Modifying oculomotor activity in awake subjects increases the amplitude of eye movements during REM sleep.

The eye movements of human subjects were experimentally modified while they were awake to determine the effect of waking experience on electroculographic activity during rapid eye movement (REM) sleep. After normal eye movements were monitored under controlled conditions, subjects spent 5 days wearing goggles that contained minification lenses and that curtailed vision to a 5 degree field. The amplitude and frequency of eye movements decreased when subjects were awake and increased during REM sleep; sleep stage durations and distributions were unaffected. Values returned to normal in the first 24 hours of recovery.

Rapid eye movement sleep PGO-type waves are present in the dorsal pons of the albino rat.

We have found rapid eye movement sleep central phasic activity in the form of episodic, repetitive, monophasic waves in the albino rat. This activity is recorded in discrete areas of the dorso-lateral pons, including the nucleus locus ceruleus. The vast majority of these waves occur during rapid eye movement sleep. Their distribution and electrophysiological characteristics are similar to those of ponto-geniculo-occipital waves in the cat.

Spontaneous middle ear muscle activity in man: a rapid eye movement sleep phenomenon.

Changes in compliance of the tympanic membrane have been detected in normal human sleep, presumably due to spontaneous contraction of the stapedius and tensor tympani muscles of the middle ear. In the waking state, these muscles generally respond to loud sound (middle ear reflex). Middle ear muscle activity typically erupts before or at the onset of rapid eye movement (REM) sleep and persists throughout the REM period in a discontinuous pattern resembling that exhibited by rapid eye movements. Approximately 80 percent of all nocturnal middle ear muscle activity is contained in REM sleep. Half of the remaining 20 percent occurs in the 10-minute intervals just prior to the onset of REM sleep. Middle ear muscle activity is often associated with other phasic events such as momentary enhancement of electromyogram inhibition, apnea, and K complexes. Rapid eye movements and middle ear muscle activity, though significantly correlated in REM sleep, are not always simultaneous.

Rapid eye movement sleep deprivation decreases long-term potentiation stability and affects some glutamatergic signaling proteins during hippocampal development.

Development of the mammalian CNS requires formation and stabilization of neuronal circuits and synaptic connections. Sensory stimulation provided by the environment orchestrates neuronal circuit formation in the waking state. Endogenous sources of activation are also implicated in these processes. Accordingly we hypothesized that sleep, especially rapid eye movement sleep (REMS), the stage characterized by high neuronal activity that is more prominent in development than adulthood, provides endogenous stimulation, which, like sensory input, helps to stabilize and refine neuronal circuits during CNS development. Young (Y: postnatal day (PN) 16) and adolescent (A: PN44) rats were rapid eye movement sleep-deprived (REMSD) by gentle cage-shaking for only 4 h on 3 consecutive days (total 12 h). The effect of REMS deprivation in Y and A rats was tested 3-7 days after the last deprivation session (Y, PN21-25; A, PN49-53) and was compared with younger (immature, I, PN9-12) untreated, age-matched, treated and normal control groups. REMS deprivation negatively affected the stability of long-term potentiation (LTP) in Y but not A animals. LTP instability in Y-REMSD animals was similar to the instability in even the more immature, untreated animals. Utilizing immunoblots, we identified changes in molecular components of glutamatergic synapses known to participate in mechanisms of synaptic refinement and plasticity. Overall, N-methyl-d-aspartate receptor subunit 2B (NR2B), N-methyl-d-aspartate receptor subunit 2A, AMPA receptor subunit 1 (GluR1), postsynaptic density protein 95 (PSD-95), and calcium/calmodulin kinase II tended to be lower in Y REMSD animals (NR2B, GluR1 and PSD-95 were significantly lower) compared with controls, an effect not present in the A animals. Taken together, these data indicate that early-life REMS deprivation reduces stability of hippocampal neuronal circuits, possibly by hindering expression of mature glutamatergic synaptic components. The findings support a role for REMS in the maturation of hippocampal neuronal circuits.

Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep.

