Sleep promotes adaptation of behavior and underlying neural plasticity in comparison to active wa... more Sleep promotes adaptation of behavior and underlying neural plasticity in comparison to active wakefulness. However, the contribution of its two main characteristics, sleep-specific brain activity and reduced stimulus interference, remains unclear. We tested healthy humans on a texture discrimination task, a proxy for neural plasticity in primary visual cortex, in the morning and retested them in the afternoon after a period of daytime sleep, passive waking with maximally reduced interference, or active waking. Sleep restored performance in direct comparison to both passive and active waking, in which deterioration of performance across repeated within-day testing has been linked to synaptic saturation in the primary visual cortex. No difference between passive and active waking was observed. Control experiments indicated that deterioration across wakefulness was retinotopically specific to the trained visual field and not due to unspecific performance differences. The restorative effect of sleep correlated with time spent in NREM sleep and with electroencephalographic slow wave energy, which is thought to reflect renormalization of synaptic strength. The results indicate that sleep is more than a state of reduced stimulus interference, but that sleep-specific brain activity restores performance by actively refining cortical plasticity.
Objective: Severe malnutrition in patients with anorexia nervosa (AN) as well as possible trait-r... more Objective: Severe malnutrition in patients with anorexia nervosa (AN) as well as possible trait-related aberrations lead to pronounced structural brain changes whose reversibility after recovery is currently unclear. Previous diffusion tensor imaging (DTI) studies investigating white matter (WM) microstructure alterations in AN are inconsistent. Methods: In this so far largest DTI study in adults, we investigated 33 AN patients, 20 recovered (REC), and 33 healthy women. DTI data were processed using the "DTI and Fiber tools," and the Computational Anatomy Toolbox. WM integrity, both in terms of fractional anisotropy (FA) and mean diffusivity (MD), was assessed. Results: We found a significant FA decrease in the corpus callosum (body) and an MD decrease in the posterior thalamic radiation in the AN group. The REC group displayed FA decrease in the corpus callosum in comparison to HC, whereas there were no MD differences between the REC and HC groups. Conclusion: Despite prolonged restoration of weight in the REC group, no significant regeneration of WM integrity in terms of FA could be observed. Transient changes in MD likely represent a reversible consequence of the acute state of starvation or result from dehydration. Reduction of FA either may be due to WM damage resulting from malnutrition or may be considered a pre-morbid marker.
Background: Arousal and sleep represent basic domains of behavior, and alterations are of high cl... more Background: Arousal and sleep represent basic domains of behavior, and alterations are of high clinical importance. Objective/Hypothesis: The aim of this study was to further elucidate the neurobiology of insomnia disorder (ID) and the potential for new treatment developments, based on the modulation of cortical activity through the non-invasive brain stimulation technique transcranial direct current stimulation (tDCS). Specifically, we tested the hypotheses that bi-frontal anodal tDCS shortens and cathodal tDCS prolongs total sleep time in patients with ID, compared to sham stimulation. Furthermore, we tested for differences in indices of arousal between ID patients and healthy controls and explored their potential impact on tDCS effects. Methods: Nineteen ID patients underwent a within-subject repeated-measures sleep laboratory study with adaptation, baseline and three experimental nights. Bifrontal anodal, cathodal and sham tDCS was delivered in a counterbalanced order immediately prior to sleep. Wake EEG was recorded prior to and after tDCS as well as on the following morning. Subsequently, we compared patients with ID to a healthy control group from an earlier dataset. Results: Against our hypothesis, we did not observe any tDCS effects on sleep continuity or sleep architecture in patients with ID. Further analyses of nights without stimulation demonstrated significantly increased levels of arousal in ID patients compared to healthy controls, as indexed by subjective reports, reduced total sleep time, increased wake after sleep onset and increased high frequency EEG power during wakefulness and NREM sleep. Of note, indices of increased arousal predicted the lack of effect of tDCS in ID patients. Conclusions: Our study characterizes for the first time differential effects of tDCS on sleep in patients with ID and healthy controls, presumably related to persistent hyperarousal in ID. These findings suggest that adapted tDCS protocols need to be developed to modulate arousal and sleep dependent on baseline arousal levels.
Chronic insomnia is one of the most prevalent central nervous system disorders. It is characteriz... more Chronic insomnia is one of the most prevalent central nervous system disorders. It is characterized by increased arousal levels, however, the neurobiological causes and correlates of hyperarousal in insomnia remain to be further determined. In the current study, magnetic resonance spectroscopy was used in the morning and evening in a well-characterized sample of 20 primary insomnia patients (12 females; 8 males; 42.7 ± 13.4 years) and 20 healthy good sleepers (12 females; 8 males; 44.1 ± 10.6 years). The most important inhibitory and excitatory neurotransmitters of the central nervous system, γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx), were assessed in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). The primary hypothesis, a diurnal effect on GABA levels in patients with insomnia, could not be confirmed. Moreover, the current results did not support previous findings of altered GABA levels in individuals with insomnia. Exploratory analyses, however, suggested that GABA levels in the ACC may be positively associated with habitual sleep duration, and, thus, reduced GABA levels may be a trait marker of objective sleep disturbances. Moreover, there was a significant GROUP x MEASUREMENT TIME interaction effect on Glx in the DLPFC with increasing Glx levels across the day in the patients but not in the control group. Therefore, Glx levels may reflect hyperarousal at bedtime in those with insomnia. Future confirmatory studies should include larger sample sizes to investigate brain metabolites in different subgroups of insomnia.
