REM sleep as a potential indicator of hyperarousal in psychophysiological and paradoxical insomnia sufferers.

STUDY OBJECTIVES: The objective was to study REM sleep macrostructure and microstructure as potential indicators of hyperarousal in insomnia by comparing good sleepers (GS) and insomnia sufferers (INS) (subdivided into psychophysiological "PSY-I" and paradoxical "PARA-I"). DESIGN: Cross-sectional comparisons of GS, PSY-I and PARA-I. SETTING: Participants slept for 4 consecutive nights in the laboratory where PSG was recorded. Nights 2 and 3 were combined to compare REM sleep between groups. PARTICIPANTS: Thirty-nine PSY-I, 27 PARA-I and 47 GS completed the study, comprising home questionnaires, clinical interviews and night PSG recordings. All participants were aged between 25 and 55 and met inclusion criteria for either PSY-I, PARA-I or GS. INTERVENTIONS N/A MEASUREMENTS AND RESULTS: Results showed no between group differences on REM sleep macrostructure. As for REM sleep microstructure, PSY-I had an increased number of wake intrusions compared to PARA-I (p=.03). Subjective SE, TST and TWT were significantly correlated with the duration of REM sleep (REMD; p≤.002) and with the proportion of REM sleep for PARA-I (p≤.06). CONCLUSIONS: REM sleep macrostructure does not seem to be an adequate indicator of hyperarousal in insomnia. However, the number of wake intrusions in REM could be used to differentiate PSY-I from PARA-I and could reflect the heightened arousal of the former group. Relationships between REM sleep duration and proportion could be linked to dream imagery activity, especially in PARA-I. Further investigations are needed to identify variables that could reflect hyperarousal and differentiate insomnia types.

Types of primary insomnia: is hyperarousal also present during napping?

STUDY OBJECTIVES: The objective of this study was to identify if hyperarousal is a 24-hour phenomenon in insomnia by comparing sleep during napping between good sleepers (GS) and Insomnia sufferers (INS) (subdivided into paradoxical "PARA-I" and psychophysiological "PSY-I") following a mentally challenging battery of cognitive tests. DESIGN: Cross-sectional comparisons of GS, PSY-I, and PARA-I. SETTING: Participants slept for 4 consecutive nights in the laboratory where PSG was recorded. Upon awakening on mornings 2 and 3, cognitive testing (lasting 90-120 min) was administered, followed by a 20-minute nap. PARTICIPANTS: Fourteen PSY-I, 12 PARA-I, and 23 GS completed the study, comprising home questionnaires, clinical interviews, night PSG recordings, cognitive testing, and nap PSG recordings. All participants were between 25 and 50 years of age and met inclusion criteria for PSY-I, PARA-I, or GS. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: On objective nap parameters, GS had a longer total sleep time (TST; p = 0.008) and better sleep efficiency (SE; p = 0.009), than PSY-I and PARA-I, and both groups of INS were awake significantly longer than GS (p = 0.003). Also, PARA-I took significantly more time than GS to fall asleep (p = 0.014). Subjectively reported sleepiness was comparable across the three groups. Positive relationships were observed between SE over the night and SE over the nap the following day. CONCLUSIONS: Results show that GS sleep better than INS during naps following prolonged cognitive testing, suggesting that, in INS, hyperarousal predominates over mental fatigue resulting from these tests. These results may parallel what is observed at night when INS experience increased cognitive load but are unable to fall asleep.

REM and NREM power spectral analysis on two consecutive nights in psychophysiological and paradoxical insomnia sufferers.