Plasma luteinizing hormone (LH) and testosterone (T) were measured by radioimmunoassay in nine pubertal boys and three sexually mature young men at 20-min intervals for 24 h. Plasma LH and T were also measured in one boy during a delayed sleep onset study. Polygraphic monitoring was carried out to identify precisely sleep onset. Wakefulness, and specific sleep stages. In all nine pubertal boys the plasma T concentration fluctuated and was significantly higher during normal nocturnal sleep as compared to daytime waking. This increased T secretion during sleep was temporally linked to the characteristic pubertal sleep augmentation of LH secretion. To define further the relationship of this increased T secretion to sleep, plasma LH and T were also measured in three of the pubertal boys after acute (1-day) reversal of the sleep-wake cycle. One of these boys was also studied after 3 days of sleep-wake cycle reversal. The results of these studies showed that plasma T was now augmented during the reversed daytime sleep period; the mean T concentrations during this period were significantly higher (P < 0.001) than during nocturnal waking in all four studies. Measurement of plasma LH and T in the three sexually mature young men showed episodic secretion of LH and T during both waking and sleep periods; there was no consistent significant augmentation of LH or T secretion during sleep. This study demonstrates that (a) in normal pubertal boys and sexually mature young men plasma T fluctuates episodically; (b) there is marked augmentation of T secretion during sleep in pubertal boys, which is dependent on increased LH secretion; (c) this pubertal LH-T secretory "program" is dependent on sleep, since it shifts with delayed sleep onset and reversal of the sleep-wake cycle; and (d) this demonstrable tropic effect of LH on T is evident only during puberty, since sexually mature young men fail to show any consistent relationship between LH and T secretion either awake or asleep.

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.

Alprazolam vs amitriptyline in depressions with reduced REM latencies.

This study was designed to compare the antidepressant effects of alprazolam, a triazolobenzodiazepine, with amitriptyline hydrochloride in a group of patients with nonpsychotic, major depressions diagnosed by Research Diagnostic Criteria. A mean rapid eye movement latency of less than 65 minutes was required to enter this study. Dexamethasone suppression tests were conducted before treatment. By strictly applied Research Diagnostic Criteria, 83.6% of the subjects were endogenous, and 34.7% were inpatients. A significantly greater percentage of alprazolam-treated patients responded within the first seven days of treatment. By the end of this six-week trial, alprazolam was associated with significant reductions in Hamilton, Beck, Covi, Raskin, and Carroll Rating scores (pretreatment to posttreatment). However, by the end of treatment the effects of amitriptyline exceeded those of alprazolam on both the Hamilton and Beck scales. These data indicate that alprazolam is not as effective as amitriptyline in major depressions with a shortened rapid eye movement latency.

Polysomnographic findings in recently drug-free and clinically remitted depressed patients.

Thirteen patients were examined by sleep polysomnograph (PSG) and the dexamethasone suppression test when clinically depressed and later when clinically remitted for six months and no longer receiving antidepressant medication for two to five weeks. None of the PSG variables (rapid eye movement [REM] latency, total sleep time, stage 1 through 4 times, REM time, and REM densities in periods 1 through 3) was significantly changed between symptomatic depression and symptom remission. While symptomatic, 11 of 13 patients exhibited a reduced REM latency (65 minutes or less). After clinical remission, eight of the 11 continued to exhibit reduced REM latencies, whereas the dexamethasone suppression test tended to show nonsuppression only during clinical depression. These data represent either longer-term (ie, slow to normalize) biologic consequences of a depressive episode or biologic antecedents of clinical depression that may herald a return of the depression in individuals vulnerable to recurrence. Whether PSG abnormalities identify clinically remitted patients who are prone to develop another depressive episode requires longitudinal follow-up studies.

A cross-sectional study of the effects of depression on REM latency.

In a cross-sectional design to address the effects of the course of depression on rapid-eye-movement (REM) latency, we have matched patients in their first-episode with (1) age-matched patients with recurrent depression, (2) onset-matched patients with recurrent depression, and (3) age-matched normal control subjects. Patients were also matched for sex and treatment site (inpatient or outpatient). No differences were found in REM latency for the three depressed groups, and all had lower REM latency than normals. This finding is taken as support for stable REM latency throughout the course of depression.

Sleep EEG and dexamethasone suppression test findings in outpatients with unipolar major depressive disorders.

