a medical student at Boston University School of Medicine who plans to specialize in molecular approaches to medical and sleep disorders.     

An ether stressor increases REM sleep in rats: possible role of prolactin

Sleep alterations after a 1-min exposure to ether vapor were studied in rats to determine if this stressor increases rapid eye-movement (REM) sleep as does an immobilization stressor. Ether exposure before light onset or dark onset was followed by significant increases in REM sleep starting approximately 3-4 h later and lasting for several hours. Non-REM (NREM) sleep and electroencephalographic slow-wave activity during NREM sleep were not altered. Exposure to ether vapor elicited prolactin (Prl) secretion. REM sleep was not promoted after ether exposure in hypophysectomized rats. If the hypophysectomy was partial and the rats secreted Prl after ether exposure, then increases in REM sleep were observed. Intracerebroventricular administration of an antiserum to Prl decreased spontaneous REM sleep and inhibited ether exposure-induced REM sleep. The results indicate that a brief exposure to ether vapor is followed by increases in REM sleep if the Prl response associated with stress is unimpaired. This suggests that Prl, which is a previously documented REM sleep-promoting hormone, may contribute to the stimulation of REM sleep after ether exposure.     

Correlation of sleep disturbances, anxiety and depression in Croatian war veterans with posttraumatic stress disorder

The aim of the study was to examine the relationships between global sleep quality and its specific components and Posttraumatic Stress Disorder (PTSD) symptom severity questionnaire. We also researched whether sleep quality and sleep disturbances differed among groups of PTSD based on symptom severity categories. This study was conducted on the sample of 120 Croatian war veterans with PTSD. The following self-report instruments were used: Pittsburgh Sleep Quality Index, the Pittsburgh Sleep Quality Index Addendum for PTSD, the Mississippi Scale for Combat-Related PTSD, the Spielberger State and Trait Anxiety Inventory and the Beck Depression Inventory. There were statistically significant differences between the three PTSD severity groups on general nervousness (PSQI-A variable), where patients with extremely severe PTSD have more symptoms of general nervousness than groups with severe or moderate PTSD. Differences were found between PTSD severity groups in episodes of terror and acting-out dreams, where patients with extremely severe PTSD have more symptoms of episodes of terror and acting-out dreams than groups with severe or moderate PTSD. Sleep quality was significantly correlated with state anxiety, trait anxiety, and depression, indicating that with decrease of anxiety and depression, sleep quality improves. Sleep latency was positively correlated with both state and trait anxiety. There wasn't any significant correlation between sleep latency and depression. Study suggests that sleep disturbances are equally severe across groups of veterans based on PTSD severity and that the severity of sleep disturbances is significantly related to severity of anxiety and depression symptoms.     

Slow wave and rem sleep mechanisms are differently altered in hereditary pick disease associated with the TAU G389R mutation

Sleep disturbances are found in the course of most dementing syndromes. We report a longitudinal polysomnographic and 18FDG-PET study in a 38-year-old male with FTDP17 carrying the Tau gene mutation G389R. All-night sleep EEG and wake cerebral glucose metabolism at rest (eyes/ears covered) of the preceding day were studied twice, eight months (Night 1; PET 1) and sixteen months (Night 2; PET 2) after the initial neurological evaluation. The Night 1 study showed sleep fragmentation associated to a short REM latency and a severe reduction of slow wave sleep, with relatively preserved NREM-REM sleep cycles; daytime PET 1 revealed severe cerebral glucose metabolic reductions in frontal and temporal areas, with relative preservation of remaining cortical regions and subcortical structures. On Night 2, the total sleep time was less than 5 hours, delta sleep and REM latency remained shortened and only two sleep cycles could be identified; daytime PET 2 exam revealed a greater cortical metabolic impairment and an involvement of subcortical brain regions as compared to PET 1. Post-mortem neuropathological data showed severe neuronal loss, spongiosis and gliosis that were mostly marked in cortical layers I, II, V and VI. In vivo, neurometabolic and post-mortem neuropathological data are consistent with and indicative of a severe dysfunction of intra- and trans-hemispheric regional connectivity and of cortico-thalamic circuits. These findings suggest that the decreased cortical and subcortical connectivity may have been the main pathophysiological mechanism responsible for delta sleep reduction and the cognitive decline.     

