A role for central nervous growth hormone-releasing hormone signaling in the consolidation of declarative memories.

Contributions of somatotropic hormonal activity to memory functions in humans, which are suggested by clinical observations, have not been systematically examined. With previous experiments precluding a direct effect of systemic growth hormone (GH) on acute memory formation, we assessed the role of central nervous somatotropic signaling in declarative memory consolidation. We examined the effect of intranasally administered growth hormone releasing-hormone (GHRH; 600 µg) that has direct access to the brain and suppresses endogenous GHRH via an ultra-short negative feedback loop. Twelve healthy young men learned word-pair associates at 2030 h and were administered GHRH and placebo, respectively, at 2100 h. Retrieval was tested after 11 hours of wakefulness. Compared to placebo, intranasal GHRH blunted GH release within 3 hours after substance administration and reduced the number of correctly recalled word-pairs by ∼12% (both P<0.05). The impairment of declarative memory consolidation was directly correlated to diminished GH concentrations (P<0.05). Procedural memory consolidation as examined by the parallel assessment of finger sequence tapping performance was not affected by GHRH administration. Our findings indicate that intranasal GHRH, by counteracting endogenous GHRH release, impairs hippocampal memory processing. They provide first evidence for a critical contribution of central nervous somatotropic activity to hippocampus-dependent memory consolidation.

Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders.

The nose provides an effective way for delivering neuropeptides to the central nervous system, bypassing the blood-brain barrier and avoiding systemic side effects. Thereby intranasal neuropeptide administration enables the modulation of central nervous signaling pathways of body weight regulation and cognitive functions. Central nervous control of energy homeostasis is assumed to rely on hypothalamic neuropeptidergic pathways that are triggered by the peripheral adiposity signals insulin and leptin conveying the amount of body fat to the brain. Melanocortins, including alpha-melanocyte stimulating hormone (alpha-MSH), are essential for inducing anorexigenic/catabolic effects, i.e. for inhibiting caloric intake and increasing energy expenditure. Insulin, in addition to its function as an adiposity signal, also influences memory formation. Here we present a series of studies on the intranasal administration of MSH/ACTH4-10, a melanocortin receptor agonist, and of insulin. Prolonged administration of MSH/ACTH4-10 induced weight loss in normal-weight, but not in overweight humans. Intranasal insulin reduced body fat and improved memory functions in the absence of adverse peripheral side effects. Our results may contribute to the future development of therapeutic strategies in disorders like obesity and cognitive impairments that derive from dysfunctions of central nervous neuropeptidergic pathways.

Prehospital noninvasive pressure support ventilation for acute cardiogenic pulmonary edema.

Severe acute cardiogenic pulmonary edema (ACPE) can successfully be treated with noninvasive pressure support ventilation (NIPSV) in a clinical setting. Whether prehospital NIPSV starting early at patients' home and being continued until hospital arrival is feasible and improves ACPE emergency care is examined in this study. End points of the study were oxygen saturation at hospital admission and clinical outcome. Twenty-three patients suffering from severe cardiac pulmonary edema with severe dyspnea, an oxygen saturation of less than 90% and basal rales were included in this controlled prospective randomized trial. All patients received standard medical treatment and 10 patients were additionally treated with NIPSV (pressure support level, 12 cmH2O; positive endexpiratory pressure, 5 cmH2O; FiO2, 0.6) whereas the other patients received oxygen (8 l/min) via Venturi face mask. Improvement in oxygen saturation was significantly faster in the NIPSV group and oxygen saturation was higher at the time of the hospital admission (NIPSV=97.3+/-0.8%; standard=89.5+/-2.7%, P=0.002). A trend toward higher troponin T levels was seen in the standard treatment group. The need for intensive care treatment did not differ, and one patient of each treatment group died in hospital. No complications were noted during the treatment with NIPSV. Prehospital NIPSV is feasible and able to improve emergency management of ACPE.

Light and darkness fail to regulate melatonin release in critically ill humans.