Study Objectives: Reference data for sleep are needed for the interpretation of clinical sleep pa... more Study Objectives: Reference data for sleep are needed for the interpretation of clinical sleep parameters. This analysis aimed to provide polysomnographymeasured, spectral analytic and subjective reference data based on a sample of healthy adults. In addition, effects of age and sex were investigated. Methods: The sample was selected from the archival database of the Sleep Center at the University Medical Center Freiburg and consisted of 206 healthy adults aged 19 to 73 years. For an adaptation and a second examination night, polysomnography parameters, spectral analytic data, and subjective sleep estimations are presented. Results: With increasing age, sleep became shorter (less total sleep time, more wake time after sleep onset) and lighter (eg, more percentage of stage N1 sleep, increase in fast activity in the beta range). Sleep in females was deeper than sleep in males (eg, higher percentage of stage N3 sleep). Females had higher overall power density than males. Altogether, it is apparent that sleep parameters exhibit high standard deviations, suggesting a high variability within healthy adults and complicating the specification of reference values. Conclusions: Our data suggest that the informative value of sleep reference data in healthy individuals is limited because of high interindividual and intraindividual variation within sleep variables. More research, preferably in the form of meta-analyses and/or large international databases, is needed to further investigate the relevance of such reference data for mental and physical health. In the absence of such knowledge, giving patients feedback about deviations from the norm in their sleep profile may give rise to ill-founded concerns and worry.
The current study was designed to further clarify the influence of brain morphology, sleep oscill... more The current study was designed to further clarify the influence of brain morphology, sleep oscillatory activity and age on memory consolidation. Specifically, we hypothesized, that a smaller volume of hippocampus, parahippocampal and medial prefrontal cortex negatively impacts declarative, but not procedural, memory consolidation. Explorative analyses were conducted to demonstrate whether a decrease in slowwave activity negatively impacts declarative memory consolidation, and whether these factors mediate age effects on memory consolidation. Thirty-eight healthy participants underwent an acquisition session in the evening and a retrieval session in the morning after night-time sleep with polysomnographic monitoring. Declarative memory was assessed with the paired-associate word list task, while procedural memory was tested using the mirror-tracing task. All participants underwent highresolution magnetic resonance imaging. Participants with smaller hippocampal, parahippocampal and medial prefrontal cortex volumes displayed a reduced overnight declarative, but not procedural memory consolidation. Mediation analyses showed significant age effects on overnight declarative memory consolidation, but no significant mediation effects of brain morphology on this association. Further mediation analyses showed that the effects of age and brain morphology on overnight declarative memory consolidation were not mediated by polysomnographic variables or sleep electroencephalogram spectral power variables. Thus, the results suggest that the association between age, specific brain area volume and overnight memory consolidation is highly relevant, but does not necessarily depend on slow-wave sleep as previously conceptualized.
Outcome variables included total sleep time (TST), wake after sleep onset (WASO), and sleep effic... more Outcome variables included total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE) averaged over 7 nights. Both "Normal" and "Sensitive" sleep-recording Fitbit modes were examined. Each commercial monitor was compared with AW-2 using paired t-test and Bland-Altman concordance analyses. Clinical acceptance was defined a priori as ≤60 minutes difference between devices for TST and WASO, and ≤10% difference for SE. Results: Fitbit (normal), Jawbone, and Misfit were in the clinically acceptable range for TST, with Fitbit (normal) and Misfit overestimating by 2 minutes and 60 minutes, respectively; and Jawbone underestimating by 15 minutes compared with AW-2 (m=406 ± 47 minutes). Fitbit (sensitive) overestimated by 160 minutes. All devices met clinically acceptable criteria but underestimated WASO by 13 minutes (Jawbone), 21 minutes (Fitbit sensitive), 23 minutes (Fitbit normal), and 25 minutes (Misfit) compared to AW-2 (m=38 ± 15 minutes). Jawbone and Fitbit (normal) met clinically acceptable criteria for SE, with both devices overestimating by 4% and 5%, respectively compared to AW-2 (m=85 ± 6%). Misfit overestimated by 12% and Fitbit (sensitive) underestimated by 30%. Conclusion: Fitbit (normal) and Jawbone accelerometers provided clinically comparable result for TST, WASO, and SE when compared to AW-2. Misfit met criteria for TST and WASO but not SE. Fitbit (sensitive) performed poorest. Further research is needed to reevaluate these findings with newer models.
Questionnaire studies suggest that stroke patients experience sustained problems with sleep and d... more Questionnaire studies suggest that stroke patients experience sustained problems with sleep and daytime sleepiness, but physiological sleep studies focussing specifically on the chronic phase of stroke are lacking. Here we report for the first time physiological data of sleep and daytime sleepiness obtained through the two gold-standard methods, nocturnal polysomnography and the Multiple sleep Latency test. Data from community-dwelling patients with chronic right-hemispheric stroke (>12 months) were compared to sex-and age-matched controls. Behavioural and physiological measures suggested that stroke patients had poorer sleep with longer sleep latencies and lower sleep efficiency. patients further spent more time awake during the night, and showed greater high-frequency power during nonReM sleep than controls. At the same time the Multiple sleep Latency test revealed greater wake efficiency in patients than controls. Importantly these findings were not due to group differences in sleep disordered breathing or periodic limb movements. post-stroke insomnia is presently not adequately addressed within the care pathway for stroke. A holistic approach to rehabilitation and care provision, that includes targeted sleep interventions, is likely to enhance long-term outcome and quality of live in those living with chronic deficits after stroke.
