Functional neuroanatomical correlates of eye movements during rapid eye movement sleep in depressed patients

In depressed patients, REM density, or the number of rapid eye movements (REMs) per minute of REM sleep, is a correlate of depression severity and clinical outcomes. We investigated the functional neuroanatomical correlates of average REM counts (RC), an automated analog of REM density, in depression. Thirteen medication-free depressed patients underwent all night polysomnography and positron emission tomography (PET) scans using [(18)F]fluoro-2-deoxy-d-glucose ([(18)F] FDG) during REM sleep. Regression analyses were conducted with Statistical Parametric Mapping (SPM-99). Average RC significantly and positively correlated with relative regional cerebral metabolic rate of glucose (rCMRglc) bilaterally in the striate cortex, the posterior parietal cortices, and in the medial and ventrolateral prefrontal cortices. Average RC were negatively correlated with rCMRglc in areas corresponding bilaterally to the lateral occipital cortex, cuneus, temporal cortices, and parahippocampal gyri. The areas where average RC was positively correlated with rCMRglc appear to constitute a diffuse cortical system involved in the regulation of emotion-induced arousal. The observed pattern of correlations suggests that average RC may be a marker of hypofrontality during REM sleep in depressed patients.     

Increased activation of anterior paralimbic and executive cortex from waking to rapid eye movement sleep in depression

BACKGROUND: Depression is associated with sleep disturbances, including alterations in rapid eye movement (REM) sleep, that may relate to the neurobiology of the disorder. Given that REM sleep activates limbic and anterior paralimbic cortex and that depressed patients demonstrate increases in electroencephalographic sleep measures of REM, we hypothesized greater activation of these structures during waking to REM sleep in depressed patients. DESIGN: Subjects completed electroencephalographic sleep and regional cerebral glucose metabolism assessments during both waking and REM sleep using [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography. SETTING: Patients and healthy subjects recruited from the general community to participate in a research study of depression at an academic medical center.Patients Twenty-four unmedicated patients who met the Structured Clinical Interview for DSM-IV criteria for current major depression and who had a score of 15 or higher on a 17-item Hamilton Rating Scale for Depression; 14 medically healthy subjects of comparable age and sex who were free of mental disorders. MAIN OUTCOME MEASURES: Electroencephalographic sleep, semiquantitative and relative regional cerebral metabolism during waking and REM sleep. RESULTS: Depressed patients showed greater REM sleep percentages. While both healthy and depressed patients activated anterior paralimbic structures from waking to REM sleep, the spatial extent of this activation was greater in the depressed patients. Additionally, depressed patients showed greater activation in bilateral dorsolateral prefrontal, left premotor, primary sensorimotor, and left parietal cortices, as well as in the midbrain reticular formation. CONCLUSIONS: Increased anterior paralimbic activation from waking to REM sleep may be related to affective dysregulation in depressed patients. Increased activation of executive cortex may be related to a cognitive dysregulation. These results suggest that altered function of limbic/anterior paralimbic and prefrontal circuits in depression is accentuated during the REM sleep state. The characteristic sleep disturbances of depression may reflect this dysregulation.     

Increased REM eye movement density in self-rated depression

Zung depression scores were positively related to eye movement density in a sample of 19 noncomplaining young adult males. The subjects were not clinically depressed and had average scores on the Depression Scale of the Minnesota Multiphasic Personality Inventory. There was no relation of Zung depression to rapid eye movement (REM) latency, stage 3 and stage 4 sleep, or REM in the first third of the sleep period. The finding is consistent with the hypothesis of a disinhibition or phase lead of REM sleep phasic events in depression.     