OBJECTIVE: Pineal dysfunction has been associated with morbidity and mortality in various animal models of severe illness, and low melatonin plasma concentrations have recently been reported in patients on the ICU. However, it is not known whether the physiological response of the pineal gland to light and darkness is preserved in critical illness. DESIGN AND PATIENTS: We examined the nocturnal release of melatonin in response to 1 h of darkness followed by 1 h of bright light (>10,000 lux) in 20 severely ill patients on a medical ICU. Eleven elderly (median age 73 years) and 9 young patients (38 years) were recruited. Melatonin plasma concentrations were measured at 30-min intervals. RESULTS: In 15 patients melatonin plasma concentration was low and responded to neither darkness nor light. In three elderly and two young patients melatonin plasma concentrations were elevated irrespective of illumination. CONCLUSIONS: The physiological regulation of melatonin secretion by darkness and light is abolished in severely ill patients.

Myocardial infarction as an uncommon clinical manifestation of intravascular large cell lymphoma.

Intravascular large cell lymphoma (IVL) is a very rare variant of non-Hodgkin's lymphoma presenting with puzzling clinical manifestations. There is a predilection for the central nervous system, but the tumour often affects also skin, lung, and kidneys while lymphadenopathy and hepatosplenomegaly are usually absent. Myocardial infarction due to IVL has not been reported so far. We here report on a 56-year-old patient who was admitted to our hospital with fever and clinical signs of erysipelas. He had a 6-month history of "collagen vasculitic disease" treated with prednisolone and azathioprine. He received antibiotic treatment, but after transient improvement fever recurred with generalized seizures and myocardial infarction, which required transfer to the intensive care unit where the patient died with signs of an acute cardiogenic shock. Autopsy revealed a generalized high-grade B cell lymphoma of IVL type affecting and obstructing small vessels of a variety of tissues including heart, brain and lungs. The tumorous obliteration of small intramyocardial vessels had led to an acute ischaemia with infarction and subsequent signs of myocardial insufficiency. To the best of the authors' knowledge myocardial infarction as a leading symptom of IVL has not been described.

Effects of cortisol suppression on sleep-associated consolidation of neutral and emotional memory.

BACKGROUND: Previous research indicates that hippocampus-dependent declarative memory benefits from early nocturnal sleep, when slow-wave sleep (SWS) prevails and cortisol release is minimal, whereas amygdala-dependent emotional memory is enhanced through late sleep, when rapid eye movement (REM) sleep predominates. The role of the strong cortisol rise accompanying late sleep for emotional memory consolidation has not yet been investigated. METHODS: Effects of the cortisol synthesis inhibitor metyrapone on sleep-associated consolidation of memory for neutral and emotional texts were investigated in a randomized, double-blind, placebo-controlled study in 14 healthy men. Learning took place immediately before treatment, which was followed by 8 hours of sleep. Retrieval was tested at 11 am the next morning. RESULTS: Metyrapone suppressed cortisol during sleep and blocked particularly the late-night rise in cortisol. It reduced SWS and concomitantly impaired the consolidation of neutral texts. Emotional texts were spared from this impairing influence, however. Metyrapone even amplified emotional enhancement in text recall indicating amygdala-dependent memory. CONCLUSIONS: Cortisol blockade during sleep impairs hippocampus-dependent declarative memory formation but enhances amygdala-dependent emotional memory formation. The natural cortisol rise during late sleep may thus protect from overshooting emotional memory formation, a mechanism possibly pertinent to the development of posttraumatic stress disorder.

Intranasal atrial natriuretic peptide acts as central nervous inhibitor of the hypothalamo-pituitary-adrenal stress system in humans.