A phylogenetic analysis of sleep architecture in mammals: the integration of anatomy, physiology, and ecology

Among mammalian species, the time spent in the two main "architectural" states of sleep--slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep--varies greatly. Previous comparative studies of sleep architecture found that larger mammals, those with bigger brains, and those with higher absolute basal metabolic rates (BMR) tended to engage in less SWS and REM sleep. Species experiencing a greater risk of predation also exhibited less SWS and REM sleep. In all cases, however, these studies lacked a formal phylogenetic and theoretical framework and used mainly correlational analyses. Using independent contrasts and an updated data set, we extended existing approaches with path analysis to examine the integrated influence of anatomy, physiology, and ecology on sleep architecture. Path model structure was determined by nonmutually exclusive hypotheses for the function of sleep. We found that species with higher relative BMRs engage in less SWS, whereas species with larger relative brain masses engage in more REM sleep. REM sleep was the only sleep variable strongly influenced by predation risk; mammals sleeping in riskier environments engage in less REM sleep. Overall, we found support for some hypotheses for the function of sleep, such as facilitating memory consolidation or learning, but not others, such as energy conservation.     

Brain oscillatory activity during sleep shows unknown dysfunctions in early encephalopathy

Electroencephalographic recordings in cirrhotic patients without overt hepatic encephalopathy (HE) have mainly been performed during wakefulness. Our aim was to quantify their alterations in nocturnal sleep electroencephalogram (EEG). In 20 patients and 20 healthy volunteers, we recorded a nocturnal digital polysomnography. Different sleep parameters were measured. Besides, we performed quantitative analysis of EEG (qEEG) as follows: spectral power in the different sleep stages was calculated in the frequency bands low δ, δ, θ, α, and σ. Also, the mean dominant frequency and Sleep Indexes were obtained. In comparison with controls, the group of patients showed (1) different alterations in both the microstructure and the macrostructure of sleep; (2) an increase in, both, θ band power and the average mean dominant frequency during rapid eye movement (REM); (3) in all sleep stages, a decrease of sleep electroencephalogram spectral power in low δ band and an increase in δ band: and (4) in stages N3 and REM, significant increases in the minimum of mean dominant frequency and in the respective sleep indexes. Therefore, in cirrhotic patients without overt HE, and likely having minimal hepatic encephalopathy, we found different alterations in both the microstructure and the macrostructure of nocturnal sleep. Also, sleep qEEG showed a brain dysfunction in slow oscillatory mechanisms intrinsic of sleep stages, with an increase in the frequency of its maximal electroencephalogram synchronization, from low δ to δ band. These alterations may reflect the onset of encephalopathy; sleep qEEG may, thus, be an adequate tool for its brain functional evaluation and follow-up.     

Sleep disruption in PTSD: A pilot study with home-based polysomnography

Sleep and Biological Rhythms - Laboratory-based sleep studies have yielded inconsistent results regarding the nature of objective sleep anomalies in posttraumatic stress disorder (PTSD). This pilot...     

Updating versus Exposure to Prevent Consolidation of Conditioned Fear

Targeting the consolidation of fear memories following trauma may offer a promising method for preventing the development of flashbacks and other unwanted re-experiencing symptoms that characterise Posttraumatic Stress Disorder (PTSD). Research has demonstrated that performing visuo-spatial tasks after analogue trauma can block the consolidation of fear memory and reduce the frequency of flashbacks. However, no research has yet used verbal techniques to alter memories during the consolidation window. This is surprising given that the most effective treatments for PTSD are verbally-based with exposure therapy and trauma-focused cognitive behavioural therapy gaining the most evidence of efficacy. Psychological therapies aim to reduce the conditioned fear response, which is in keeping with the preliminary finding that an increased propensity for fear conditioning may be a vulnerability factor for PTSD. Our research had two aims. We investigated the degree to which individual differences in fear conditioning predict the development of PTSD symptoms. We also compared the preventative effects of two clinically informed psychological techniques administered during the consolidation window: exposure to the trauma memory and updating the meaning of the trauma. 115 healthy participants underwent a fear conditioning paradigm in which traumatic film stimuli (unconditioned stimuli) were paired with neutral stimuli (conditioned stimuli). Participants were randomly allocated to an updating, exposure or control group to compare the effects on the conditioned fear response and on PTSD symptomatology. The results showed that stronger conditioned responses at acquisition significantly predicted the development of PTSD symptoms. The updating group, who verbally devalued the unconditioned stimulus within the consolidation window, experienced significantly lower levels of PTSD symptoms during follow-up than the exposure and control groups. These findings are consistent with clinical interventions for chronic PTSD and have important implications for identifying those at risk as well as for designing novel early interventions to prevent the development of PTSD.     