The objectives of the study were to examine EEG activities using power spectral analysis (PSA) of good sleepers (GS), psychophysiological (PsyI) and paradoxical (ParI) insomnia sufferers on two consecutive nights. Participants completed three nights of PSG recordings in a sleep laboratory following a clinical evaluation. Participants were 26 PsyI, 20 ParI and 21 GS (mean age=40 years, SD=9.4). All sleep cycles of Nights 2 and 3 were retained for PSA. The absolute and relative activity in frequency bands (0.00 to 125.00 Hz) were computed at multiple frontal, central and parietal sites in REM and NREM sleep. Mixed model ANOVAs were performed with absolute and relative PSA data to assess differences between groups and nights. Over the course of the two nights, more absolute delta activity at F3, C3, and P3 was observed in ParI compared with PsyI suggesting deactivation of the left hemisphere in ParI and/or hyperactivation in PsyI. Further analysis on absolute PSA data revealed that differences between groups relate mostly to NREM. In REM, lower relative activity in slower frequency bands was found in ParI in comparison with GS and less relative theta activity was found in PsyI compared with GS implying higher activation in insomnia. In addition, between nights variability has been found in absolute powers of faster frequency bands (beta to omega). Signs of decreased cortical activity in absolute PSA in NREM combined with increased relative cortical activation in REM were found in ParI which might contribute to the misperception of sleep in ParI.

Information processing varies between insomnia types: measures of N1 and P2 during the night.

This study compared cortical arousal mechanisms during the night using event-related potentials (N1 and P2), and compared sleep misperception in 30 adults with psychophysiological insomnia (Psy-I), 28 adults with paradoxical insomnia (Para-I), and 30 good sleepers (GS). Participants (age range = 25-55 years) spent 4 consecutive nights in the laboratory, and Night-4 data were used for analysis. N1 amplitude was generally larger in both insomnia groups compared to GS, and P2 amplitude was larger in Para-I than in the 2 other groups, especially in REM sleep. Results suggest that, although hyperarousal appears to persist during sleep in adults with insomnia, inhibition deficits are more likely to be present in Para-I compared to Psy-I.

Cerebral asymmetry in insomnia sufferers.

Cerebral asymmetry is used to describe the differences in electroencephalographic activity between regions of the brain. The objective of this study was to document frontal, central, and parietal asymmetry in psychophysiological (Psy-I) and paradoxical (Para-I) insomnia sufferers as well as good sleeper (GS) controls, and to compare their patterns of asymmetry to others already found in anxiety and depression. Additionally, asymmetry variations between nights were assessed. Participants were 17 Psy-I, 14 Para-I, and 19 GS (mean age = 40 years, SD = 9.4). They completed three nights of polysomnography (PSG) recordings following a clinical evaluation in a sleep laboratory. All sleep cycles of Nights 2 and 3 were retained for power spectral analysis. The absolute activity in frequency bands (0.00-125.00 Hz) was computed at multiple frontal, central, and parietal sites in rapid eye movement and non-rapid eye movement sleep to provide cerebral asymmetry measures. Mixed model ANOVAs were computed to assess differences between groups and nights. Correlations were performed with asymmetry and symptoms of depression and anxiety from self-reported questionnaires. Over the course of the two nights, Para-I tended to present hypoactivation of their left frontal region but hyperactivation of their right one compared with GS. As for Psy-I, they presented increased activation of their right parietal region compared with Para-I. Asymmetry at frontal, central, and parietal region differed between nights. On a more disrupted night of sleep, Psy-I had increased activity in their right parietal region while Para-I presented a decrease in cerebral activity in the right central region on their less disrupted night of sleep. Anxious and depressive symptoms did not correlate with asymmetry at any region. Therefore, Psy-I and Para-I present unique patterns of cerebral asymmetry that do not relate to depression or anxiety, and asymmetry varies between nights, maybe as a consequence of variability in objective sleep quality from night to night.

Are individuals with paradoxical insomnia more hyperaroused than individuals with psychophysiological insomnia? Event-related potentials measures at the peri-onset of sleep.

Preliminary QEEG studies suggest that individuals with paradoxical insomnia (Para-I) display higher cortical arousal than those with psychophysiological insomnia (Psy-I). Lately, finer measures, such as event-related potentials, and especially the N1 and P2 components have been used to document arousal processes in individuals with insomnia. The objective of the present study was to further circumscribe arousal in Psy-I and Para-I using N1, P2 and the waking processing negativity (wPN). N1 and P2 were recorded in the evening, at sleep-onset and in early stage 2 sleep in 26 good sleepers, 26 Psy-I and 26 Para-I. An oddball paradigm was used and participants received the instruction to ignore all stimuli at all times. Three difference waves (wPNs) were computed to evaluate the transition from wakefulness to sleep onset, from sleep onset to sleep and from wakefulness to sleep. Results revealed that N1 was smaller during wakefulness and sleep onset for Psy-I, while it was larger for Para-I during these same times. P2 was smaller at sleep onset for Psy-I than for Para-I and GS, while P2 during wakefulness and stage 2 sleep was larger for Para-I than GS. WPNs revealed that Psy-I showed fewer changes in information processing, while Para-I showed larger changes between recording times. Psy-I appear to present an inability to inhibit information processing during sleep onset, while Para-I seem to present overall enhanced attentional processing that results in a greater need for inhibition.

