Clinical effectiveness of internet-based cognitive behavioral therapy for insomnia in routine secondary care: results of a randomized controlled trial.

Introduction: Delivering cognitive behavioral therapy for insomnia over the internet bears the advantage of accessibility and uptake to many patients suffering from chronic insomnia. In the current study, we aimed to investigate the effectiveness of internet-based cognitive behavioral therapy for insomnia (iCBT-I) in routine care. Materials and methods: We conducted a two-arm non-blinded randomized controlled trial with care as usual (CAU) as a control condition. Participants were recruited in a specialized outpatient sleep medicine department. Both arms had access to other healthcare resources, and the intervention group had access to the iCBT-I program for 2 months. The primary outcome was insomnia severity, measured by the Insomnia Severity Index (ISI). Secondary outcomes were fatigue severity, daytime sleepiness, affective symptoms, dysfunctional beliefs and attitudes about sleep, sleep locus of control, sleep hygiene, sleep efficiency (SE), sleep onset latency, wake time after sleep onset (WASO), and total sleep time (TST). Linear mixed models for repeated measures were used to analyze the longitudinal data at baseline, post-treatment, and after 3 months of follow-up. The trial was registered at www.clinicaltrials.gov (NCT04300218 21.04.2020). Results: The results showed a significant time*group interaction effect (p = 0.001) at post-treatment with between-group effect size (d = 0.51), indicating that the ISI decreased by a score of 3.8-fold in the iCBT-I group than in the CAU group. There was no significant difference in ISI between groups at follow-up. Regarding secondary outcomes, dysfunctional beliefs about sleep, SE, and WASO decreased significantly during treatment in the intervention group with between-group effect sizes d = 0.35, d = -0.51, and d = 0.47, respectively. At the follow-up, between-group effects on DBAS and SE remained significant: d = 0.36 and d = -0.63, respectively. For TST, we observed a significant time*group effect of d = -0.38 only after follow-up. Conclusion: Our findings suggest that iCBT-I has a significant effect on insomnia severity at post-treatment compared to CAU. iCBT-I further improved dysfunctional beliefs about sleep and improved subjective sleep characteristics, such as SE, WASO, and TST during 3 months after treatment. Clinical trial registration: www.clinicaltrials.gov, identifier (NCT04300218).

Impact of Comorbid Sleep-Disordered Breathing and Atrial Fibrillation on the Long-Term Outcome After Ischemic Stroke.

BACKGROUND: Sleep-disordered breathing (SDB) and atrial fibrillation (AF) are highly prevalent in patients with stroke and are recognized as independent risk factors for stroke. Little is known about the impact of comorbid SDB and AF on long-term outcomes after stroke. METHODS: In this prospective cohort study, 353 patients with acute ischemic stroke or transient ischemic attacks were analyzed. Patients were screened for SDB by respiratory polygraphy during acute hospitalization. Screening for AF was performed using a 7-day ECG up to 3× in the first 6 months. Follow-up visits were scheduled at 1, 3, 12, 24, and 36 months poststroke. Cox regression models adjusted for various factors (age, sex, body mass index, hypertension, diabetes, dyslipidemia, and heart failure) were used to assess the impact of comorbid SDB and AF on subsequent death or cerebro-cardiovascular events. RESULTS: Among 353 patients (299 ischemic stroke and 54 transient ischemic attacks), median age, 67 (interquartile range, 57-74) years with 63% males. Moderate-to-severe SDB (apnea-hypopnea index score, ≥15/h) was present in 118 (33.4%) patients. Among the 56 (15.9%) patients with AF, 28 had comorbid moderate-to-severe SDB and AF. Over 36 months, there were 12 deaths and 67 recurrent cerebro-cardiovascular events. Patients with comorbid moderate-to-severe SDB and AF had a higher risk of subsequent death or cerebro-cardiovascular events compared with those with only moderate-to-severe SDB without AF (hazard ratio, 2.49 [95% CI, 1.18-5.24]) and to those without moderate-to-severe SDB or AF (hazard ratio, 2.25 [95% CI, 1.12-4.50]). However, no significant difference was found between the comorbid moderate-to-severe SDB and AF group and the group with only AF without moderate-to-severe SDB (hazard ratio, 1.64 [95% CI, 0.62-4.36]). CONCLUSIONS: Comorbid moderate-to-severe SDB and AF significantly increase the risk of long-term mortality or recurrent cerebro-cardiovascular events after acute ischemic stroke. Considering both conditions as cumulative and modifiable cerebro-cardiovascular risk factors is of interest for the management of acute stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02559739.