Rapid eye movement sleep characteristics during and after mood-disturbing events

Twenty-nine women undergoing divorce were monitored for six nights to explore the relation of mood disturbance and rapid eye movement (REM) sleep. Follow-up evaluations were completed on 13 women one to two years later. The more traditional women were more depressed and had shortened REM latencies. Depression was also related to an irregular eye movement density sequence throughout the night. Although depression and REM latency were both significantly improved at follow-up, the REM latency of those initially most depressed remained at a lower than normal level and the eye movement density sequency remained irregular, suggesting some lag in the sleep response or a traitlike vulnerability to future depression.     

抑郁症患者REM睡眠研究

目的：探讨抑郁症患者快眼动睡眠的异常改变以及与临床的相关性。方法：对１８例抑郁症患者和１９名正常对照者进行睡眠脑电图检查,并予以比较。结果;抑郁症患者出现明显的ＲＥＭ潜零碎 期缩短和ＲＥＭ密度增加,且与抑郁严重程度显著相关。结论：ＲＥＭ睡眠的潜伏期缩短和密度增加可作为抑郁症诊断中具有参考价值的生物学指标。     

Comparison between eye movement latency and REM sleep parameters in major depression

Alterations of sleep can be observed polysomnographically in approximately 90 percent of depressed patients. Most of the registered sleep abnormalities in depression also occur in other psychiatric disorders. Only some types of REM sleep alterations – short REM latency, increase of REM density and shortening of mean latency of eye movements – were reported as more specific for affective disorders. In the present study polysomnograms of 21 medication free patients with major depressive disorder (assessed with a structured interview for DSM-III-R and Hamilton Scale) and 21 healthy controls were analysed. REM latency (LREM), REM density (RD), latencies of eye movements (LEM) and mean latency of eye movements (M-LEM) were calculated for both groups. Depressed patients (compared with healthy controls) showed increased RD (38.2% vs. 28.2%, p < 0.0001), shortened M-LEM (35.7 s vs. 48.3 s, p < 0.04) and shortening of LEM in the 1st (28.9 s vs. 48.9 s, p < 0.007) and 4th (27.0 s vs. 59.1 s, p < 0.043) REM sleep periods. LREM was not shortened significantly in depressives (78.5 min vs. 91.3 min, ns). In healthy subjects a negative correlation between M-LEM and RD was found (rho = − 0.47, p < 0.03). Since in the current study depressed patients differed from healthy controls, especially concerning phasic activity during REM sleep, presented data support the essential role of REM density for the assessment of sleep in depression. As a quick and easy manner to compute measurement, M-LEM is suggested as additional parameter for the assessment of phasic activity during REM sleep. Received: 23 March 1999 / Accepted: 23 November 1999     

Sleep in depression: the influence of age,gender and diagnostic subtype on baseline sleep and the cholinergic REM induction test with RS 86

Summary One hundred and eight healthy controls and 178 patients with a major depressive disorder according to DSM-III were investigated in the sleep laboratory after a 7-day drug wash-out period. Subsamples of 36 healthy controls and 56 patients additionally took part in the cholinergic rapid eye movement (REM) sleep induction test with RS 86. Data analysis revealed that age exerted powerful influences on sleep in control subjects and depressed patients. Sleep efficiency and amount of slow wave sleep (SWS) decreased with age, whereas the number of awakenings, early morning awakening, and amounts of wake time and stage 1 increased with age. REM latency was negatively correlated with age only in the group of patients with a major depression. Statistical analysis revealed group differences for almost all parameters of sleep continuity with disturbed indices in the depressed group. Differences in SWS were not detected. REM latency and REM density were altered in depression compared to healthy subjects. Sex differences existed for the amounts of stage 1 and SWS. The cholinergic REM induction test resulted in a significantly more pronounced induction of REM sleep in depressed patients compared with healthy controls, provoking sleep onset REM periods as well in those depressed patients showing baseline REM latencies in the normal range. Depressed patients with or without melancholia (according to DSM-III) did not differ from each other, either concerning baseline sleep or with respect to the results of the cholinergic REM induction test. The results stress the importance of age when comparing sleep patterns of healthy controls with those of depressed patients. Furthermore they underline the usefulness of the cholinergic REM induction test for differentiating depressed patients from healthy controls and support the reciprocal interaction model of nonREM-REM regulation and the cholinergic-aminergic imbalance hypothesis of affective disorders.     