The dexamethasone suppression test (DST) and sleep EEG were compared in three different descriptive diagnostic schemes in 70 adult patients with nonpsychotic, unipolar major depressive disorder according to Research Diagnostic Criteria. Endogenous (E)/nonendogenous (NE), primary/secondary, and Winokur's family history subtypes were evaluated. The E/NE subclassification was best supported by both biological measures. The DST provided a highly specific (95%), relatively accurate measure (confidence interval of 87%), although its sensitivity was rather low (41%) in this largely outpatient sample. A REM latency of 62 min or less provided a more sensitive (66%) but less specific (79%) indicator of E depression. Stage 4 time and age may add to the information provided by REM latency alone in identifying E patients.

Age-adjusted threshold values for reduced REM latency in unipolar depression using ROC analysis.

To determine an age-adjusted, clinically meaningful depressive diathesis, we have implemented Receiver Operator Characteristic (ROC) analysis for mean rapid eye movement (REM) latency in patients with unipolar depression. Depressed patients were compared with age-matched normal control subjects. Sensitivity and specificity estimates were calculated for selected threshold values on the ROC curves as well as for the Research Diagnostic Criteria endogenous/nonendogenous subtype. The mean REM latency value of 65.0-66.0 min was most sensitive and specific for depressed patients aged 35-72. The threshold value of 70.0 min appeared optimally sensitive and specific for depressed patients aged 20-34. There was no effect of age on REM latency in the normal control sample. Among depressed patients there was an effect of age but this was clearly observable only in nonendogenous depressed patients.

Which endogenous depressive symptoms relate to REM latency reduction?

In most research dealing with biological abnormalities in depression, the clinical diagnosis of depression is made and the occurrence of a biological abnormality, for example, reduced REM latency, is documented. In this study, that design was reversed; REM latency was used as a grouping variable to assess empirically the "biological" priority of Research Diagnostic Criteria endogenous symptoms. We found that terminal insomnia, pervasive anhedonia, unreactive mood, and appetite loss were most likely to discriminate among "reduced" and "nonreduced" REM latency depressions at various threshold values. Contrary to expectation, diurnal mood variation was found equivalently in all categories of REM latency studied. Implications for clinical decision making based on endogenous symptoms are discussed.

Sleep EEG features of adolescents with major depression.

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 the findings in depressed adolescents are equivocal. Three consecutive nights of polysomnographic recordings were obtained in 31 hospitalized depressed adolescents and 17 age-matched normal controls. The depressed adolescents had a shorter REM latency, shorter sleep latency, more REM sleep, and less stage 3 nonREM (NREM) sleep. There was a trend for melancholic and suicidal patients to have a shorter REM latency.

Polysomnographic findings and dexamethasone nonsuppression in unipolar depression: a replication and extension.

To evaluate the replicability of our previous findings of increased incidence of biological dysregulation in endogenous depression, we have studied a new series of patients with major depressive disorder, unipolar type (n = 103). The subtypes compared were defined by Research Diagnostic Criteria and were endogenous/nonendogenous, primary/secondary, and Winokur's family history classification. As an extension of the research, we evaluated the endogenous subtype more precisely by distinguishing those patients who met criteria for probable endogenous, comparing them to both endogenous and nonendogenous depressed patients. The findings of the replication study were consistent with our earlier report; the incidence of both dexamethasone nonsuppression and reduced rapid eye movement (REM) latency was higher in those with endogenous depression. Findings for each of the other subtypes revealed no differences. The probable endogenous depressed patients were comparable to the nonendogenous depressed patients in all variables measured.

Dexamethasone response, thyrotropin-releasing hormone stimulation, rapid eye movement latency, and subtypes of depression.

