Mareen Seeck-Hirschner

Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy

BACKGROUND The neuropeptides hypocretin-1 and -2 (hcrt-1 and -2, also known as orexin A and B) are crucially involved in the regulation of sleep/wake states. On the one hand, the sleep-wake disorder narcolepsy can be caused by an hcrt-1 deficiency. On the other, intracerebral administration of hcrt-1 produces an increase in wakefulness at the expense of REM sleep in normal and narcoleptic animals. In humans intranasal administration has been shown to effectively deliver neuropeptides directly to the central nervous system. We hypothesised that the intranasal application of hcrt-1 increases wakefulness and reduces REM sleep in the natural human hcrt-1 deficiency narcolepsy with cataplexy. METHODS In this double-blind, random-order crossover, placebo-controlled, within-subject design study we administered human recombinant hcrt-1 (435 nmol) intranasally to eight subjects with narcolepsy with cataplexy before night sleep, followed by standard polysomnography. RESULTS Although intranasal administration of hcrt-1 had no statistically significant effect on nocturnal wakefulness, we found that it reduced REM sleep quantity, particularly during the second half of the recording. Furthermore, intranasal hcrt-1 had a clear REM sleep stabilising effect and led to significantly reduced direct wake to REM transitions. CONCLUSION In this pilot study we found, first, evidence that the intranasal administration of hcrt-1 has functional effects on sleep in narcolepsy with cataplexy. Our results may encourage the use of the intranasal approach in further studies on hypocretinergic sleep regulation and might also contribute to the future development of a causal treatment for narcolepsy with cataplexy.

Effects of daytime naps on procedural and declarative memory in patients with schizophrenia.

Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory. Straight memory deficits and sleep disturbances are well-known in patients with schizophrenia. This study tested the hypothesis that patients with schizophrenia have a deficit in procedural and declarative memory consolidation after a short midday nap when compared to healthy controls and patients with remitted to moderate major depression. Following a normal nights sleep, 22 healthy subjects, 20 patients with major depression and 21 patients with schizophrenia were studied in a napping and wake condition in a random-order cross-over design, early in the afternoon. To test declarative memory, the Rey-Osterrieth Complex Figure Test respectively the Taylor Complex Figure Test and, for procedural learning, a mirror tracing task were performed. The present study is the first to demonstrate significant differences between individuals with schizophrenia, depression and healthy matched controls with regard to measures of sleep and memory performance after a short period of daytime sleep (napping). In particular we found that a daytime nap of only about 40min led to improvement of declarative memory performance in all investigated groups, whereas no beneficial effect was seen on procedural performance in the group of medicated patients with schizophrenia in contrast to healthy controls and patients with remitted to moderate major depression.

The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy

Narcolepsy with cataplexy is a sleep dysregulation disorder with alterations of REM sleep, i.e., sleep onset REM periods and REM sleep instability. Deficient orexin-A (hypocretin-1) signaling is assumed to be a major cause of narcolepsy with cataplexy. In this study we investigated fourteen subjects with narcolepsy with cataplexy in a within-subject, random-order crossover, placebo-controlled design. Patients received double-blinded intranasal orexin-A (435 nmol) or sterile water (placebo) in the morning. Administration was preceded by an adaptation night and followed by a modified maintenance of wakefulness test, attention testing and a second full night of polysomnographic recording. We found comparable sleep behavior during the adaptation nights between both conditions. After orexin-A administration patients had less wake-REM sleep transitions and a decreased REM sleep duration. In the subsequent night, patients showed an increased N2 duration. In the test of divided attention, patients had fewer false reactions after orexin-A administration. Our results support orexin-A to be a REM sleep stabilizing factor and provide functional signs for effects of orexin-A on sleep alterations and attention in narcolepsy with cataplexy.