Blood pressure variability, nocturnal heart rate variability and endothelial function predict recurrent cerebro-cardiovascular events following ischemic stroke.

Introduction: Cardiovascular parameters characterizing blood pressure (BP), heart rate (HR), endothelial function and arterial stiffness predict cerebro-cardiovascular events (CCVE) in the general population. Considering the paucity of data in stroke patients, we assessed these parameters as potential predictors of recurrent CCVE at acute stroke stroke. Patients and methods: This is a secondary outcome analysis of a prospective observational longitudinal Sleep Deficiency & Stroke Outcome Study (ClinicalTrials.gov Identifier: NCT02559739). The study consecutively recruited acute ischemic stroke patients. Cardiovascular parameters (blood pressure variability [BPV], heart rate variability [HRV], endothelial function, and arterial stiffness) were assessed within the first week post-stroke. Future CCVE were recorded over a 3-year follow-up. Multivariate Cox regression analysis was used to investigate the prognostic value of 48 cardiovascular parameters regarding CCVE risk. Results: Out of 447 recruited patients, 359 were included in this analysis. 20% of patients developed a future CCVE. A high variability of systolic BP (n = 333) and nocturnal HR (non-linear parameters; n = 187) at acute stroke predicted CCVE risk after adjustment for demographic parameters, cardiovascular risk factors and mean BP or HR, respectively. Endothelial dysfunction (n = 105) at acute stroke predicted CCVE risk after adjustment for age and sex, but not after adjustment for cardiovascular risk factors. Diurnal HR and arterial stiffness at acute stroke were not associated with CCVE risk. Conclusion: High blood pressure variability, high nocturnal HRV and endothelial function contribute to the risk for future CCVE after stroke.

Multiple sleep-wake disturbances after stroke predict an increased risk of cardio-cerebrovascular events or death: A prospective cohort study.

BACKGROUND AND PURPOSE: Contradictory evidence on the impact of single sleep-wake-disturbances (SWD), such as sleep-disorderd breating (SDB) or insomnia, in patients with stroke, on the risk of subsequent cardio- and cerebrovascular events (CCE) and death, exists. Very recent studies in the general population suggest that the presence of multiple SWD increases cardio-cerebrovascular risk. Hence, the aim of this study was to asssess whether a novel score capturing the burden of multiple SWD, a so called "sleep burden index", is predictive for subsequent CCE including death in a prospectively followed cohort of stroke patients. METHODS: Patients with acute ischemic stroke or transient ischemic attack (TIA) were prospectively recruited. Four SWD were analyzed: (i) SDB with respirography; (ii) insomnia (defined using the insomnia severity index [ISI]); (iii) restless legs syndrome (RLS; defined using the International RLS Study Group rating scale); and (iv) self-estimated sleep duration at 1 and 3 months. A "sleep burden index", calculated using the mean of z-transformed values from assessments of these four SWD, was created. The occurrence of CCE was recorded over a mean ± standard deviation (SD) follow-up of 3.2 ± 0.3 years. RESULTS: We assessed 437 patients (87% ischemic stroke, 13% TIA, 64% males) with a mean ± SD age of 65.1 ± 13.0 years. SDB (respiratory event index ≥ 5/h) was present in 66.2% of these patients. Insomnia (ISI ≥ 10), RLS and extreme sleep duration affected 26.2%, 6.4% and 13.7% of the patients 3 months post-stroke. Seventy out of the 437 patients (16%) had at least one CCE during the follow-up. The sleep burden index was associated with a higher risk for subsequent CCE, including death (odds ratio 1.80 per index unit, 95% confidence interval 1.19-2.72; p = 0.0056). CONCLUSION: The presence of multiple SWDs constitutes a risk for subsequent CCE (including death) within the first 3 years following stroke. Larger systematic studies should assess the utility of the sleep burden index for patients' risk stratification in clinical practice.

Guided Internet-Based Cognitive Behavioral Therapy for Insomnia: Prognostic and Treatment-Predictive Factors.