Earlier onset of delta-retrovirus-induced leukemia after splenectomy.

Infection by delta-retroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) is mostly asymptomatic. Indeed, only a minority (<5%) of delta-retrovirus infected hosts will develop either lymphoproliferative or neurodegenerative diseases after long latency periods. In fact, the host immune response is believed to tightly control viral replication but this assumption has not been definitely proven in vivo. Here, we provide direct experimental evidence demonstrating that integrity of the spleen is required to control pathogenesis. In the BLV model, we show that asplenia decreases efficiency of the immune response and induces an imbalance in cell dynamics resulting in accelerated onset of leukemia. These observations enlighten a potential threat in splenectomized HTLV-1 carriers and justify a regular preventive evaluation.

Spontaneous K-complexes in chronic psychophysiological insomnia.

OBJECTIVE: Spontaneous K-complexes are electroencephalographic features unique to non-rapid eye movement sleep. It has been suggested that this phasic event is a sleep-protective mechanism. Because insomnia sufferers report poor sleep quantity and quality, the objective of this study was to document the occurrence of spontaneous K-complexes in Stage 2 sleep of individuals with chronic insomnia. Specifically, the number and density of spontaneous K-complexes were studied in psychophysiological insomnia sufferers. SETTING: This study took place in a sleep and event-related potentials laboratory. DESIGN: Spontaneous K-complexes were scored during Stage 2 sleep on the second and third nights of a four-consecutive-nights protocol of polysomnographic recordings. PARTICIPANTS: The sample included 14 participants suffering from psychophysiological insomnia (INS group; mean age=44.1 years) and 14 good sleepers (mean age=38.1 years). Participants underwent sleep and psychological evaluations. INS group participants met the diagnostic criteria for primary psychophysiological insomnia (mean duration of insomnia=9.6 years). INTERVENTION: Not applicable. RESULTS: The total number of spontaneous K-complexes and the density according to the total time spent in Stage 2 sleep (spontaneous K-complexes per minute) were compiled. Repeated-measures analyses of variance showed no significant difference in the number and density of spontaneous K-complexes between the INS group (313.98 and 2.66) and the GS group (361.10 and 2.88), respectively. CONCLUSION: These results suggest no deficiency in the sleep-protective mechanism of psychophysiological insomnia sufferers in comparison with good sleepers, as measured by the spontaneous K-complexes' number and density.

Sleep spindles in chronic psychophysiological insomnia.

OBJECTIVE: A sleep spindle is an electroencephalographic feature that is unique to sleep. It has been suggested that this phasic event has a sleep-protective function. The objective of the present study was to document one aspect of sleep protection in chronic insomnia sufferers: the number and density of sleep spindles in Stage 2 sleep. METHODS: Sleep spindles were scored during Stage 2 sleep on the second and third nights of a protocol of polysomnographic recordings that lasted for four consecutive nights. The sample included 16 participants suffering from insomnia (INS group; mean age=43.4 years) and 14 good sleepers (GS group; mean age=38.1 years). Participants underwent sleep and psychological evaluations. The INS group participants met the diagnostic criteria for primary psychophysiological insomnia (mean duration of insomnia=9.6 years). RESULTS: The total number of sleep spindles in Stage 2 sleep and the density (sleep spindles per minute) according to the total time spent in Stage 2 sleep were compiled. Repeated-measures analyses of variance showed no significant difference in the number and in the density of sleep spindles between the INS group (68.46 and 0.60, respectively) and the GS group (56.28 and 0.46, respectively). CONCLUSION: These results suggest no deficiency in the sleep-protection mechanism of psychophysiological insomnia sufferers in comparison with good sleeper controls, as measured by the number and density of sleep spindles.