Reduced rapid eye movement sleep latency in patients with parkinson's disease

Summary Rapid eye movement (REM) sleep latency (time from sleep onset to the first REM episode) was measured in 39 patients with idiopathic Parkinson's disease. Reduced REM sleep latency (65.0 min) was found in a high proportion of patients (69%). Since reduced REM sleep latency may be a trait-like abnormality relatively specific to primary depression, we evaluated this parameter in two groups of parkinsonian patients: depressed (16 patients) and non-depressed (23 patients). Its incidence was significantly higher in depressed patients with Parkinson's disease.     

Children with major depression show reduced rapid eye movement latencies

A substantial body of research in adults has established that certain sleep polysomnographic abnormalities are commonly found in depressed patients, including sleep continuity disturbances, reduced slow-wave sleep, shortened rapid eye movement (REM) latency, and increased REM density. To date, these abnormalities have not been documented in depressed children compared with age-matched controls. Three consecutive nights of polysomnographic recordings were obtained in 25 hospitalized depressed children and 20 age-matched healthy controls. The depressed patients had reduced REM latencies. The shortest single-night REM latency of each individual was the most sensitive discriminating value between depressed subjects and controls. The influence of different scoring criteria in distinguishing depressed children from healthy children is discussed. In addition, depressed children had an increased sleep latency and increased REM time but did not have stage 4 differences.     

Forebrain activation in REM sleep: an FDG PET study

Rapid eye movement (REM) sleep is a behavioral state characterized by cerebral cortical activation with dreaming as an associated behavior. The brainstem mechanisms involved in the generation of REM sleep are well-known, but the forebrain mechanisms that might distinguish it from waking are not well understood. We report here a positron emission tomography (PET) study of regional cerebral glucose utilization in the human forebrain during REM sleep in comparison to waking in six healthy adult females using the ¹⁸F-deoxyglucose method. In REM sleep, there is relative activation, shown by increased glucose utilization, in phylogenetically old limbic and paralimbic regions which include the lateral hypothalamic area, amygdaloid complex, septal–ventral striatal areas, and infralimbic, prelimbic, orbitofrontal, cingulate, entorhinal and insular cortices. The largest area of activation is a bilateral, confluent paramedian zone which extends from the septal area into ventral striatum, infralimbic, prelimbic, orbitofrontal and anterior cingulate cortex. There are only small and scattered areas of apparent deactivation. These data suggest that an important function of REM sleep is the integration of neocortical function with basal forebrain-hypothalamic motivational and reward mechanisms. This is in accordance with views that alterations in REM sleep in psychiatric disorders, such as depression, may reflect dysregulation in limbic and paralimbic structures.     

Rapid eye movement density shows trends across REM periods but is uncorrelated with NREM delta in young and elderly human subjects

Saccade-like eye movements are the most prominent phasic component of rapid eye movement (REM) sleep. Eye movement density (EMD) appears to be negatively related to sleep depth. Thus, EMD is depressed by sleep deprivation. We sought to determine in 19 young normal (YN) and 19 elderly normal (EN) subjects: (a) whether EMD is correlated with delta EEG in baseline sleep; (b) whether EMD is increased by daytime naps; and (c) whether EMD patterns across sleep cycles differ in the two age groups. Subjects participated in four separate 2-day recording sessions, each consisting of a baseline night, a daytime nap, and post nap night. EMD was measured as 0.3-2 Hz integrated amplitude (IA)/20 s stage REM. EMD was not correlated with rate of non rapid eye movement (NREM) delta production (power/min) in the baseline sleep of either group. Changes in EMD and delta power/min on post nap nights also were uncorrelated. These data indicate that very strong changes in sleep depth (state) are required to overcome the individual stability (traits) of NREM delta and eye movement density. ANOVA for EMD across REM periods 1-4 showed a significant cycle effect and a significant age x cycle interaction. These effects were mainly due to YNs having depressed EMD in the first REM period, likely due to the low arousal level early in sleep in these subjects. Compared with waking saccades the saccade eye movements of REM sleep have received little investigation. Further study of these movements could shed new light on neurophysiology of REM sleep. Such studies might also be clinically useful because the density of these movements appears to be related to depression and (independently) to cognitive function in individuals with brain impairment.     