Objectives: We previously (2008) found an association between REM sleep duration and perceived wa... more Objectives: We previously (2008) found an association between REM sleep duration and perceived wakefulness in 81 patients with primary insomnia (PI) in addition to a clearly increased arousal index in REM sleep. The current study aimed to replicate and extend the previous findings. Methods: Polysomnogram (PSG) and subjective sleep quality questionnaire (Schlaffragebogen A, SFA) data of PI patients and matched good sleeper controls (GSC) were evaluated for group differences. Results: One hundred and fifty-six new PI patients could be matched to the same number of GSC (GSC; 60M, 96F; Mean age PI: 42.6 ± 12.4 years, GSC: 42.2 ± 13.4 years). PI patients had a higher wake time within bed time as well as lower REM and sleep stage 2 time. The association between perceived wake time and REM sleep time could be replicated in this new and larger group, as well as a clearly increased arousal index in REM sleep, while the arousal index in NREM sleep was significantly but less strongly increased. Conclusion: We postulate that the psychophysiological hyperarousal characteristic for primary insomnia is particularly expressed as a REM sleep alteration. REM sleep appears to be particularly vulnerable to pre-sleep worries, leading to increased retrospective recall of this time as wake time and a lower restorative sleep quality
Study Objectives: Sleep has been demonstrated to significantly modulate brain plasticity and the ... more Study Objectives: Sleep has been demonstrated to significantly modulate brain plasticity and the manifestation of mental disorders. However, previous studies on the impact of disrupted sleep on brain structure have reported inconsistent results. The current study aimed at investigating brain morphometry in a well-characterized large sample of primary insomnia (PI) patients in comparison to good sleeper controls. Design: Automated parcellation and pattern recognition approaches were supplemented by voxel-wise analyses of gray and white matter volumes to analyze MR images. All analyses included age, sex, and total intracranial volume as covariates. Setting: Department of Psychiatry and Psychotherapy of the University of Freiburg Medical Center. Participants: 28 PI patients (10 males; 18 females; 43.7 ± 14.2 years) and 38 healthy good sleepers (17 males; 21 females; 39.6 ± 8.9 years). Interventions: N/A Results: No significant between-group differences were observed in any of the investigated brain morphometry variables. Conclusions: Altered brain function in insomnia does not seem to have a substantial impact on brain morphometry on a macroscopic level
Sleep, depression and insomnia have manifold associations. Psychiatric sleep research in affectiv... more Sleep, depression and insomnia have manifold associations. Psychiatric sleep research in affective disorders has demonstrated that sleep in depression is characterized by an impairment of sleep continuity, deficits in slow wave sleep and a disinhibition of REM sleep (including shortened REM latency and increased REM density). Traditionally, insomnia, i.e. prolonged latency to fall asleep and increased frequency of nocturnal wake periods, was considered as an unspecific symptom of affective disorders. In the meantime, a shift in clinical and scientific focus has taken place viewing insomnia in addition as an independent diagnostic entity and as a clinical predictor of depression. Unfortunately, the neurobiological processes underlying the relationships between sleep, insomnia and depression have not been fully identified yet. It is clear that both insomnia and depression are characterized by alterations in the arousal system in the CNS presenting as hyperarousal. Moreover, insomniac patients display reduced and fragmented REM sleep periods, which might interfere negatively with basal processes of emotion regulation. The alterations in the arousal system and the interaction of it with the affect-regulatory system over the course of time might influence cognitive systems and hence lead to the clinical picture of depression. Given the suggestion of insomnia symptoms as possibly involved in the causation and the maintenance of psychopathology in general, this type of sequence might also be found in relation to other mental disorders
We found that a quadratic, rather than a linear, relationship existed between time to sleep onset... more We found that a quadratic, rather than a linear, relationship existed between time to sleep onset and performance on the final cued recall test. In other words, participants who delayed going to sleep by several hours (approximately 3-9 hours) performed better at test and lost proportionally fewer word pairs across the delayed retention interval than participants who went to sleep sooner than 3 hours after Encoding or later than 9 hours after Encoding. Conclusion: Sleeping immediately after learning new information is not as beneficial as delaying sleep for several hours. However, delaying sleep for longer periods of time (more than 9 hours) is also less beneficial for memory. The critical window in which sleep is most beneficial for consolidating new declarative memory is approximately between 3 and 9 hours. Support (If Any): None.
Differences between subjective sleep perception and sleep determined by polysomnography (PSG) are... more Differences between subjective sleep perception and sleep determined by polysomnography (PSG) are prevalent, particularly in patients with primary insomnia, indicating that the two measures are partially independent. To identify individualized treatment strategies, it is important to understand the potentially different mechanisms influencing subjective and PSG-determined sleep. The aim of this study was to investigate to what extent three major components of insomnia models, i.e. sleep effort, dysfunctional beliefs and attitudes about sleep, and presleep arousal, are associated with subjective insomnia severity and PSG-determined sleep. A sample of 47 patients with primary insomnia according to DSM-IV criteria and 52 good sleeper controls underwent 2 nights of PSG and completed the Glasgow Sleep Effort Scale, the Dysfunctional Beliefs and Attitudes about Sleep Scale, the Pre-Sleep Arousal Scale and the Insomnia Severity Index. Regression analyses were conducted to investigate the impact of the three predictors on subjective insomnia severity and PSG-determined total sleep time. All analyses were adjusted for age, gender, depressive symptoms and group status. The results showed that subjective insomnia severity was associated positively with sleep effort. PSG-determined total sleep time was associated negatively with somatic presleep arousal and dysfunctional beliefs and attitudes about sleep. This pattern of results provides testable hypotheses for prospective studies on the impact of distinct cognitive and somatic variables on subjective insomnia severity and PSG-determined total sleep time.
ABSTRACT Current diagnostic concepts, i.e. ICD-10 or DSM IV, do not fully encompass the complexit... more ABSTRACT Current diagnostic concepts, i.e. ICD-10 or DSM IV, do not fully encompass the complexity and heterogeneity of insomnia disorders. Advances have been made with ICSD-2 and the Research Diagnostic Criteria (RDC). Further progress will be made with the DSM V, which will encompass a main diagnostic category of “insomnia disorder”. Concerning etiological and pathophysiological assumptions, the hyperarousal model has gained wide-spread attention. Nevertheless, many of its tenets have only been confirmed by single studies, so further clinical research will be necessary to fully support the model. Additionally, animal models of insomnia are needed to advance the understanding of basic mechanisms involved in insomnia. With respect to treatment, there is a lack of new developments in the field of hypnotics for Europe. Concerning cognitive behavioral therapy of insomnia (CBT-I), much empirical evidence underlines that this type of treatment should be the first line treatment for insomnia. Unfortunately, only a minority of patients seem to have access to the benefits of this treatment due to a lack of resources. Stepped-care models for insomnia suggest self-help programs, internet-based approaches, community-centered activities (specially trained nurses) and as a last resort medical specialists and sleep experts to treat insomnia.