Understanding which factors predict the outcome of internet-based cognitive behavioral therapy for insomnia (iCBT-I) may help to tailor this intervention to the patient's needs. We have conducted a secondary analysis of a randomized, controlled trial comparing a multicomponent iCBT-I (MCT) and an online sleep restriction therapy (SRT) for 83 chronic insomnia patients. The difference in the Insomnia Severity Index from pre- to post-treatment and from pre-treatment to follow-up at 6 months after treatment was the dependent variable. Prognostic and treatment-predictive factors assessed at baseline were analyzed with multiple linear regression. The shorter duration of insomnia, female gender, high health-related quality of life, and the higher total number of clicks had prognostic value for a better outcome. Other factors were found to be prognostic for outcome at the follow-up assessment: treatment with benzodiazepines, sleep quality, and personal significance of sleep problems. A high level of dysfunctional beliefs and attitudes about sleep (DBAS) was a moderator for better effects in the MCT at post-treatment assessment. Various prognostic factors (e.g., duration of insomnia, gender, or quality of life) may influence the success of treatment. The DBAS scale may be recommended to select patients for MCT rather than SRT.

Frequency and evolution of sleep-wake disturbances after ischemic stroke: A 2-year prospective study of 437 patients.

OBJECTIVE: In the absence of systematic and longitudinal data, this study prospectively assessed both frequency and evolution of sleep-wake disturbances (SWD) after stroke. METHODS: In 437 consecutively recruited patients with ischemic stroke or transient ischemic attack (TIA), stroke characteristics and outcome were assessed within the 1st week and 3.2 ± 0.3 years (M±SD) after the acute event. SWD were assessed by interview and questionnaires at 1 and 3 months as well as 1 and 2 years after the acute event. Sleep disordered breathing (SDB) was assessed by respirography in the acute phase and repeated in one fifth of the participants 3 months and 1 year later. RESULTS: Patients (63.8% male, 87% ischemic stroke and mean age 65.1 ± 13.0 years) presented with mean NIHSS-score of 3.5 ± 4.5 at admission. In the acute phase, respiratory event index was >15/h in 34% and >30/h in 15% of patients. Over the entire observation period, the frequencies of excessive daytime sleepiness (EDS), fatigue and insomnia varied between 10-14%, 22-28% and 20-28%, respectively. Mean insomnia and EDS scores decreased from acute to chronic stroke, whereas restless legs syndrome (RLS) percentages (6-9%) and mean fatigue scores remained similar. Mean self-reported sleep duration was enhanced at acute stroke (month 1: 07:54 ± 01:27h) and decreased at chronic stage (year 2: 07:43 ± 01:20h). CONCLUSIONS: This study documents a high frequency of SDB, insomnia, fatigue and a prolonged sleep duration after stroke/TIA, which can persist for years. Considering the negative effects of SWD on physical, brain and mental health these data suggest the need for a systematic assessment and management of post-stroke SWD.

Effect of early sleep apnoea treatment with adaptive servo-ventilation in acute stroke patients on cerebral lesion evolution and neurological outcomes: study protocol for a multicentre, randomized controlled, rater-blinded, clinical trial (eSATIS: early Sleep Apnoea Treatment in Stroke).

BACKGROUND: Sleep-disordered breathing (SDB) is highly prevalent in acute ischaemic stroke and is associated with worse functional outcome and increased risk of recurrence. Recent meta-analyses suggest the possibility of beneficial effects of nocturnal ventilatory treatments (continuous positive airway pressure (CPAP) or adaptive servo-ventilation (ASV)) in stroke patients with SDB. The evidence for a favourable effect of early SDB treatment in acute stroke patients remains, however, uncertain. METHODS: eSATIS is an open-label, multicentre (6 centres in 4 countries), interventional, randomized controlled trial in patients with acute ischaemic stroke and significant SDB. Primary outcome of the study is the impact of immediate SDB treatment with non-invasive ASV on infarct progression measured with magnetic resonance imaging in the first 3 months after stroke. Secondary outcomes are the effects of immediate SDB treatment vs non-treatment on clinical outcome (independence in daily functioning, new cardio-/cerebrovascular events including death, cognition) and physiological parameters (blood pressure, endothelial functioning/arterial stiffness). After respiratory polygraphy in the first night after stroke, patients are classified as having significant SDB (apnoea-hypopnoea index (AHI) > 20/h) or no SDB (AHI < 5/h). Patients with significant SDB are randomized to treatment (ASV+ group) or no treatment (ASV- group) from the second night after stroke. In all patients, clinical, physiological and magnetic resonance imaging studies are performed between day 1 (visit 1) and days 4-7 (visit 4) and repeated at day 90 ± 7 (visit 6) after stroke. DISCUSSION: The trial will give information on the feasibility and efficacy of ASV treatment in patients with acute stroke and SDB and allows assessing the impact of SDB on stroke outcome. Diagnosing and treating SDB during the acute phase of stroke is not yet current medical practice. Evidence in favour of ASV treatment from a randomized multicentre trial may lead to a change in stroke care and to improved outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02554487 , retrospectively registered on 16 September 2015 (actual study start date, 13 August 2015), and www.kofam.ch (SNCTP000001521).