Increased hypothalamo-pituitary-adrenal activity contributes to morbidity in widespread metabolic and psychiatric diseases. Inhibition of hypercortisolism represents a promising therapeutic strategy in these conditions, which currently cannot be used. Here, we tested the hypothesis that atrial natriuretic peptide (ANP) administered intranasally is a safe and feasible inhibitor of pituitary-adrenal activity at the central nervous level. Thirty minutes after intranasal administration of ANP (1 mg) and placebo, pituitary-adrenal activity was stimulated in 18 healthy men by two tests: 1) a standard insulin-hypoglycemia test and 2) CRH combined with vasopressin (VP), respectively. ACTH, cortisol, VP, blood pressure, heart rate, and measures of fluid balance were also recorded. Pretreatment with ANP suppressed cortisol (P < 0.01) and ACTH (P < 0.05) secretory responses to insulin-induced hypoglycemia to about half of that seen after placebo, but pituitary-adrenal activity was not suppressed by CRH/VP injection (P > 0.7). Indicators of fluid balance, cardiovascular parameters, and self-report measures were not influenced by the treatment. Results indicate a strong inhibition of stimulated pituitary-adrenal activity after intranasal administration of ANP. The absence of an effect on CRH/VP-induced pituitary-adrenal responses suggests a direct action of the peptide on the central nervous system inhibiting stimulated hypothalamo-pituitary-adrenal activity at the hypothalamic level.

Sleep enhances the human antibody response to hepatitis A vaccination.

OBJECTIVE: The common belief that sleep supports immune defense has received surprisingly little direct experimental support. The antibody response to vaccination provides a valid tool to assess the influence of sleep on adaptive immune functioning in humans, which is also clinically relevant. METHODS: Two groups of healthy humans (N = 19) not previously infected with hepatitis A virus (HAV) were studied. On the night after primary vaccination with inactivated HAV, which took place at 0900 hours, one group had regular sleep. The other group stayed awake, and did not sleep before 2100 hours the following day. HAV antibody titers were measured repeatedly until 28 days after vaccination. Plasma hormone concentrations and white blood cell (WBC) subset counts were determined on the night and day after vaccination. RESULTS: Subjects who had regular sleep after vaccination, displayed a nearly two-fold higher HAV antibody titer after 4 weeks than subjects staying awake on this night (p=.018). Compared with wakefulness, sleep after vaccination distinctly increased release of several immune-stimulating hormones including growth hormone, prolactin, and dopamine (p <.01). Concentrations of thyrotropin, norepinephrine, and epinephrine were lowered by sleep (p <.02), whereas sleep only marginally influenced WBC subset counts. CONCLUSIONS: Data suggest that sleep compared with sleep deprivation on the night after vaccination improves the formation of antigen-specific immune defense as reflected by antibody production in humans. Sleep presumably acts by inducing a hormonal environment in secondary lymphoid tissues, enhancing lymphocyte proliferation and differentiation and finally antibody synthesis. Results underscore the importance of sleep for immunocompetence.

Evidence for lower sympathetic nerve activity in young adults with low birth weight.

OBJECTIVE: A dysfunction of the sympathetic nervous system may contribute to the development of hypertension and obesity in subjects with low birth weight (LBW). The present study examines resting sympathetic nerve traffic and its baroreflex modulation to the muscle vascular bed in healthy LBW subjects. DESIGN: Case-control studies of 13 healthy LBW subjects (< 2500 g at term) aged 20-30 years and 13 normal birth weight subjects (NBW; 3200-3700 g) closely matched for age, gender and body mass index. METHODS: Muscle sympathetic nerve activity (MSNA) recordings from the superficial peroneal nerve, blood pressure and heart rate were obtained at rest, during an inspiratory apnoea and a cold pressor test. Baroreflex function was evaluated by short-term infusion of nitroprusside and phenylephrine, respectively, in nine subjects of each group. RESULTS: During resting conditions burst frequency was significantly lower in LBW subjects (LBW: 24.7 +/- 2.4; NBW: 34.4 +/- 2.1 bursts/min, P < 0.05). When normalized for the different baseline values, baroreflex-mediated changes in MSNA were similar in both groups. Maximal MSNA levels in response to inspiratory apnoea and the cold pressor test did not differ between the groups. Blood pressure and heart rate were similar in LBW and NBW subjects both at rest and during sympatho-excitatory manoeuvres. CONCLUSIONS: Subjects born too small for their gestational age show a significantly lower sympathetic nerve activity under baseline conditions. Given the different baseline values, the sympathetic response to haemodynamic alteration is not affected in LBW subjects, and maximal activation during non-haemodynamic sympatho-excitatory manoeuvres is preserved.