Increased Intra-Subject Variability (ISV) is a candidate endophenotype of ADHD. ISV's relationshi... more Increased Intra-Subject Variability (ISV) is a candidate endophenotype of ADHD. ISV's relationship with response speed is highly relevant for ADHD as patients are highly variable but typically no slower than controls. This brief report addresses the relationship between variability and speed by employing dimensional analyses for differentiated performance measures, with a particular focus on the ex-Gaussian measures, across relevant ADHD studies and in young healthy adults (N = 70). For both patients with ADHD and healthy adults, we found that reaction time standard deviation and mean reaction time were strongly correlated, thus failing to dissociate, but ex-Gaussian tau (t) shared only little variance with Gaussian mu (m), thus dissociating slow responses (t) from response speed or-if given-slow responding (m). Our results highlight the utility of employing the ex-Gaussian measures to disentangle ISV and speed, particularly for ADHD data as patients make more slow responses but are not overall slower than typical controls.
According to the World Health Organization, cardiovascular diseases are the leading cause of deat... more According to the World Health Organization, cardiovascular diseases are the leading cause of death in the world. Therefore, early prevention of these diseases is a public health priority. Epidemiological data suggest that insomnia may be a modifiable risk factor for cardiovascular diseases. A randomized controlled trial in a sample of insomnia patients without cardiovascular disease was conducted to investigate the effects of insomnia treatment on early markers of cardiovascular diseases assessed by 24‐hr ambulatory blood pressure, heart rate and heart rate variability monitoring, and morning fasting blood samples. Forty‐six patients with insomnia disorder were randomized to cognitive behavioural therapy for insomnia (CBT‐I; n = 23) or a waitlist control condition (n = 23). Contrary to the hypothesis, intention‐to‐treat analyses did not show any significant treatment effects on early markers of cardiovascular disease (d = 0.0–0.6) despite successful insomnia treatment (d = 1.3). Pot...
The first point highlighted by Tang et al. is about our search strategy. Particularly, the author... more The first point highlighted by Tang et al. is about our search strategy. Particularly, the authors demonstrate concerns on searching the literature only through PubMed. We totally agree with this concern, but we have to point out that this is not the case of our systematic review. We performed our systematic research in “Pubmed”, “PsycINFO” and “MEDLINE” databases. Cochrane Collaboration Guidelines for searching literature [1] were followed. Consistently, several search strategies were used in addition to the standard literature databases. We identified further studies from the references of the screened full-texts and we collected data from non-published studies (searching in the grey literature, non published literature and contacting authors in the field to obtain further data). This extensive search strategy was adopted by our group in several previous publications [3-5]. Indeed, we did not search relevant literature in Embase database. Nevertheless, evidences are available that indicate that low risks of biases are associated by searching literature in Medline but not Embase [2]. Furthermore, our keywords were chosen accurately and they were comprehensive of synonymous and “*” as to include all existing suffixes: (((pregnan*[Title/Abstract] OR “expect* mother*” [Title/Abstract] OR “mother*”[Title/Abstract])) AND ((insomnia*[Title/Abstract] OR sleep*[Title/Abstract])) AND ((treat* [Title/Abstract] OR therap*[Title/Abstract] OR intervention [Title/ Abstract]))). Indeed, these terms were not searched as “Keywords”, but as indicated as any word in the title or the abstract. For this reason the provided keywords search is actually much more extensive than the relatively broad categorization by MeSH. Finally, we include articles in the following languages: English, Italian, German, Spanish, and French. Indeed, we did not search relevant literature in Chinese databases as unfortunately we did not have the possibility to read in Chinese. Nevertheless, our systematic review was not focused on Chinese medicine treatments. A further comment by Tang et al. was on the inappropriateness of our interventions’ classification. As stated by the authors “Complementary medicine is not standard therapy, which, instead, is utilized along with standard medical therapy. Alternative medicine is considered as the replacement of standard medical therapy”. In our systematic review, only one study was found that evaluated the efficacy of Acupuncture on insomnia [6] and the authors used acupuncture in an alternative way (instead of conventional medical treatment) and not in a complementary way (in combination with conventional medical treatment) [7]. For this reason, this study was categorized in the alternative interventions section. Tang and colleagues also commented on the inappropriateness of our choice to evaluate with Risk of Bias Cochrane Collaboration’s tool [8] only for Randomized Controlled Trial and they stated that we have used the Newcastle-Ottawa Scale (NOS) for non-randomized clinical trial studies’ evaluation. Actually, we did not use the Newcastle-Ottawa Scale (NOS) for non-randomized studies, but we decided to provide a qualitative critical evaluation of the level of evidence of non-randomized controlled trials. That is, the risk of bias of the interpretation of the results of non-randomized trials included in our systematic review was qualitatively assessed and considered. The authors comment on the necessity to evaluate in our systematic review the safety of the interventions. This was actually done whenever information about safety was reported (e.g. for pharmacotherapy and acupuncture). Finally, Tang and colleagues commented on the similarity of two of the included studies in our systematic review [9,10]. These studies were conducted by the same research group. In one of this study [11], hospitalized pregnant women were evaluated, whether in the other study, non-hospitalized pregnant women were recruited
Sleep problems during pregnancy are prevalent and could be linked to negative outcomes during pre... more Sleep problems during pregnancy are prevalent and could be linked to negative outcomes during pregnancy or post-partum. However, these complaints are often underdiagnosed and undertreated. This review aimed to systematically assess the effectiveness of different interventions to ameliorate poor sleep quality and insomnia during pregnancy. Pubmed, PsycINFO and Medline databases were systematically searched without publication period restriction until 3 rd May 2019. Eligible studies had to: include pregnant women of any age and gestational age; use clinical intervention designs targeted at improving sleep outcome; report pre-and post-treatment data for one or more sleep-related outcomes; be published in English, Italian, German, Spanish, or French. Sixteen studies were selected including 1252 expecting mothers. Studies evaluated the efficacy of various interventions: cognitive behavioral interventions for insomnia (4); pharmacotherapy (1); acupuncture (1); mindfulness and yoga (3); relaxation (5) and herbal medication (2). Only six were randomized controlled trials, and only four evaluated longitudinal outcomes. Preliminary support was found for all interventions, but our knowledge is still too limited by lack of evidence. There is an utmost urgency to perform high-quality randomized controlled trials for insomnia interventions during pregnancy and to implement effective programs in standard gynecological care.