Treating insomnia in Swiss primary care practices: A survey study based on case vignettes.

Guidelines recommend cognitive behavioural therapy for insomnia (CBT-I) as first-line treatment for chronic insomnia, but it is not clear how many primary care physicians (PCPs) in Switzerland prescribe this treatment. We created a survey that asked PCPs how they would treat chronic insomnia and how much they knew about CBT-I. The survey included two case vignettes that described patients with chronic insomnia, one with and one without comorbid depression. PCPs also answered general questions about treating chronic insomnia and about CBT-I and CBT-I providers. Of the 820 Swiss PCPs we invited, 395 (48%) completed the survey (mean age 54 years; 70% male); 87% of PCPs prescribed sleep hygiene and 65% phytopharmaceuticals for the patient who had only chronic insomnia; 95% prescribed antidepressants for the patient who had comorbid depression. In each case, 20% of PCPs prescribed benzodiazepines or benzodiazepine receptor agonists, 8% prescribed CBT-I, 68% said they knew little about CBT-I, and 78% did not know a CBT-I provider. In the clinical case vignettes, most PCPs treated chronic insomnia with phytopharmaceuticals and sleep hygiene despite their lack of efficacy, but PCPs rarely prescribed CBT-I, felt they knew little about it, and usually knew no CBT-I providers. PCPs need more information about the benefits of CBT-I and local CBT-I providers and dedicated initiatives to implement CBT-I in order to reduce the number of patients who are prescribed ineffective or potentially harmful medications.

Effectiveness and Cost-Effectiveness of Internet-Based Cognitive Behavioral Therapy for Insomnia in Clinical Settings.

BACKGROUND: Internet-delivered cognitive-behavior treatment for insomnia (iCBT-I) has the potential to fill the gap created by the discrepancy between insomnia cases and number of trained professionals. Although the effectiveness of this method was proven in multiple studies conducted in research settings, its feasibility in routine care is still unclear. Predictors, mediators, and moderators of treatment effect remain uncertain since previous studies often give contradictory results. The present study aims to investigate clinical effectiveness and cost-effectiveness of an internet-based CBT-I program Sleepsy in comparison with care as usual (CAU) among patients with CI recruited from clinical settings. Baseline data will be further analyzed to find predictors of treatment outcome. METHODS/DESIGN: The proposed study is a parallel-group randomized controlled trial comparing CAU plus iCBT-I with CAU in a clinical setting. One hundred ten participants will be referred from the medical doctors in Moscow. Both groups will have access to CAU, which corresponds to the treatment prescribed by the referring doctor. Patients of the first group will additionally get access to the iCBT-I program with the opportunity to contact a specialist (guidance on request) in a secured environment. The primary outcome is insomnia severity change from pre- to post-treatment. Secondary outcomes include change of subjective sleep characteristics, life quality, fatigue, daytime sleepiness, comorbid affective disorders, dysfunctional beliefs about sleep, sleep hygiene, healthcare consumption, productivity losses, and longer term outcomes at 3 months follow-up. Predictor analysis will include baseline scores of the aforementioned outcomes along with treatment expectancies and personality traits. DISCUSSION: The proposed study is one of the first studies evaluating whether iCBT-I also works in routine care. We expect that recruitment of the participants let us determine the target group more precisely and exclude health problems interfering with treatment. Using CAU as control condition may result in a loss of power to detect a meaningful difference. Nevertheless, this approach is reasonable since it reconstructs the clinical situation faced by practicing doctors.

Prevalence and management of chronic insomnia in Swiss primary care: Cross-sectional data from the "Sentinella" practice-based research network.