Fear extinction and BDNF: translating animal models of PTSD to the clinic

Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophin involved in synaptic plasticity processes that are required for long-term learning and memory. Specifically, BDNF gene expression and activation of its high-affinity tropomyosin-related kinase B (TrkB) receptor are necessary in the amygdala, hippocampus and prefrontal cortex for the formation of emotional memories, including fear memories. Among the psychiatric disorders with altered fear processing, there is post-traumatic stress disorder (PTSD) which is characterized by an inability to extinguish fear memories. Since BDNF appears to enhance extinction of fear, targeting impaired extinction in anxiety disorders such as PTSD via BDNF signalling may be an important and novel way to enhance treatment efficacy. The aim of this review is to provide a translational point of view that stems from findings in the BDNF regulation of synaptic plasticity and fear extinction. In addition, there are different systems that seem to alter fear extinction through BDNF modulation like the endocannabinoid system and the hypothalamic-pituitary adrenal axis. Recent work also finds that the pituitary adenylate cyclase-activating polypeptide and PAC1 receptor, which are upstream of BDNF activation, may be implicated in PTSD. Especially interesting are data that exogenous fear extinction enhancers such as antidepressants, histone deacetylases inhibitors and D-cycloserine, a partial N-methyl d-aspartate agonist, may act through or in concert with the BDNF-TrkB system. Finally, we review studies where recombinant BDNF and a putative TrkB agonist, 7,8-dihydroxyflavone, may enhance extinction of fear. These approaches may lead to novel agents that improve extinction in animal models and eventually humans.     

Murine GRPR and stathmin control in opposite directions both cued fear extinction and neural activities of the amygdala and prefrontal cortex

Extinction is an integral part of normal healthy fear responses, while it is compromised in several fear-related mental conditions in humans, such as post-traumatic stress disorder (PTSD). Although much research has recently been focused on fear extinction, its molecular and cellular underpinnings are still unclear. The development of animal models for extinction will greatly enhance our approaches to studying its neural circuits and the mechanisms involved. Here, we describe two gene-knockout mouse lines, one with impaired and another with enhanced extinction of learned fear. These mutant mice are based on fear memory-related genes, stathmin and gastrin-releasing peptide receptor (GRPR). Remarkably, both mutant lines showed changes in fear extinction to the cue but not to the context. We performed indirect imaging of neuronal activity on the second day of cued extinction, using immediate-early gene c-Fos. GRPR knockout mice extinguished slower (impaired extinction) than wildtype mice, which was accompanied by an increase in c-Fos activity in the basolateral amygdala and a decrease in the prefrontal cortex. By contrast, stathmin knockout mice extinguished faster (enhanced extinction) and showed a decrease in c-Fos activity in the basolateral amygdala and an increase in the prefrontal cortex. At the same time, c-Fos activity in the dentate gyrus was increased in both mutant lines. These experiments provide genetic evidence that the balance between neuronal activities of the amygdala and prefrontal cortex defines an impairment or facilitation of extinction to the cue while the hippocampus is involved in the context-specificity of extinction.     

Protocol for Studying Extinction of Conditioned Fear in Naturally Cycling Female Rats

Extinction of conditioned fear has been extensively studied in male rodents. Recently, there have been an increasing number of studies indicating that neural mechanisms for certain behavioral tasks and response behaviors are different in females and males. Using females in research studies can represent a challenge because of the variation of gonadal hormones during their estrous cycle. This protocol describes well-established procedures that are useful in investigating the role of estrogen in fear extinction memory consolidation in female rats. Phase of the estrous cycle and exogenous estrogen administration prior to extinction training can influence extinction recall 24 hr later. The vaginal swabbing technique for estrous phase identification described here aids the examination and manipulation of naturally cycling gonadal hormones. The use of this basic rodent model may further delineate the mechanisms by which estrogen can modulate fear extinction memory in females.     