Sleep promotes adaptation of behavior and underlying neural plasticity in comparison to active wa... more Sleep promotes adaptation of behavior and underlying neural plasticity in comparison to active wakefulness. However, the contribution of its two main characteristics, sleep-specific brain activity and reduced stimulus interference, remains unclear. We tested healthy humans on a texture discrimination task, a proxy for neural plasticity in primary visual cortex, in the morning and retested them in the afternoon after a period of daytime sleep, passive waking with maximally reduced interference, or active waking. Sleep restored performance in direct comparison to both passive and active waking, in which deterioration of performance across repeated within-day testing has been linked to synaptic saturation in the primary visual cortex. No difference between passive and active waking was observed. Control experiments indicated that deterioration across wakefulness was retinotopically specific to the trained visual field and not due to unspecific performance differences. The restorative effect of sleep correlated with time spent in NREM sleep and with electroencephalographic slow wave energy, which is thought to reflect renormalization of synaptic strength. The results indicate that sleep is more than a state of reduced stimulus interference, but that sleep-specific brain activity restores performance by actively refining cortical plasticity.
Objective: Severe malnutrition in patients with anorexia nervosa (AN) as well as possible trait-r... more Objective: Severe malnutrition in patients with anorexia nervosa (AN) as well as possible trait-related aberrations lead to pronounced structural brain changes whose reversibility after recovery is currently unclear. Previous diffusion tensor imaging (DTI) studies investigating white matter (WM) microstructure alterations in AN are inconsistent. Methods: In this so far largest DTI study in adults, we investigated 33 AN patients, 20 recovered (REC), and 33 healthy women. DTI data were processed using the "DTI and Fiber tools," and the Computational Anatomy Toolbox. WM integrity, both in terms of fractional anisotropy (FA) and mean diffusivity (MD), was assessed. Results: We found a significant FA decrease in the corpus callosum (body) and an MD decrease in the posterior thalamic radiation in the AN group. The REC group displayed FA decrease in the corpus callosum in comparison to HC, whereas there were no MD differences between the REC and HC groups. Conclusion: Despite prolonged restoration of weight in the REC group, no significant regeneration of WM integrity in terms of FA could be observed. Transient changes in MD likely represent a reversible consequence of the acute state of starvation or result from dehydration. Reduction of FA either may be due to WM damage resulting from malnutrition or may be considered a pre-morbid marker.
Background: Arousal and sleep represent basic domains of behavior, and alterations are of high cl... more Background: Arousal and sleep represent basic domains of behavior, and alterations are of high clinical importance. Objective/Hypothesis: The aim of this study was to further elucidate the neurobiology of insomnia disorder (ID) and the potential for new treatment developments, based on the modulation of cortical activity through the non-invasive brain stimulation technique transcranial direct current stimulation (tDCS). Specifically, we tested the hypotheses that bi-frontal anodal tDCS shortens and cathodal tDCS prolongs total sleep time in patients with ID, compared to sham stimulation. Furthermore, we tested for differences in indices of arousal between ID patients and healthy controls and explored their potential impact on tDCS effects. Methods: Nineteen ID patients underwent a within-subject repeated-measures sleep laboratory study with adaptation, baseline and three experimental nights. Bifrontal anodal, cathodal and sham tDCS was delivered in a counterbalanced order immediately prior to sleep. Wake EEG was recorded prior to and after tDCS as well as on the following morning. Subsequently, we compared patients with ID to a healthy control group from an earlier dataset. Results: Against our hypothesis, we did not observe any tDCS effects on sleep continuity or sleep architecture in patients with ID. Further analyses of nights without stimulation demonstrated significantly increased levels of arousal in ID patients compared to healthy controls, as indexed by subjective reports, reduced total sleep time, increased wake after sleep onset and increased high frequency EEG power during wakefulness and NREM sleep. Of note, indices of increased arousal predicted the lack of effect of tDCS in ID patients. Conclusions: Our study characterizes for the first time differential effects of tDCS on sleep in patients with ID and healthy controls, presumably related to persistent hyperarousal in ID. These findings suggest that adapted tDCS protocols need to be developed to modulate arousal and sleep dependent on baseline arousal levels.
Chronic insomnia is one of the most prevalent central nervous system disorders. It is characteriz... more Chronic insomnia is one of the most prevalent central nervous system disorders. It is characterized by increased arousal levels, however, the neurobiological causes and correlates of hyperarousal in insomnia remain to be further determined. In the current study, magnetic resonance spectroscopy was used in the morning and evening in a well-characterized sample of 20 primary insomnia patients (12 females; 8 males; 42.7 ± 13.4 years) and 20 healthy good sleepers (12 females; 8 males; 44.1 ± 10.6 years). The most important inhibitory and excitatory neurotransmitters of the central nervous system, γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx), were assessed in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). The primary hypothesis, a diurnal effect on GABA levels in patients with insomnia, could not be confirmed. Moreover, the current results did not support previous findings of altered GABA levels in individuals with insomnia. Exploratory analyses, however, suggested that GABA levels in the ACC may be positively associated with habitual sleep duration, and, thus, reduced GABA levels may be a trait marker of objective sleep disturbances. Moreover, there was a significant GROUP x MEASUREMENT TIME interaction effect on Glx in the DLPFC with increasing Glx levels across the day in the patients but not in the control group. Therefore, Glx levels may reflect hyperarousal at bedtime in those with insomnia. Future confirmatory studies should include larger sample sizes to investigate brain metabolites in different subgroups of insomnia.