We investigated the prevalence and treatment of patients with chronic insomnia presenting to Swiss primary care physicians (PCPs) part of "Sentinella", a nationwide practice-based research network. Each PCP consecutively asked 40 patients if they had sleep complaints, documented frequency, duration, comorbidities, and reported ongoing treatment. We analysed data of 63% (83/132) of the PCPs invited. The PCPs asked 76% (2,432/3,216) of included patients about their sleep (51% female); 31% (761/2,432) of these had had insomnia symptoms; 36% (875/2,432) had current insomnia symptoms; 11% (269/2,432) met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for chronic insomnia (61% female). In all, 75% (201/269) of patients with chronic insomnia had comorbidities, with 49% (99/201) reporting depression. Chronic insomnia was treated in 78% (209/269); 70% (188/268) took medication, 38% (102/268) benzodiazepines or benzodiazepine receptor agonists, 32% (86/268) took antidepressants. Only 1% (three of 268) had been treated with cognitive behavioural therapy for insomnia (CBT-I). A third of patients presenting for a non-urgent visit in Swiss primary care reported insomnia symptoms and 11% met the DSM-5 criteria for chronic insomnia. Hypnotics were the most common treatment, but almost no patients received first-line CBT-I. Reducing the burden of insomnia depends on disseminating knowledge about and access to CBT-I, and encouraging PCPs to discuss it with and offer it as a first-line treatment to patients with chronic insomnia.

[Internet-based cognitive behavioral therapy of insomnia and nightmare disorder]. / Internetbasierte kognitive Verhaltenstherapie der Insomnie und Albtraumstörung.

Cognitive behavioral therapeutic interventions are considered to be one of the most effective forms of treatment of various mental disorders. Besides being very frequent, sleep disorders, such as insomnia and nightmare disorder are often not treated effectively and guideline-conform, mainly due to the lack of qualified psychotherapists. Implementation of modern technical options, such as web-based psychotherapy can help to overcome this problem. This article presents the current situation in the treatment of insomnia and nightmare disorders as particularly well-suited fields of application. For insomnia there are several English language and also recently German language options, which for example were also evaluated for the application to work-related stress and sleep disorders. In this respect, procedures with and without contact to a therapist or multicomponent procedures and single interventions can be differentiated. For nightmare disorders imagery rehearsal therapy provides a structure, which can also easily be transferred to an internet-based therapy program. The currently beginning use of internet-based treatment of sleep disorders does not yet utilize all theoretically available technical possibilities. The potential of internet-based therapy is extremely versatile and it remains for medical sleep experts to consider which method can be used for which indications.

A randomized controlled trial comparing guided internet-based multi-component treatment and internet-based guided sleep restriction treatment to care as usual in insomnia.

BACKGROUND: Internet-based cognitive behavioral treatment (iCBT-I) for insomnia comprising different sleep-related cognitive and behavioral interventional components has shown some promise. However, it is not known which components are necessary for a good treatment outcome. METHOD: People suffering from insomnia (N = 104) without any other comorbid psychiatric disorders were randomized (2:2:1) to two guided internet-based self-help interventions for insomnia [multi-component cognitive behavioral self-help intervention (MCT); sleep restriction intervention for insomnia (SRT)], and care as usual [CAU]. In all three conditions, additional care or treatment was allowed. The primary outcome was insomnia severity measured with the insomnia severity index (ISI) at eight weeks. Furthermore, the two active conditions were compared regarding sleep efficacy from daily diary data over the eight weeks, and other measures from the daily protocols. Secondary outcomes included sleep quality, depressive symptoms, dysfunctional beliefs, and quality of life at post-treatment (eight weeks) and follow-up (six months after randomization). RESULTS: Both conditions were more effective than CAU at post-treatment, with medium to large between-group effect sizes on the primary outcome (ISI; MCT: Cohen's d = -1.15; SRT: d = -0.68) and small to medium between-group effect sizes for secondary outcomes. Treatment gains were maintained at six-month follow-up. Active conditions did not differ from each other on all measures from pre to post, except for dysfunctional beliefs about sleep, and sleep protocol data throughout the intervention. Participants in MCT were significantly more satisfied with the intervention than participants in SRT. CONCLUSIONS: Results of the present study indicate that CAU + MCT and CAU + SRT are both effective compared to CAU. There were no statistical differences regarding efficacy between the two active conditions, but participants in MCT reported to be more satisfied with the intervention.