抑郁症患者可乐定快速眼运动睡眠抑制试验的对照研究

目的探讨重性抑郁症患者α2-肾上腺能受体功能状况。方法对15例重性抑郁症患者（抑郁症组）和15名正常人（正常对照组）分别进行多导睡眠脑电图检查。在第1个快速眼运动（REM）睡眠周期结束10min内,向所有被试者静脉注射可乐定（剂量按2mg/kg体重计算,并稀释于9ml生理盐水中）,比较两组的睡眠情况。结果可乐定注射前,抑郁症组的REM比例［（26.8±5.6）%］、REM次数［（6.8±1.2）次］及REM时间［（120.6±25.1）min］较正常对照组增加［分别为（19.2±3.3）%、（4.9±0.8）次、（78.8±14.4）min;P<0.05］,REM潜伏期缩短［（64.1±27.0）min,对照组为（96.1±27.0）min］;可乐定注射后,对两组非快速眼运动睡眠几乎无影响,而抑郁症组和对照组的REM比例［分别为（21.3±4.8）%和（13.6±2.7）%］、次数［分别为（5.3±1.2）次和（3.8±0.6）次］、时间［（101.0±24.0）min和（61.0±10.3）min］分别较注射前减少（P<0.05）,抑郁症组第1次和第2次REM间隔时间的差值小于正常对照组（P<0.01）;而两组REM潜伏期注射前后的差异均无显著性。提示抑郁症患者REM睡眠的可乐定反映较正常对照组迟钝。结论重性抑郁症患者可能存在α2-肾上腺能受体功能低下。     

Rapid eye movement sleep deprivation as a probe in elderly subjects

The effects of a 2-night rapid eye movement (REM) sleep deprivation (RSD) procedure on electroencephalographic sleep and mood were examined in 15 healthy elderly control subjects, 14 elderly patients with endogenous depression, and 15 patients with primary degenerative dementia. Compared with control subjects, both patient groups maintained a higher amount of REM sleep time and REM activity during RSD. Unexpectedly, depressed patients showed little rebound in visually scored or automated REM sleep measures following RSD, and they showed stability of REM activity temporal distribution from baseline to recovery conditions. This contrasted with the rebound in REM sleep activity seen in control subjects, and the more modest increase in demented patients. The RSD was fairly specific, with some impact on delta sleep during the procedure but not during recovery sleep. Mood ratings were unaffected by RSD. These findings demonstrated a greater plasticity of REM sleep regulation in the healthy elderly control subjects and suggested a higher REM "pressure" with a "ceiling effect" in depressed patients. Patients with dementia appeared to have an impaired capacity to respond to the challenge of RSD.     

The cholinergic rapid eye movement sleep induction test with RS-86. State or trait marker of depression?

Rapid eye movement (REM) sleep disinhibition at the beginning of the night is one of the most frequently described biologic abnormalities in depression. As REM sleep in animals and humans seems to be facilitated by cholinergic neuronal activity, it has been postulated that REM sleep disinhibition in depression is a consequence of cholinergic neuronal overactivity. The current study with the newly available cholinergic agonist RS-86, which is orally active, has a half-life of six to eight hours, and exhibits only minor peripheral side effects, supports this assumption. The application of this compound before sleep led to a significantly faster induction of REM sleep at the beginning of the night in patients with major depressive disorders compared with healthy subjects and patients with other nondepressive psychiatric diseases, such as eating disorders. Whereas 14 of 16 depressed patients displayed sleep-onset REM periods after the administration of RS-86, this happened only in three of the 16 healthy controls and in one of the 20 patients with other diagnoses. The increased susceptibility of REM sleep to cholinergic stimulation was limited to the state of depression and was not observed in a group of remitted depressed patients.     