Reduced sleep-associated consolidation of declarative memory in attention-deficit/hyperactivity disorder

OBJECTIVE Sleep supports the consolidation of declarative memory. Patients with attention-deficit/hyperactivity disorder (ADHD) are not only characterized by sleep problems but also by declarative memory deficits. Given that the consolidation of declarative memory during sleep is supported by slow oscillations, which are predominantly generated by the prefrontal cortex, and that ADHD patients display low prefrontal brain activity, we assumed that ADHD patients show reduced sleep-associated consolidation of declarative memory. METHODS The impact of sleep on the consolidation of declarative memory was examined with a picture recognition task. Twelve ADHD patients (10-16 years) and 12 healthy controls participated in two experimental conditions: in the sleep condition, learning was performed in the evening and picture recognition was tested after nocturnal sleep; in the wake condition, learning was conducted in the morning while retrieval took place after a day of wakefulness. RESULTS Analyses of recognition accuracy revealed reduced sleep-associated enhancement of recognition accuracy in ADHD. While sleep-associated enhancement of recognition accuracy was correlated with slow oscillation power during non-REM sleep in healthy controls, no such correlations were observed in ADHD. CONCLUSIONS These data indicate a deficit in sleep-associated consolidation of declarative memory in ADHD. Moreover, our results suggest reduced functionality of slow oscillations in sleep-associated consolidation of declarative memory in ADHD.

Changes in CREB Phosphorylation and BDNF Plasma Levels during Psychotherapy of Depression

Background: The cyclic adenosine monophosphate response element-binding proteins (CREB) and their interaction with brain-derived neurotrophic factor (BDNF) are essential elements in signal transduction pathways important for cellular resilience and neuroplasticity. They play a decisive role in the concept of altered neuroplasticity in major depression. We have previously demonstrated that the increase in phosphorylated CREB (pCREB) in T lymphocytes is significantly associated with clinical improvement in patients treated with antidepressants. In the present study, we focused on patients treated only with psychotherapy to exclude direct pharmacological actions. In addition to pCREB, we also measured the BDNF plasma levels. Methods: pCREB in T lymphocytes was determined by Western blot; the BDNF plasma levels with solid-phase ELISA. Psychopathology was evaluated with the Hamilton Rating Scale for Depression (HAMD). Thirty patients meeting DSM-IV criteria for major depressive episodes (MDE) were recruited into this 6-week study. They received interpersonal psychotherapy (IPT) twice weekly. Results: After 6 weeks of IPT, 17 patients responded (reduction of ≥50% of baseline HAMD); after 1 week of treatment pCREB increased significantly compared to the nonresponder group. Measurement of the BDNF plasma levels revealed no differences between the responder and nonresponder groups. Furthermore, the correlations between BDNF plasma levels and pCREB were not significant. Conclusions: The early increase in pCREB is related to treatment response and does not depend on pharmacological interventions or BDNF plasma levels. For the first time, cellular biological markers could be associated with response to psychotherapy.

Treatment of patients with borderline personality disorder and comorbid posttraumatic stress disorder using narrative exposure therapy : a feasibility study