Signs of insomnia in borderline personality disorder individuals.

STUDY OBJECTIVES: Recent findings suggest few differences in sleep continuity and quality between borderline personality disorder individuals (BPD-I) and good sleepers (GS). Nonetheless, BPD-I show marked discrepancies between subjective and objective sleep measures. The objective of this study was to document sleep in BPD-I, GS, and insomnia sufferers (paradoxical, Para-I; psychophysiological, Psy-I). PARTICIPANTS: Twelve BPD-I (mean age 33.3 years), 15 GS (mean age 34.1 years), 15 Para-I (mean age 41.1 years), and 15 Psy-I (mean age 36.6 years). METHODS: Participants underwent 3 consecutive nights of polysomnography recordings. All participants completed a clinical interview and 2 weeks of sleep diaries. BPD-I received DIB-R assessment. Participants were not suffering from any other psychopathology and were drug free. RESULTS: Subjectively, BPD-I and GS laboratory sleep reports were similar. However, Psy-I and Para-I took longer to fall asleep, were awake longer after sleep onset and during the night, slept less, and had lower sleep efficiency than both GS and BPD-I (p < 0.05). Objectively, BPD-I, Psy-I, and Para-I had longer sleep onset, shorter sleep time, and lower sleep efficiency on all 3 nights than GS (p < 0.05). Furthermore, BPD-I had more stage 4 (both in proportion and time) than Para-I on all 3 nights (p < 0.05). CONCLUSION: Results suggest that BPD-I suffer from insomnia. While BDI-I reported feeling less refreshed upon awakening, they spent more time in stage 4 than other individuals. As BPD-I are very sensitive to loneliness and interpersonal stressors, laboratory settings might provide a secure context facilitating sleep.

Chronic psychophysiological insomnia: hyperarousal and/or inhibition deficits? An ERPs investigation.

STUDY OBJECTIVES: Chronic primary insomnia has been hypothesized to result from conditioned arousal or the inability to initiate normal sleep processes. The event-related potentials (ERPs) N1, P2, and N350 are useful indexes of arousal. The objective is to compare these ERPs in primary chronic psychophysiological insomniacs (INS) and good sleepers (GS) during multiple recordings. PARTICIPANTS: Participants were 15 INS (mean age = 46 years, SD = 7.5) and 16 GS (mean age = 37 years, SD = 10.1). METHODS AND PROCEDURE: Following a multistep clinical evaluation, INS and GS participants underwent 4 consecutive nights of PSG recordings (N1 to N4). ERPs were recorded on the 3rd and 4th nights in the sleep laboratory (N3 and N4). ERPs recordings were made during wake on both nights (in the evening and upon awakening), with the addition of sleep-onset recordings on N4. Auditory stimuli consisted of "standard" and "deviant" tones. STATISTICAL ANALYSIS: Repeated measures ANOVAs were computed for each ERP for each recording for each type of stimulus. RESULTS: The amplitude of P2 and N350 was greater for the deviant than for the standard stimulus in both groups. The amplitude of N1 was larger in INS than GS in the morning and the evening. While the amplitude of N350 was larger in GS than in INS at sleep onset, the amplitude of P2 was greater in INS than in GS at that time. CONCLUSION: Signs of greater cortical arousal in psychophysiological insomnia individuals are observed, especially upon awakening in the morning. However, at sleep onset, difficulties from disengaging from wake processes and some inability at initiating normal sleep processes appear also present in individuals with insomnia compared to good sleepers.

Cell dynamics and immune response to BLV infection: a unifying model.