Sleep-Wake Disorders in Stroke-Increased Stroke Risk and Deteriorated Recovery? An Evaluation on the Necessity for Prevention and Treatment.

PURPOSE OF REVIEW: Sleep-wake disorders (SWD) are common not only in the general population but also in stroke patients, in whom SWD may be pre-existent or appear "de novo" as a consequence of brain damage. Despite increasing evidence of a negative impact of SWD on cardiocerebrovascular risk, cognitive functions, and quality of life, SWD are insufficiently considered in the prevention and management of patients with stroke. This narrative review aims at summarizing the current data on the bidirectional link between SWD and stroke. RECENT FINDINGS: Several studies have demonstrated that sleep-disordered breathing (SDB) is an independent risk factor for stroke and has a detrimental effect on stroke recovery. Short and long sleep duration and possibly other SWD (e.g., insomnia, circadian rhythm disorders) may also increase the risk of stroke and influence its outcome. Data on SDB treatment increasingly indicate a benefit on stroke risk and evolution while treatment of other SWD is still limited. A systematic search for SWD in stroke patients is justified due to their high frequency and their negative impact on stroke outcomes. Clinicians should actively consider available treatment options.

Rapid eye movements sleep as a predictor of functional outcome after stroke: a translational study.

Study Objectives: Sleep disturbances are common in acute stroke patients and are linked with a negative stroke outcome. However, it is also unclear which and how such changes may be related to stroke outcome. To explore this link, we performed a sleep electroencephalogram (EEG) study in animals and humans after ischemic stroke. Methods: (1) Animal study: 12 male rats were assigned to two groups: ischemia (IS) and sham surgery (Sham). In both groups, sleep architecture was investigated 24 h before surgery and for the following 3 days. (2) Human study: 153 patients with ischemic stroke participating in the SAS-CARE prospective, multicenter cohort study had a polysomnography within 9 days after stroke onset. Functional stroke outcome was assessed by the modified Rankin Scale (mRS) at hospital discharge (short-term outcome) and at a 3-month follow-up (long-term outcome). Results: (1) Animal study: rapid eye movement (REM) sleep was significantly reduced in the IS group compared to the Sham group. (2) Human study: patients with poor short-term functional outcome had a reduction of REM sleep and prolonged REM latency during the acute phase of stroke. REM latency was the only sleep EEG variable found to be significantly related to short- and long-term functional impairment in a multiple linear regression analysis. Conclusions: Acute ischemic stroke is followed by a significant reduction of REM sleep in animals and humans. In humans, this reduction was linked with a bad stroke outcome; in addition, REM latency was found to be an independent predictor of stroke evolution. Potential explanations for this role of REM sleep in stroke are discussed. Clinical Trial Registration: http://clinicaltrials.gov. Unique identifier: NCT01097967.

The role of sleep in recovery following ischemic stroke: A review of human and animal data.

Despite advancements in understanding the pathophysiology of stroke and the state of the art in acute management of afflicted patients as well as in subsequent neurorehabilitation training, stroke remains the most common neurological cause of long-term disability in adulthood. To enhance stroke patients' independence and well-being it is necessary, therefore, to consider and develop new therapeutic strategies and approaches. We postulate that sleep might play a pivotal role in neurorehabilitation following stroke. Over the last two decades compelling evidence for a major function of sleep in neuroplasticity and neural network reorganization underlying learning and memory has evolved. Training and learning of new motor skills and knowledge can modulate the characteristics of subsequent sleep, which additionally can improve memory performance. While healthy sleep appears to support neuroplasticity resulting in improved learning and memory, disturbed sleep following stroke in animals and humans can impair stroke outcome. In addition, sleep disorders such as sleep disordered breathing, insomnia, and restless legs syndrome are frequent in stroke patients and associated with worse recovery outcomes. Studies investigating the evolution of post-stroke sleep changes suggest that these changes might also reflect neural network reorganization underlying functional recovery. Experimental and clinical studies provide evidence that pharmacological sleep promotion in rodents and treatment of sleep disorders in humans improves functional outcome following stroke. Taken together, there is accumulating evidence that sleep represents a "plasticity state" in the process of recovery following ischemic stroke. However, to test the key role of sleep and sleep disorders for stroke recovery and to better understand the underlying molecular mechanisms, experimental research and large-scale prospective studies in humans are necessary. The effects of hospital conditions, such as adjusting light conditions according to the patients' sleep-wake rhythms, or sleep promoting drugs and non-invasive brain stimulation to promote neuronal plasticity and recovery following stroke requires further investigation.