Changes of Sleep Adaptation in Hospitalized Patients with Depression

Sleep adaptation in an unfamiliar environment, the so-called “first-night effect”, is known to occur in healthy individuals. To avoid the confounding effects of the “first-night effect”, the first-night sleep data are not used in most of sleep studies. In the present study, we examined changes of sleep adaptation in hospitalized patients with depression. Polysomnographic recordings were obtained for two consecutive nights from 14 patients, and sleep parameters were compared between both nights. Total sleep time, sleep latency, awakening times, movement awakening time, sleep efficiency, sleep architecture, rapid eye movement (REM) sleep latency, REM intensity, REM density, REM time, REM cycles, and other indicators showed no significant difference (p > 0.05) between the first and second nights. To conclude, hospitalized patients with depression have relatively less change in sleep adaptation, thus, the data from their first night do not need to be discarded.     

Sex hormones, insulin sensitivity, and diabetes mellitus

Sex differences and the role of gonadal hormones in modulating insulin sensitivity and glucose tolerance are of increasing interest and importance because of the increasing prevalence of type 2 diabetes mellitus and the metabolic abnormalities associated with aging. Body composition is closely associated with insulin sensitivity, and increased body fat, particularly in the visceral compartment, is a risk factor for developing type 2 diabetes mellitus. Sex differences in body composition and/or insulin sensitivity are evident in humans throughout the lifespan. Ovarian hormones influence insulin sensitivity across the menstrual cycle, during pregnancy, and in the menopausal transition. Similarly, estrogens and progestins used for contraception and hormone replacement therapy affect glucoregulation. Nonhuman primates and humans have similar life histories and reproductive characteristics. As a result, nonhuman primates provide a valuable model for investigating factors related to insulin sensitivity. Studies of nonhuman primates have contributed significantly to our understanding of sex differences and the influence of sex steroids in this context. This brief review surveys present knowledge of the sex differences in body composition, insulin sensitivity, and risk for development of type 2 diabetes mellitus derived from studies in humans and nonhuman primates. The influences of endogenous and exogenous gonadal steroids are emphasized.     

A Drosophila dopamine transporter mutant,fumin (fmn), is defective in arousal regulation

Sleep and Biological Rhythms - Physiologically, sleep is defined by electroencephalography, and typical REM and NREM sleep occur only in mammalian and avian species. But sleep-like inactive states...     

Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights

Sleep, circadian rhythm, and neurobehavioral performance measures were obtained in five astronauts before, during, and after 16-day or 10-day space missions. In space, scheduled rest-activity cycles were 20-35 min shorter than 24 h. Light-dark cycles were highly variable on the flight deck, and daytime illuminances in other compartments of the spacecraft were very low (5.0-79.4 lx). In space, the amplitude of the body temperature rhythm was reduced and the circadian rhythm of urinary cortisol appeared misaligned relative to the imposed non-24-h sleep-wake schedule. Neurobehavioral performance decrements were observed. Sleep duration, assessed by questionnaires and actigraphy, was only approximately 6.5 h/day. Subjective sleep quality diminished. Polysomnography revealed more wakefulness and less slow-wave sleep during the final third of sleep episodes. Administration of melatonin (0.3 mg) on alternate nights did not improve sleep. After return to earth, rapid eye movement (REM) sleep was markedly increased. Crewmembers on these flights experienced circadian rhythm disturbances, sleep loss, decrements in neurobehavioral performance, and postflight changes in REM sleep.     

Some indices of the activity of the brain in "rapid" sleep preceeded or not preceeded by delta-sleep]

In order to study the functional interaction between the delta sleep and the REM sleep some psychophysiological features of REM sleep were examined in REM-onset (without any preceding delta sleep--"early REM period") and in the REM period (REMP) terminating the normal sleep cycle (with the preceding delta sleep) of 92 daytime sleep attacks in 10 narcoleptic patients. Under these conditions the significant differences exist in the characteristics of the dream reports and in subjective estimations of sleep quality and duration. Sleep was evaluated as "superficial" and underestimations of sleep duration took place after an early REMP. Correct estimations of sleep duration and evaluations of sleep as "deep" dominated after REMP enging sleep cycles. The results obtained indicate the functional interaction between the delta sleep and REM sleep existing in the sleep cycle and largely determining the psychic content of the brain activity in the REM sleep.