comorbid PTSD. Within an open trial, 10 women with BPD and comorbid PTSD were treated at the Center of Integrative Psychiatry in Kiel using NET. NET is a standardized, controlled short-term intervention which is based on the core assumption that a maladaptive traumarelated network of memory representations has resulted from multiple adverse and fearful experiences [9] . NET is now considered to be a comparatively well-tested therapy approach for patients who have survived different types of trauma, ranging from domestic violence and emotional neglect to organized violence [10, 11] . It aims primarily at reducing PTSD symptoms by changing associative memory related to the traumatic experiences through recall of the event and exposure, assigning each event the respective time and place at which it had been experienced. This promotes a coherent autobiographical memory associated with the sensory, affective and cognitive cues of the event [12] , and in addition has nondissociative effects [6] . After detailed psychoeducation, the patient is encouraged to narrate the events of his/her life in a chronological order, from birth to the present day, by using a ‘lifeline’ (symbolized by a line or rope and flowers representing well-remembered positive, and stones representing the traumatic events). In a client-friendly therapeutic environment, it is possible to link the various components (thoughts, emotions, body reactions, contextual information) and integrate them into the patient’s biography. For a more detailed explanation of the basic theoretical assumptions and the method, we refer to Neuner et al. [12] and Schauer et al. [13] . During the period between January 2009 and May 2010, 12 women presenting with BPD and comorbid PTSD were recruited from our clinic. After psychological diagnoses considering the inand exclusion criteria, of those informed about the study, no one refused; 2 women dropped out for practical reasons. Six women underwent therapy in a hospital, 3 on an outpatient basis, and 1 patient started treatment in hospital but then continued her therapy as an outpatient. Whenever possible, the medication administered to the patients during treatment was kept stabile. On average, the women were 33 years old (range: 19–45 years), and all had already received some form of psychoand pharmacotherapy, although none had received trauma-focused treatment before. Prior to treatment, a diagnosis was reached by conducting a standardized and structured clinical interview based on the Mini-International Neuropsychiatric Interview [14] and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders [15] . After the initial diagnosis, the Posttraumatic Stress Diagnostic Scale (PDS) was applied as an interview [16, 17] . This instrument records PTSD symptoms in accordance with the DSM-IV. Depression symptoms were assessed by clinician ratings using the Hamilton Depression Rating Scale (HAM-D) [18, 19] , as well as by means of the Hopkins Symptom Checklist 25 (HSCL25) [20–22] . The severity of BPD symptoms was evaluated by selfAn increasing number of women (0.8–2% of the general public) seem to be affected by borderline personality disorder (BPD) [1] . Whereas BPD is already characterized by a high rate of psychiatric problems, current evaluations indicate that the frequency of comorbid posttraumatic stress disorder (PTSD) ranges between 33 and 61% among patients with BPD [2–4] . Clinicians have frequently noted that a combination of BPD and PTSD leads to mutual amplification of symptoms and thus to most severe impairment of functioning on all levels. A main symptom of BPD concerns sudden, intensive and aversive tension that is difficult for these patients to endure and to regulate [5, 6] . When there is comorbid PTSD, BPD symptoms are potentially intensified by the related anxiety, hyperarousal and intrusions, triggering sudden, uncontrollable and incomprehensible attacks of tension and fear. This prompts a vicious circle of uncontrollable swings in tension and dysfunctional behavioral patterns (e.g. self-inflicted pain and injuries), which in turn makes it impossible to modify maladaptive core beliefs. It has frequently been assumed that patients being treated for BPD can only start to confront traumatic experiences once they have been sufficiently stabilized [3] . Neuner [7] carried out a critical examination of the processes involved in stabilization and confrontation and concluded that little evidence suggests that a stabilization phase prior to trauma exposure would be useful. A suitable trauma-focused therapy for patients with BPD and comorbid PTSD seems essential in order to reduce the burden of symptoms and to help patients understand and integrate the traumatic experiences into their lives. So far, there have been few attempts to treat both BPD and PTSD simultaneously [8] . The present approach sought to test the feasibility of narrative exposure therapy (NET), a trauma-focused therapy suitable for both inand outpatient settings which can be taught to clinically experienced therapists in a short-term training program and implemented in a comprehensive treatment for BPD patients with Received: February 9, 2011 Accepted after revision: May 22, 2011 Published online: November 25, 2011

Sleep in major depression: relation to memory performance and outcome after interpersonal psychotherapy.

Background: Earlier findings suggest both a link between sleep and memory consolidation and a relationship between abnormal sleep at baseline and poor treatment outcome in major depression after interpersonal psychotherapy (IPT). Methods: Pre-treatment polysomnography was examined in 32 patients with a major depressive episode (mean age = 39.5 years, 20 women). Declarative memory was tested by the Rey-Osterrieth Complex Figure Test and a paired associative word list and procedural learning was assessed by a mirror tracing skill. All patients were treated with IPT according to the manual and did not receive any antidepressant medication. Twenty-three patients took part in a minimum of 12 sessions of IPT. Remission was defined as 2 consecutive weeks with a score <8 on the Hamilton Rating Scale of Depression. Results: Declarative visual memory performance was associated with total sleep time and total amount of rapid eye movement sleep. In IPT remitters (n = 14), there was a trend towards a decrease in rapid eye movement density (first period) and a significant decrease in delta power in pre-treatment sleep in comparison to non-remitters (n = 9). Treatment outcome after IPT was also associated with declarative memory performance at baseline (as a trend). Conclusions: Further indications of a role of sleep in memory processes and of the importance of specific sleep parameters as markers for a positive treatment response to psychotherapy were found.