Unconscious relational encoding depends on hippocampus.

Textbooks divide between human memory systems based on consciousness. Hippocampus is thought to support only conscious encoding, while neocortex supports both conscious and unconscious encoding. We tested whether processing modes, not consciousness, divide between memory systems in three neuroimaging experiments with 11 amnesic patients (mean age=45.55 years, standard deviation=8.74, range=23-60) and 11 matched healthy control subjects. Examined processing modes were single item versus relational encoding with only relational encoding hypothesized to depend on hippocampus. Participants encoded and later retrieved either single words or new relations between words. Consciousness of encoding was excluded by subliminal (invisible) word presentation. Amnesic patients and controls performed equally well on the single item task activating prefrontal cortex. But only the controls succeeded on the relational task activating the hippocampus, while amnesic patients failed as a group. Hence, unconscious relational encoding, but not unconscious single item encoding, depended on hippocampus. Yet, three patients performed normally on unconscious relational encoding in spite of amnesia capitalizing on spared hippocampal tissue and connections to language cortex. This pattern of results suggests that processing modes divide between memory systems, while consciousness divides between levels of function within a memory system.

Integrating events across levels of consciousness.

Our knowledge grows as we integrate events experienced at different points in time. We may or may not become aware of events, their integration, and their impact on our knowledge and decisions. But can we mentally integrate two events, if they are experienced at different time points and at different levels of consciousness? In this study, an event consisted of the presentation of two unrelated words. In the stream of events, half of events shared one component ("tree desk" … "desk fish") to facilitate event integration. We manipulated the amount of time and trials that separated two corresponding events. The contents of one event were presented subliminally (invisible) and the contents of the corresponding overlapping event supraliminally (visible). Hence, event integration required the binding of contents between consciousness levels and between time points. At the final test of integration, participants judged whether two supraliminal test words ("tree fish") fit together semantically or not. Unbeknown to participants, half of test words were episodically related through an overlap ("desk"; experimental condition) and half were not (control condition). Participants judged episodically related test words to be closer semantically than unrelated test words. This subjective decrease in the semantic distance between test words was both independent of whether the invisible event was encoded first or second in order and independent of the number of trials and the time that separated two corresponding events. Hence, conscious and unconscious memories were mentally integrated into a linked mnemonic representation.

Sleep stage II contributes to the consolidation of declarative memories.

Various studies suggest that non-rapid eye movement (NREM) sleep, especially slow-wave sleep (SWS), is vital to the consolidation of declarative memories. However, sleep stage 2 (S2), which is the other NREM sleep stage besides SWS, has gained only little attention. The current study investigated whether S2 during an afternoon nap contributes to the consolidation of declarative memories. Participants learned associations between faces and cities prior to a brief nap. A cued recall test was administered before and following the nap. Spindle, delta and slow oscillation activity was recorded during S2 in the nap following learning and in a control nap. Increases in spindle activity, delta activity, and slow oscillation activity in S2 in the nap following learning compared to the control nap were associated with enhanced retention of face-city associations. Furthermore, spindles tended to occur more frequently during up-states than down-states within slow oscillations during S2 following learning versus S2 of the control nap. These findings suggest that spindles, delta waves, and slow oscillations might promote memory consolidation not only during SWS, as shown earlier, but also during S2.

Formation of semantic associations between subliminally presented face-word pairs.

Recent evidence suggests that consciousness of encoding is not necessary for the rapid formation of new semantic associations. We investigated whether unconsciously formed associations are as semantically precise as would be expected for associations formed with consciousness of encoding during episodic memory formation. Pairs of faces and written occupations were presented subliminally for unconscious associative encoding. Five minutes later, the same faces were presented suprathreshold for the cued unconscious retrieval of face-occupation associations. Retrieval instructions required participants to classify the presented individuals according to their putative (1) regularity of income, (2) length of education, and (3) creativity value of occupational activity. The three instructions yielded more classifications consistent with a person's occupation if the person had been subliminally presented with his written occupation versus a meaningless word (control condition). This suggests that consciousness is not necessary to encode, long-term store, and retrieve semantically precise associations between primarily unrelated items.