Bovine Leukemia virus (BLV) is the natural etiological agent of a lymphoproliferative disease in cattle. BLV can also be transmitted experimentally to a related ruminant species, sheep, in which the pathogenesis is more acute. Although both susceptible species develop a strong anti-viral immune response, the virus persists indefinitely throughout life, apparently at a transcriptionally silent stage, at least in a proportion of infected cells. Soon after infection, these humoral and cytotoxic activities very efficiently abolish the viral replicative cycle, permitting only mitotic expansion of provirus-carrying cells. Short term cultures of these infected cells initially indicated that viral expression protects against spontaneous apoptosis, suggesting that leukemia is a process of accumulation of long-lived cells. This conclusion was recently reconsidered following in vivo dynamic studies based on perfusions of nucleoside (bromodeoxyuridine) or fluorescent protein markers (CFSE). In sheep, the turnover rate of infected cells is increased, suggesting that a permanent clearance process is exerted by the immune system. Lymphocyte trafficking from and to the secondary lymphoid organs is a key component in the maintenance of cell homeostasis. The net outcome of the immune selective pressure is that only cells in which the virus is transcriptionally silenced survive and accumulate, ultimately leading to lymphocytosis. Activation of viral and/or cellular expression in this silent reservoir with deacetylase inhibitors causes the collapse of the proviral loads. In other words, modulation of viral expression appears to be curative in lymphocytic sheep, an approach that might also be efficient in patients infected with the related Human T-lymphotropic virus type 1. In summary, a dynamic interplay between BLV and the host immune response modulates a complex equilibrium between (i) viral expression driving (or) favoring proliferation and (ii) viral silencing preventing apoptosis. As conclusion, we propose a hypothetical model unifying all these mechanisms.

Spleen-dependent turnover of CD11b peripheral blood B lymphocytes in bovine leukemia virus-infected sheep.

Lymphocyte homeostasis is determined by a critical balance between cell proliferation and death, an equilibrium which is deregulated in bovine leukemia virus (BLV)-infected sheep. We have previously shown that an excess of proliferation occurs in lymphoid tissues and that the peripheral blood population is prone to increased cell death. To further understand the mechanisms involved, we evaluated the physiological role of the spleen in this accelerated turnover. To this end, B lymphocytes were labeled in vivo using a fluorescent marker (carboxyfluorescein diacetate succinimidyl ester), and the cell kinetic parameters (proliferation and death rates) of animals before and after splenectomy were compared. We show that the enhanced cell death observed in BLV-infected sheep is abrogated after splenectomy, revealing a key role of the spleen in B-lymphocyte dynamics.

Peripheral blood B-cell death compensates for excessive proliferation in lymphoid tissues and maintains homeostasis in bovine leukemia virus-infected sheep.

The size of a lymphocyte population is primarily determined by a dynamic equilibrium between cell proliferation and death. Hence, lymphocyte recirculation between the peripheral blood and lymphoid tissues is a key determinant in the maintenance of cell homeostasis. Insights into these mechanisms can be gathered from large-animal models, where lymphatic cannulation from individual lymph nodes is possible. In this study, we assessed in vivo lymphocyte trafficking in bovine leukemia virus (BLV)-infected sheep. With a carboxyfluorescein diacetate succinimidyl ester labeling technique, we demonstrate that the dynamics of lymphocyte recirculation is unaltered but that accelerated proliferation in the lymphoid tissues is compensated for by increased death in the peripheral blood cell population. Lymphocyte homeostasis is thus maintained by biphasic kinetics in two distinct tissues, emphasizing a very dynamic process during BLV infection.

Characterization of a putative founder mutation that accounts for the high incidence of cystinosis in Brittany.

Cystinosis is an autosomal recessive disorder, characterized by an accumulation of intralysosomal cystine, with an incidence of 1 in 100,000 to 200,000 live births. A higher incidence of cystinosis, 1 in 26,000 live births, has been reported in the western French province of Brittany. PCR amplification and sequencing has identified a 27-bp deletion starting 3 bp before the end of exon 8 and continuing into intron 8, 898-900+24del27, which has only been detected in families from this region. Reverse transcription-PCR amplification of RNA from an affected individual has shown that this mutation is indeed a splice-site mutation and results in the production of aberrant transcripts. These transcripts are predicted to either severely truncate cystinosin or alter its topology, thus accounting for the severe phenotype of these individuals. The mutation 898-900+24del27 has been identified in 7 of 18 alleles studied. This mutation is likely to be a founder mutation and would account for the higher incidence of cystinosis in Brittany.(1)