Declarative Memory Performance Is Associated With the Number of Sleep Spindles in Elderly Women

OBJECTIVE Recent evidence suggests that the sleep-dependent consolidation of declarative memory relies on the nonrapid eye movement rather than the rapid eye movement phase of sleep. In addition, it is known that aging is accompanied by changes in sleep and memory processes. Hence, the purpose of this study was to investigate the overnight consolidation of declarative memory in healthy elderly women. SETTING Sleep laboratory of University. PARTICIPANTS Nineteen healthy elderly women (age range: 61-74 years). MEASUREMENTS We used laboratory-based measures of sleep. To test declarative memory, the Rey-Osterrieth Complex Figure Test was performed. RESULTS Declarative memory performance in elderly women was associated with Stage 2 sleep spindle density. Women characterized by high memory performance exhibited significantly higher numbers of sleep spindles and higher spindle density compared with women with generally low memory performance. CONCLUSION The data strongly support theories suggesting a link between sleep spindle activity and declarative memory consolidation.

A flow-cytometric method to investigate glutamate-receptor-sensitivity in whole blood platelets - Results from healthy controls and patients with schizophrenia

Hypofunction of glutamate receptors may contribute to the symptoms of schizophrenia. Human platelets express glutamate receptors and can serve as peripheral surrogate model for neuronal cells. Aim of this study was to establish a fast and sensitive flow-cytometric method to determine the glutamate-dependent kinetics of intracellular calcium ([Ca++]i) mobilization in platelets of schizophrenic patients. Glutamate stimulated [Ca++]i response was measured with a flow-cytometer in anti-CD-41a-labelled whole blood platelets of treated schizophrenic patients (n=18) and controls (n=18). In two control experiments the NMDA-receptor antagonist MK-801 and the dopamine antagonist amisulpride, respectively, were added to probes from healthy subjects. Stimulation with glutamate led dose-dependently to a mobilization of [Ca++]i in both healthy controls and patients. This effect was significantly reduced in patients. In vitro NMDA-antagonism inhibited the glutamate response, whereas dopamine-antagonism had no effect. Our flow-cytometric method allows to measure glutamate-receptor mediated [Ca++]i response in whole blood platelets, without requiring platelet rich preparations. The reduced glutamate-response in the patients was not explained by a direct inhibitory treatment effect. However, further studies with drug naive patients will be necessary to find out whether or not the observed hypoglutamergic function of platelets is endogenous to the disorder.

Sleep at baseline and after electroconvulsive therapy in patients with major depression

Sleep in major depressive disorder is frequently altered and possibly indicative for treatment outcomes. For example, increased rapid eye movement (REM-) sleep density seems to predict worse treatment outcomes of psychotherapy. We therefore investigated pre-treatment sleep and sleep changes after termination of electroconvulsive therapy (ECT). Sleep was polysomnographically recorded. The analysed sample consisted of 15 inpatients with ages ranging from 30 to 80 (mean 59 years). ECT was applied two times a week up to 7 weeks. Stable remission of depressive symptoms was defined by a score in the Hamilton Rating Scale of Depression <8 at six months after ECT. The main results were an increase in sleep efficiency and a decrease in the number of awakenings within the course of ECT in the entire patient group. Significant increases in slow wave sleep and REM sleep duration and a significant decrease in REM density were only seen in stable remitters and not in non-remitters. In pre-treatment baseline sleep a higher REM density of the first REM sleep period was significantly associated with better ECT outcome. In conclusion, REM density of the first REM sleep period seems to be an interesting candidate as putative predictor of stable treatment outcome of ECT.