Improvement of sleep and pituitary-adrenal inhibition after subchronic intranasal vasopressin treatment in elderly humans.

Subchronic intranasal treatment with argininevasopressin (AVP) has been shown to exert a strong ameliorating effect on sleep and slow wave sleep (SWS) deficits in elderly. However, AVP is also a potent stimulus of the pituitary-adrenal stress system, which is usually inhibited during early, SWS-rich sleep. A disinhibition of pituitary-adrenal activity during sleep is correlated with aging and is considered a pathologic factor contributing to various age-related diseases. Here, we examined whether the beneficial effect of prolonged intranasal AVP administration on sleep in aged would be associated with a concomitant decrease in pituitary-adrenal inhibition and effects on other neuroendocrine features of sleep. Twenty-six healthy elderly (mean 72.9 yr) with mild sleep complaints were investigated in a placebo controlled double-blind study. One group was treated daily each morning and evening with intranasal AVP (2 x 20 IU) for 10 weeks, the other received placebo. During polysomnographical recordings taken at the beginning and end of the treatment period, blood was sampled every 15 min. Intranasal AVP increased SWS on average by +21.5 min (p<0.02). The effect persisted on the night after acute withdrawal of the peptide treatment with no rebound occurring. Notably, rather than increasing pituitary-adrenal activity, AVP decreased the early sleep cortisol nadir on average by 0.5 microg/dl (p<0.05). AVP did not induce any measurable changes in fluid balance or cardiovascular activity. Overall, results indicate a promoting effect of AVP on SWS in aged accompanied by a beneficial rather than impairing influence on the neuroendocrine pattern of sleep.

Growth hormone-releasing hormone facilitates hypoglycemia-induced release of cortisol.

Early sleep in humans is characterized by a distinct suppression of pituitary-adrenal activity coinciding with enhanced activity of the somatotropic axis. Here, we tested in awake humans the hypothesis of an inhibiting influence of hypothalamic growth hormone-releasing hormone (GHRH) on pituitary-adrenal activity. For this purpose, pituitary-adrenal activity was stimulated in 10 men through a standard insulin-hypoglycemia-test (IHT) and in another 10 men through combined administration of CRH/vasopressin. Stimulation was performed in each man on three conditions following pretreatment with Placebo and GHRH administered intravenously (50 microg) or intranasally (300 microg) 1 h before. GH, ACTH and cortisol as well as blood pressure and heart rate were measured repeatedly. Contrary to expectations, pretreatment with GHRH did not suppress but enhanced secretion of cortisol upon insulin-induced hypoglycemia regardless of the route of GHRH pretreatment (p<0.05). In contrast, GHRH did not facilitate cortisol release after stimulation with CRH/vasopressin. Changes in ACTH remained inconsistent. Plasma levels of GH increased significantly after i.v. GHRH application, but remained unchanged after the intranasal administration. Blood pressure and heart rate were not influenced by the treatments. Results indicate facilitating effects of GHRH mediated at a suprapituitary (i.e. hypothalamic) level as suggested by restriction of the effect to the hypoglycemia-induced cortisol release with no effects after pituitary stimulation with CRH/vasopressin.

Post-trial administration of vasopressin in humans does not enhance memory formation (vasopressin and memory consolidation).

Many animal studies show an enhancing effect of vasopressin (VP) on memory, but not all human studies could confirm this finding. This study examined the influence of post-learning administration of VP (40 IU, intranasally) on the consolidation of declarative memories in healthy humans during different intervals of sleep and waking. We could not find any effect of VP on memory consolidation, but EEG activity indicated a significant arousing influence of VP. Results suggest that if VP affects memory function it might do so primarily at the stage of encoding of the materials to be learned but it leaves unaffected processes of consolidation.