Study Objectives: Reference data for sleep are needed for the interpretation of clinical sleep pa... more Study Objectives: Reference data for sleep are needed for the interpretation of clinical sleep parameters. This analysis aimed to provide polysomnographymeasured, spectral analytic and subjective reference data based on a sample of healthy adults. In addition, effects of age and sex were investigated. Methods: The sample was selected from the archival database of the Sleep Center at the University Medical Center Freiburg and consisted of 206 healthy adults aged 19 to 73 years. For an adaptation and a second examination night, polysomnography parameters, spectral analytic data, and subjective sleep estimations are presented. Results: With increasing age, sleep became shorter (less total sleep time, more wake time after sleep onset) and lighter (eg, more percentage of stage N1 sleep, increase in fast activity in the beta range). Sleep in females was deeper than sleep in males (eg, higher percentage of stage N3 sleep). Females had higher overall power density than males. Altogether, it is apparent that sleep parameters exhibit high standard deviations, suggesting a high variability within healthy adults and complicating the specification of reference values. Conclusions: Our data suggest that the informative value of sleep reference data in healthy individuals is limited because of high interindividual and intraindividual variation within sleep variables. More research, preferably in the form of meta-analyses and/or large international databases, is needed to further investigate the relevance of such reference data for mental and physical health. In the absence of such knowledge, giving patients feedback about deviations from the norm in their sleep profile may give rise to ill-founded concerns and worry.
The current study was designed to further clarify the influence of brain morphology, sleep oscill... more The current study was designed to further clarify the influence of brain morphology, sleep oscillatory activity and age on memory consolidation. Specifically, we hypothesized, that a smaller volume of hippocampus, parahippocampal and medial prefrontal cortex negatively impacts declarative, but not procedural, memory consolidation. Explorative analyses were conducted to demonstrate whether a decrease in slowwave activity negatively impacts declarative memory consolidation, and whether these factors mediate age effects on memory consolidation. Thirty-eight healthy participants underwent an acquisition session in the evening and a retrieval session in the morning after night-time sleep with polysomnographic monitoring. Declarative memory was assessed with the paired-associate word list task, while procedural memory was tested using the mirror-tracing task. All participants underwent highresolution magnetic resonance imaging. Participants with smaller hippocampal, parahippocampal and medial prefrontal cortex volumes displayed a reduced overnight declarative, but not procedural memory consolidation. Mediation analyses showed significant age effects on overnight declarative memory consolidation, but no significant mediation effects of brain morphology on this association. Further mediation analyses showed that the effects of age and brain morphology on overnight declarative memory consolidation were not mediated by polysomnographic variables or sleep electroencephalogram spectral power variables. Thus, the results suggest that the association between age, specific brain area volume and overnight memory consolidation is highly relevant, but does not necessarily depend on slow-wave sleep as previously conceptualized.
Outcome variables included total sleep time (TST), wake after sleep onset (WASO), and sleep effic... more Outcome variables included total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE) averaged over 7 nights. Both "Normal" and "Sensitive" sleep-recording Fitbit modes were examined. Each commercial monitor was compared with AW-2 using paired t-test and Bland-Altman concordance analyses. Clinical acceptance was defined a priori as ≤60 minutes difference between devices for TST and WASO, and ≤10% difference for SE. Results: Fitbit (normal), Jawbone, and Misfit were in the clinically acceptable range for TST, with Fitbit (normal) and Misfit overestimating by 2 minutes and 60 minutes, respectively; and Jawbone underestimating by 15 minutes compared with AW-2 (m=406 ± 47 minutes). Fitbit (sensitive) overestimated by 160 minutes. All devices met clinically acceptable criteria but underestimated WASO by 13 minutes (Jawbone), 21 minutes (Fitbit sensitive), 23 minutes (Fitbit normal), and 25 minutes (Misfit) compared to AW-2 (m=38 ± 15 minutes). Jawbone and Fitbit (normal) met clinically acceptable criteria for SE, with both devices overestimating by 4% and 5%, respectively compared to AW-2 (m=85 ± 6%). Misfit overestimated by 12% and Fitbit (sensitive) underestimated by 30%. Conclusion: Fitbit (normal) and Jawbone accelerometers provided clinically comparable result for TST, WASO, and SE when compared to AW-2. Misfit met criteria for TST and WASO but not SE. Fitbit (sensitive) performed poorest. Further research is needed to reevaluate these findings with newer models.
Questionnaire studies suggest that stroke patients experience sustained problems with sleep and d... more Questionnaire studies suggest that stroke patients experience sustained problems with sleep and daytime sleepiness, but physiological sleep studies focussing specifically on the chronic phase of stroke are lacking. Here we report for the first time physiological data of sleep and daytime sleepiness obtained through the two gold-standard methods, nocturnal polysomnography and the Multiple sleep Latency test. Data from community-dwelling patients with chronic right-hemispheric stroke (>12 months) were compared to sex-and age-matched controls. Behavioural and physiological measures suggested that stroke patients had poorer sleep with longer sleep latencies and lower sleep efficiency. patients further spent more time awake during the night, and showed greater high-frequency power during nonReM sleep than controls. At the same time the Multiple sleep Latency test revealed greater wake efficiency in patients than controls. Importantly these findings were not due to group differences in sleep disordered breathing or periodic limb movements. post-stroke insomnia is presently not adequately addressed within the care pathway for stroke. A holistic approach to rehabilitation and care provision, that includes targeted sleep interventions, is likely to enhance long-term outcome and quality of live in those living with chronic deficits after stroke.