Lithium carbonate: effects on sleep patterns of normal and depressed subjects and its use in sleep-wake pathology

The effects of lithium carbonate on sleep patterns have been investigated both acutely in normal and depressed subjects and chronically in depressed subjects. In normal subjects receiving lithium for two weeks total sleep time did not vary, REM sleep decreased and REM sleep latency increased. In depressed subjects, either on short therm therapy or on long term therapy stages 3 and 4 increased, REM sleep decreased, REM latency increased and REM activity/time spent asleep (an index of REM intensity per minute of sleep) decreased. Plasma lithium levels were negatively correlated with REM sleep percentage and positively correlated with REM sleep latency. Besides, it has been shown in one paper that short term therapy with lithium caused small but significant delays in the sleep-wake circadian rhythm. These effects are of interest in view of polygraphic sleep abnormalities found in affective disorders and possible circadian disturbances accounting for these abnormalities. Indeed lithium might act in correcting spezial sleep abnormalities and/or circadian disturbances. In addition to its predominant use for the prophylaxis of recurrent mania and depression, lithium carbonate has been proposed and tried in the prophylactic treatment of abnormally prolonged sleep episodes featuring the Kleine-Levin syndrome.     

Sleep and manipulations of the sleep-wake rhythm in depression

OBJECTIVE: Disturbed sleep is typical for most depressed patients and complaints about disordered sleep are the hallmarks of the disorder. Polysomnographic sleep research has demonstrated that besides impaired sleep continuity, sleep in depression is characterized by a reduction of slow wave sleep and a disinhibition of random eye movement (REM) sleep, with a shortening of REM latency, a prolongation of the first REM period and increased REM density. METHOD: Our own experimental work has focused on the reciprocal interaction hypothesis of non-REM and REM sleep regulation as a model to explain the characteristic features of depressed sleep. RESULTS: In agreement with the major tenet of this model, administration of cholinomimetics provoked shortened REM latency in healthy subjects and led to an even stronger REM sleep disinhibition in depressed patients. Manipulations of the sleep-wake cycle, such as sleep deprivation or a phase advance of the sleep period, alleviate depressive symptoms. CONCLUSION: These data indicate a strong bidirectional relationship between sleep, sleep alterations and depression.     

抑郁症和精神分裂症的快眼动睡眠研究

目的探讨抑郁症与精神分裂症的快眼动（ＲＥＭ）睡眠特征。方法用睡眠实验技术对正常受试者、抑郁症和精神分裂症患者各３０例进行多导睡眠图的通夜描录，并结合临床指标，对三组受试者的９项ＲＥＭ睡眠指标进行对照分析。结果抑郁症和精神分裂症有着不同的ＲＥＭ睡眠特征。抑郁症ＲＥＭ睡眠潜伏期（ＲＬ）缩短，ＲＥＭ活动度、强度、密度增高和睡眠次数增多，汉米尔顿抑郁量表分与ＲＬ呈负相关。精神分裂症ＲＥＭ睡眠指标个体间差异大，１０例患者睡眠图的觉醒阶段中发现ＲＥＭ睡眠的插入现象。结论研究抑郁症有异常ＲＥＭ睡眠指标，而ＲＬ则为反映抑郁程度的特殊指标；ＲＥＭ睡眠的插入代表了部分精神分裂症患者的电生理特征     

Diurnal variation in regional brain glucose metabolism in depression.