Most prior studies of mood disorders have used a single laboratory test to assist in differential diagnosis, prediction of treatment response, and prediction of relapse. This study compared three laboratory measures in a combined in- and outpatient sample of depressed patients. Dexamethasone suppression test (DST) nonsuppression occurred in 46% of patients with endogenous major depression, in 15% with nonendogenous major depression, and in 56% with bipolar, depressed phase disorder. A blunted thyrotropin-releasing hormone stimulation test (TRH-ST) occurred in 25% of patients with endogenous, 10% with nonendogenous, and 44% with bipolar, depressed phase disorder. Reduced REM latency was found in 65% of endogenous major depressions, in 34% of nonendogenous major depressions, and in 53% of bipolar, depressed phase disorders. Fifty-one percent of those with reduced REM latency also evidenced DST nonsuppression. When the endogenous major depression and bipolar, depressed phase groups were combined, 28% had no laboratory abnormality, whereas 8% evidenced all three. These findings suggest that 1) endogenous/nonendogenous unipolar groups are distinguished by all three laboratory tests; 2) most patients with a blunted TRH-ST also evidence DST nonsuppression; and 3) one half of patients with reduced REM latency evidence DST nonsuppression. Sensitivity is greatest and specificity is lowest for REM latency, followed by the DST and then the TRH-ST.

Digital period analysis of sleep EEG in depression.

The period-analyzed sleep electroencephalogram (EEG) was compared in a group of 9 depressed outpatients and 9 age-matched normal controls. Both groups showed rhythms in beta, delta, and theta activity with an approximately 90-min period. The phase and coherence between fast and slow frequency EEG measures, however, differed significantly in the two groups. Beta and delta rhythms were less coherent in the depressed outpatient sample. The control group showed higher coherence and a strong coupling of beta and delta activity. These preliminary data suggest that depression may be associated with some degree of ultradian rhythm disturbances though periodicity is unaffected.

Reduced REM latency predicts response to tricyclic medication in depressed outpatients.

Forty-two outpatients with major depressive disorder entered a double-blind, randomized trial of either desipramine or amitriptyline for a minimum of 6 weeks. Pretreatment polysomnographic and clinical measures were used to predict response. Response was defined as a 17-item Hamilton Rating Scale for Depression score less than or equal to 9 at the end of treatment. There was a 61.1% response rate for patients treated with amitriptyline and a 66.7% response rate for patients treated with desipramine. Reduced REM latency (2-night mean less than or equal to 65.0 min) predicted a positive response to these tricyclic antidepressants. REM latency did not differentiate between desipramine or amitriptyline responders. More patients with reduced REM latency (80%) responded to treatment compared with patients with nonreduced REM latency (50%). The 80% response rate in reduced REM latency depressed patients confirms our previous findings in a mixed inpatient and outpatient sample. Contrary to our hypothesis, in this sample, endogenous depression was not associated with a good response to tricyclic medication.

Sleep EEG findings in depressed children and adolescents.

Sleep polysomnographic data on 17 juveniles (age 9 to 14) with major depression revealed abnormalities similar to those in depressed adults.

Controlled comparison of electrophysiological sleep in families of probands with unipolar depression.

OBJECTIVE: This study presents polysomnographic data and psychiatric history for parents and siblings of probands with unipolar depression and short REM latency, probands with unipolar depression and normal REM latency, and normal comparison probands. METHOD: Parents and adult siblings (N = 252) of probands (N = 64) were evaluated for lifetime history of psychiatric disorders and were studied in the sleep laboratory for 3 nights. RESULTS: REM latency predicted lifetime history of major depression. Short REM latency was also associated with slow wave sleep deficits. Rate of short REM latency in relatives of depressed probands with short REM latency quadrupled the rate in relatives of both depressed probands with normal REM latency and normal probands. Lifetime risk of depression was almost twice as high in relatives of depressed probands with short REM latency as in relatives of depressed probands with normal REM latency. CONCLUSIONS: Short REM latency and slow wave sleep deficits are familial. Short REM latency is associated with increased risk of major depression beyond the familial risk associated with a depressed proband. Polysomnographic abnormalities also occurred in unaffected relatives. Although the data can be considered only suggestive, these findings indicate that polysomnographic abnormalities may precede the clinical expression of depression and may be useful in identifying those at highest risk for the illness.

Reduced rapid eye movement latency. A predictor of recurrence in depression.

In this longitudinal study of 25 successfully treated depressed patients, rapid eye movement (REM) latency during an episode of depression was evaluated as a predictor of recurrence. Patients with reduced REM latency prior to treatment were more likely to develop another episode of depression during the follow-up period.