Objectives: We previously (2008) found an association between REM sleep duration and perceived wa... more Objectives: We previously (2008) found an association between REM sleep duration and perceived wakefulness in 81 patients with primary insomnia (PI) in addition to a clearly increased arousal index in REM sleep. The current study aimed to replicate and extend the previous findings. Methods: Polysomnogram (PSG) and subjective sleep quality questionnaire (Schlaffragebogen A, SFA) data of PI patients and matched good sleeper controls (GSC) were evaluated for group differences. Results: One hundred and fifty-six new PI patients could be matched to the same number of GSC (GSC; 60M, 96F; Mean age PI: 42.6 ± 12.4 years, GSC: 42.2 ± 13.4 years). PI patients had a higher wake time within bed time as well as lower REM and sleep stage 2 time. The association between perceived wake time and REM sleep time could be replicated in this new and larger group, as well as a clearly increased arousal index in REM sleep, while the arousal index in NREM sleep was significantly but less strongly increased. Conclusion: We postulate that the psychophysiological hyperarousal characteristic for primary insomnia is particularly expressed as a REM sleep alteration. REM sleep appears to be particularly vulnerable to pre-sleep worries, leading to increased retrospective recall of this time as wake time and a lower restorative sleep quality
Study Objectives: Sleep has been demonstrated to significantly modulate brain plasticity and the ... more Study Objectives: Sleep has been demonstrated to significantly modulate brain plasticity and the manifestation of mental disorders. However, previous studies on the impact of disrupted sleep on brain structure have reported inconsistent results. The current study aimed at investigating brain morphometry in a well-characterized large sample of primary insomnia (PI) patients in comparison to good sleeper controls. Design: Automated parcellation and pattern recognition approaches were supplemented by voxel-wise analyses of gray and white matter volumes to analyze MR images. All analyses included age, sex, and total intracranial volume as covariates. Setting: Department of Psychiatry and Psychotherapy of the University of Freiburg Medical Center. Participants: 28 PI patients (10 males; 18 females; 43.7 ± 14.2 years) and 38 healthy good sleepers (17 males; 21 females; 39.6 ± 8.9 years). Interventions: N/A Results: No significant between-group differences were observed in any of the investigated brain morphometry variables. Conclusions: Altered brain function in insomnia does not seem to have a substantial impact on brain morphometry on a macroscopic level
Sleep, depression and insomnia have manifold associations. Psychiatric sleep research in affectiv... more Sleep, depression and insomnia have manifold associations. Psychiatric sleep research in affective disorders has demonstrated that sleep in depression is characterized by an impairment of sleep continuity, deficits in slow wave sleep and a disinhibition of REM sleep (including shortened REM latency and increased REM density). Traditionally, insomnia, i.e. prolonged latency to fall asleep and increased frequency of nocturnal wake periods, was considered as an unspecific symptom of affective disorders. In the meantime, a shift in clinical and scientific focus has taken place viewing insomnia in addition as an independent diagnostic entity and as a clinical predictor of depression. Unfortunately, the neurobiological processes underlying the relationships between sleep, insomnia and depression have not been fully identified yet. It is clear that both insomnia and depression are characterized by alterations in the arousal system in the CNS presenting as hyperarousal. Moreover, insomniac patients display reduced and fragmented REM sleep periods, which might interfere negatively with basal processes of emotion regulation. The alterations in the arousal system and the interaction of it with the affect-regulatory system over the course of time might influence cognitive systems and hence lead to the clinical picture of depression. Given the suggestion of insomnia symptoms as possibly involved in the causation and the maintenance of psychopathology in general, this type of sequence might also be found in relation to other mental disorders
We found that a quadratic, rather than a linear, relationship existed between time to sleep onset... more We found that a quadratic, rather than a linear, relationship existed between time to sleep onset and performance on the final cued recall test. In other words, participants who delayed going to sleep by several hours (approximately 3-9 hours) performed better at test and lost proportionally fewer word pairs across the delayed retention interval than participants who went to sleep sooner than 3 hours after Encoding or later than 9 hours after Encoding. Conclusion: Sleeping immediately after learning new information is not as beneficial as delaying sleep for several hours. However, delaying sleep for longer periods of time (more than 9 hours) is also less beneficial for memory. The critical window in which sleep is most beneficial for consolidating new declarative memory is approximately between 3 and 9 hours. Support (If Any): None.
Differences between subjective sleep perception and sleep determined by polysomnography (PSG) are... more Differences between subjective sleep perception and sleep determined by polysomnography (PSG) are prevalent, particularly in patients with primary insomnia, indicating that the two measures are partially independent. To identify individualized treatment strategies, it is important to understand the potentially different mechanisms influencing subjective and PSG-determined sleep. The aim of this study was to investigate to what extent three major components of insomnia models, i.e. sleep effort, dysfunctional beliefs and attitudes about sleep, and presleep arousal, are associated with subjective insomnia severity and PSG-determined sleep. A sample of 47 patients with primary insomnia according to DSM-IV criteria and 52 good sleeper controls underwent 2 nights of PSG and completed the Glasgow Sleep Effort Scale, the Dysfunctional Beliefs and Attitudes about Sleep Scale, the Pre-Sleep Arousal Scale and the Insomnia Severity Index. Regression analyses were conducted to investigate the impact of the three predictors on subjective insomnia severity and PSG-determined total sleep time. All analyses were adjusted for age, gender, depressive symptoms and group status. The results showed that subjective insomnia severity was associated positively with sleep effort. PSG-determined total sleep time was associated negatively with somatic presleep arousal and dysfunctional beliefs and attitudes about sleep. This pattern of results provides testable hypotheses for prospective studies on the impact of distinct cognitive and somatic variables on subjective insomnia severity and PSG-determined total sleep time.
ABSTRACT Current diagnostic concepts, i.e. ICD-10 or DSM IV, do not fully encompass the complexit... more ABSTRACT Current diagnostic concepts, i.e. ICD-10 or DSM IV, do not fully encompass the complexity and heterogeneity of insomnia disorders. Advances have been made with ICSD-2 and the Research Diagnostic Criteria (RDC). Further progress will be made with the DSM V, which will encompass a main diagnostic category of “insomnia disorder”. Concerning etiological and pathophysiological assumptions, the hyperarousal model has gained wide-spread attention. Nevertheless, many of its tenets have only been confirmed by single studies, so further clinical research will be necessary to fully support the model. Additionally, animal models of insomnia are needed to advance the understanding of basic mechanisms involved in insomnia. With respect to treatment, there is a lack of new developments in the field of hypnotics for Europe. Concerning cognitive behavioral therapy of insomnia (CBT-I), much empirical evidence underlines that this type of treatment should be the first line treatment for insomnia. Unfortunately, only a minority of patients seem to have access to the benefits of this treatment due to a lack of resources. Stepped-care models for insomnia suggest self-help programs, internet-based approaches, community-centered activities (specially trained nurses) and as a last resort medical specialists and sleep experts to treat insomnia.