BACKGROUND: This study compared diurnal variation in mood and regional cerebral metabolic rate of glucose (rCMRglc) in depressed and healthy subjects. METHODS: Depressed and healthy subjects were investigated using [18F]-fluoro-deoxyglucose positron emission tomography scans during morning and evening wakefulness. All subjects completed subjective mood ratings at both times of day. Statistical parametric mapping was used to compare rCMRglc between the two groups across time of day. RESULTS: Depressed patients showed evening mood improvements compared with healthy subjects. Compared with healthy subjects, depressed patients showed smaller increases in rCMRglc during evening relative to morning wakefulness in lingual and fusiform cortices, midbrain reticular formation, and locus coeruleus and greater increases in rCMRglc in parietal and temporal cortices. Depressed patients had hypermetabolism in limbic-paralimbic regions and hypometabolism in frontal and parietal cortex at both times of day compared with healthy subjects. CONCLUSIONS: Variation in rCMRglc differs across times of day in depressed and healthy subjects. In depressed patients, evening mood improvements were associated with increased metabolic activity in ventral limbic-paralimbic, parietal, temporal, and frontal regions and in the cerebellum. This increased metabolic pattern during evening wakefulness may reflect partial normalization of primary and compensatory neural systems involved in affect production and regulation.     

Heart rate variability and cordance in rapid eye movement sleep as biomarkers of depression and treatment response

ObjectivesThe relevance of rapid eye movement (REM) sleep in affective disorders originates from its well-known abnormalities in depressed patients, who display disinhibition of REM sleep reflected by increased frequency of rapid eye movements (REM density). In this study we examined whether heart rate variability (HRV) and prefrontal theta cordance, both derived from REM sleep, could represent biomarkers of antidepressant treatment response.MethodsIn an open-label, case-control design, thirty-three in-patients (21 females) with a depressive episode were treated with various antidepressants for four weeks. Response to treatment was defined as a ≥50% reduction of HAM-D score at the end of the fourth week. Sleep EEG was recorded after the first and the fourth week of medication. HRV was derived from 3-min artifact-free electrocardiogram segments during REM sleep. Cordance was computed for prefrontal EEG channels in the theta frequency band during tonic REM sleep.ResultsHRV during REM sleep was decreased in depressed patients at week four as compared to controls (high effect size; Cohen's d > 1), and showed a negative correlation with REM density in both, healthy subjects and patients at week four. Further, the fourteen responders had significantly higher prefrontal theta cordance as compared to the nineteen non-responders after the first week of antidepressant medication; in contrast, HRV at week one did not discriminate between responders and non-responders.ConclusionsOur data suggest that HRV in REM sleep categorizes healthy subjects and depressed patients, whereas REM sleep-derived prefrontal cordance may predict the response to antidepressant treatment in depressed patients.     

Rapid eye movement sleep patterns of brain activation and deactivation occur within unique functional networks

Rapid eye movement (REM) sleep is a paradoxical state where the individual appears asleep while the electroencephalogram pattern resembles that of wakefulness. Regional differences in brain metabolism have been observed during REM sleep compared to wakefulness, but it is not known whether the spatial distribution of metabolic differences corresponds to known functional networks in the brain. Here, we use a combination of techniques to evaluate the networks associated with sites of REM sleep activation and deactivation from previously published positron emission tomography studies. We use seed‐based functional connectivity from healthy adults acquired during quiet rest to show that REM‐activation regions are functionally connected in a network that includes retrosplenial cingulate cortex, parahippocampal gyrus, and extrastriate visual cortices, corresponding to components of the default mode network and visual networks. Regions deactivated during REM sleep localize to right‐lateralized fronto‐parietal and salience networks. A negatively correlated relationship was observed between REM‐activation and deactivation networks. Together, these findings show that regional activation and deactivation patterns of REM sleep tend to occur in distinct functional connectivity networks that are present during wakefulness, providing insights regarding the differential contributions of brain regions to the distinct subjective experiences that occur during REM sleep (dreaming) relative to wakefulness.