Increased Intra-Subject Variability (ISV) is a candidate endophenotype of ADHD. ISV's relationshi... more Increased Intra-Subject Variability (ISV) is a candidate endophenotype of ADHD. ISV's relationship with response speed is highly relevant for ADHD as patients are highly variable but typically no slower than controls. This brief report addresses the relationship between variability and speed by employing dimensional analyses for differentiated performance measures, with a particular focus on the ex-Gaussian measures, across relevant ADHD studies and in young healthy adults (N = 70). For both patients with ADHD and healthy adults, we found that reaction time standard deviation and mean reaction time were strongly correlated, thus failing to dissociate, but ex-Gaussian tau (t) shared only little variance with Gaussian mu (m), thus dissociating slow responses (t) from response speed or-if given-slow responding (m). Our results highlight the utility of employing the ex-Gaussian measures to disentangle ISV and speed, particularly for ADHD data as patients make more slow responses but are not overall slower than typical controls.
According to the World Health Organization, cardiovascular diseases are the leading cause of deat... more According to the World Health Organization, cardiovascular diseases are the leading cause of death in the world. Therefore, early prevention of these diseases is a public health priority. Epidemiological data suggest that insomnia may be a modifiable risk factor for cardiovascular diseases. A randomized controlled trial in a sample of insomnia patients without cardiovascular disease was conducted to investigate the effects of insomnia treatment on early markers of cardiovascular diseases assessed by 24‐hr ambulatory blood pressure, heart rate and heart rate variability monitoring, and morning fasting blood samples. Forty‐six patients with insomnia disorder were randomized to cognitive behavioural therapy for insomnia (CBT‐I; n = 23) or a waitlist control condition (n = 23). Contrary to the hypothesis, intention‐to‐treat analyses did not show any significant treatment effects on early markers of cardiovascular disease (d = 0.0–0.6) despite successful insomnia treatment (d = 1.3). Pot...
The first point highlighted by Tang et al. is about our search strategy. Particularly, the author... more The first point highlighted by Tang et al. is about our search strategy. Particularly, the authors demonstrate concerns on searching the literature only through PubMed. We totally agree with this concern, but we have to point out that this is not the case of our systematic review. We performed our systematic research in “Pubmed”, “PsycINFO” and “MEDLINE” databases. Cochrane Collaboration Guidelines for searching literature [1] were followed. Consistently, several search strategies were used in addition to the standard literature databases. We identified further studies from the references of the screened full-texts and we collected data from non-published studies (searching in the grey literature, non published literature and contacting authors in the field to obtain further data). This extensive search strategy was adopted by our group in several previous publications [3-5]. Indeed, we did not search relevant literature in Embase database. Nevertheless, evidences are available that indicate that low risks of biases are associated by searching literature in Medline but not Embase [2]. Furthermore, our keywords were chosen accurately and they were comprehensive of synonymous and “*” as to include all existing suffixes: (((pregnan*[Title/Abstract] OR “expect* mother*” [Title/Abstract] OR “mother*”[Title/Abstract])) AND ((insomnia*[Title/Abstract] OR sleep*[Title/Abstract])) AND ((treat* [Title/Abstract] OR therap*[Title/Abstract] OR intervention [Title/ Abstract]))). Indeed, these terms were not searched as “Keywords”, but as indicated as any word in the title or the abstract. For this reason the provided keywords search is actually much more extensive than the relatively broad categorization by MeSH. Finally, we include articles in the following languages: English, Italian, German, Spanish, and French. Indeed, we did not search relevant literature in Chinese databases as unfortunately we did not have the possibility to read in Chinese. Nevertheless, our systematic review was not focused on Chinese medicine treatments. A further comment by Tang et al. was on the inappropriateness of our interventions’ classification. As stated by the authors “Complementary medicine is not standard therapy, which, instead, is utilized along with standard medical therapy. Alternative medicine is considered as the replacement of standard medical therapy”. In our systematic review, only one study was found that evaluated the efficacy of Acupuncture on insomnia [6] and the authors used acupuncture in an alternative way (instead of conventional medical treatment) and not in a complementary way (in combination with conventional medical treatment) [7]. For this reason, this study was categorized in the alternative interventions section. Tang and colleagues also commented on the inappropriateness of our choice to evaluate with Risk of Bias Cochrane Collaboration’s tool [8] only for Randomized Controlled Trial and they stated that we have used the Newcastle-Ottawa Scale (NOS) for non-randomized clinical trial studies’ evaluation. Actually, we did not use the Newcastle-Ottawa Scale (NOS) for non-randomized studies, but we decided to provide a qualitative critical evaluation of the level of evidence of non-randomized controlled trials. That is, the risk of bias of the interpretation of the results of non-randomized trials included in our systematic review was qualitatively assessed and considered. The authors comment on the necessity to evaluate in our systematic review the safety of the interventions. This was actually done whenever information about safety was reported (e.g. for pharmacotherapy and acupuncture). Finally, Tang and colleagues commented on the similarity of two of the included studies in our systematic review [9,10]. These studies were conducted by the same research group. In one of this study [11], hospitalized pregnant women were evaluated, whether in the other study, non-hospitalized pregnant women were recruited
Sleep problems during pregnancy are prevalent and could be linked to negative outcomes during pre... more Sleep problems during pregnancy are prevalent and could be linked to negative outcomes during pregnancy or post-partum. However, these complaints are often underdiagnosed and undertreated. This review aimed to systematically assess the effectiveness of different interventions to ameliorate poor sleep quality and insomnia during pregnancy. Pubmed, PsycINFO and Medline databases were systematically searched without publication period restriction until 3 rd May 2019. Eligible studies had to: include pregnant women of any age and gestational age; use clinical intervention designs targeted at improving sleep outcome; report pre-and post-treatment data for one or more sleep-related outcomes; be published in English, Italian, German, Spanish, or French. Sixteen studies were selected including 1252 expecting mothers. Studies evaluated the efficacy of various interventions: cognitive behavioral interventions for insomnia (4); pharmacotherapy (1); acupuncture (1); mindfulness and yoga (3); relaxation (5) and herbal medication (2). Only six were randomized controlled trials, and only four evaluated longitudinal outcomes. Preliminary support was found for all interventions, but our knowledge is still too limited by lack of evidence. There is an utmost urgency to perform high-quality randomized controlled trials for insomnia interventions during pregnancy and to implement effective programs in standard gynecological care.
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