As an indicator of cortical excitability, direct current (DC) potentials were recorded from thirs... more As an indicator of cortical excitability, direct current (DC) potentials were recorded from thirsted subjects before, during and after drinking 400 ml of water. Self-rated thirst was distinctly reduced after drinking. Compared with control conditions in which the subjects remained thirsty, during drinking a widespread negative potential shift occurred averaging over -70 microV at Cz. At the transition from the consumatory phase to the postconsumption phase, a slow positive potential shift commenced that was most pronounced over the anterior cortex (averaging over +40 microV at Fz) and persisted for more than 3 min after drinking. Control conditions excluded muscle activity, ocular movements, and changes in body fluid and serum osmolality as possible non-neuronal sources of the DC-potential changes. The sequence of negative and positive potential shifts associated with drinking indicates a coordinate regulation of cortical excitability that may facilitate consumatory behavior and its context-dependent encoding into memory.
A previous experiment indicated a greater efficacy of episodic than continuous growth hormone (GH... more A previous experiment indicated a greater efficacy of episodic than continuous growth hormone (GH)-releasing hormone (GHRH) administration in enhancing sleep. The greater efficacy of episodic administration could principally result from two factors, i.e. the greater peak concentration reached after episodic administration or the recurrence of increasing slopes in GHRH concentration. In order to investigate which factor essentially determines the pharmacodynamics of sleep promotion after GHRH, effects after a transient high peak in GHRH concentration were compared with those of repetitive increases in GHRH concentration. Sleep, plasma concentrations of GH, and GHRH were examined in healthy subjects after evening administration of a 'single' i.v. bolus of 50 micrograms GHRH, after five 'repetitive' boluses of 10 micrograms GHRH, and after placebo. Compared with placebo, single GHRH significantly increased time spent in stage 4 sleep (p < .01) and in stage 2 sleep, reduced time spent in wakefulness and onset latency of stage 4 sleep (p < .05, for each), while repetitive GHRH remained without effects. GH secretory activity also tended to be higher after single than repetitive GHRH. Thus, results suggest the relevance of a transiently high concentration of GHRH in blood as an essential factor in enhancing the central nervous sleep process.
The cytokine IL-6 has been considered to exert neuromodulating influences on the brain, with prom... more The cytokine IL-6 has been considered to exert neuromodulating influences on the brain, with promoting influences on sleep. Sleep enhances the consolidation of memories, and, in particular, late nocturnal sleep also represents a period of enhanced IL-6 signaling, due to a distinctly enhanced availability of soluble IL-6 receptors during this period, enabling trans-signaling of IL-6 to neurons. Thus, a contribution of IL-6 to sleep-dependent memory consolidation is hypothesized. To test this hypothesis, we compared effects of intranasally administered IL-6 (vs. placebo) on sleep-dependent consolidation of declarative (neutral and emotional texts, 2-dimensional object location) and procedural (finger sequence tapping) memories in 17 healthy young men. IL-6 distinctly improved the sleep-related consolidation of emotional text material (P<0.03), which benefits mostly from sleep in the second night-half, in which rapid eye movement sleep (REM) dominates the non-REM-REM sleep cycle. During this second night-half, the amount of electroencephalogram slow-wave activity (0.5-4 Hz) distinctly increased after IL-6 (P<0.01). Other types of memory were not affected. The ability of IL-6 to enhance sleep-associated emotional memory consolidation highlights an example of a functional interaction between the central nervous and immune system.-Benedict, C.,
Slow oscillations originating in the prefrontal neocortex during slowwave sleep (SWS) group neuro... more Slow oscillations originating in the prefrontal neocortex during slowwave sleep (SWS) group neuronal network activity and thereby presumably support the consolidation of memories. Here, we investigated whether the grouping influence of slow oscillations extends to hippocampal sharp wave-ripple (SPW) activity thought to underlie memory replay processes during SWS. The prefrontal surface EEG and multiunit activity (MUA), along with hippocampal local field potentials (LFP) from CA1, were recorded in rats during sleep. Average spindle and ripple activity and event correlation histograms of SPWs were calculated, time-locked to half-waves of slow oscillations. Results confirm decreased prefrontal MUA and spindle activity during EEG slow oscillation negativity and increases in this activity during subsequent positivity. A remarkably close temporal link was revealed between slow oscillations and hippocampal activity, with ripple activity and SPWs being also distinctly decreased during negative half-waves and increased during slow oscillation positivity. Fine-grained analyses of temporal dynamics revealed for the slow oscillation a phase delay of approximately 90 ms with reference to up and down states of prefrontal MUA, and of only approximately 60 ms with reference to changes in SPWs, indicating that up and down states in prefrontal MUA precede corresponding changes in hippocampal SPWs by approximately 30 ms. Results support the notion that the depolarizing surface-positive phase of the slow oscillation and the associated up state of prefrontal excitation promotes hippocampal SPWs via efferent pathways. The preceding disfacilitation of hippocampal events temporally coupled to the negative slow oscillation half-wave appears to serve a synchronizing role in this neocorticohippocampal interplay.
Slow wave sleep, hallmarked by the occurrence of slow oscillations (SO), plays an important role ... more Slow wave sleep, hallmarked by the occurrence of slow oscillations (SO), plays an important role for the consolidation of hippocampus-dependent memories. Transcranial stimulation by weak electric currents oscillating at the endogenous SO frequency (SO-tDCS) during post-learning sleep was previously shown by us to boost SO activity and improve the consolidation of hippocampus-dependent memory in human subjects. Here, we aimed at replicating and extending these results to a rodent model. Rats were trained for 12 days at the beginning of their inactive phase in the reference memory version of the radial arm maze. In a between subjects design, animals received SO-tDCS over prefrontal cortex (PFC) or sham stimulation within a time frame of 1 h during subsequent non-rapid eye movement (NREM) sleep. Applied over multiple daily sessions SO-tDCS impacted cortical network activity as measured by EEG and behavior: at the EEG level, SO-tDCS enhanced post-stimulation upper delta (2-4 Hz) activity whereby the first stimulations of each day were preferentially affected. Furthermore, commencing on day 8, SO-tDCS acutely decreased theta activity indicating long-term effects on cortical networks. Behaviorally, working memory for baited maze arms was enhanced up to day 4, indicating enhanced consolidation of task-inherent rules, while reference memory errors did not differ between groups. Taken together, we could show here for the first time an effect of SO-tDCS during NREM sleep on cognitive functions and on cortical activity in a rodent model.
Intranasal administration of angiotensin II (ANGII) affects blood pressure in a mode different fr... more Intranasal administration of angiotensin II (ANGII) affects blood pressure in a mode different from intravenously administered ANGII via a direct access to the brain bypassing the blood-brain barrier. This clinical study investigated blood pressure regulation after intranasal ANGII administration in healthy humans, whereas systemic, blood-mediated effects of ANGII were specifically blocked. In a balanced crossover design, men (n=8) and women (n=8) were intranasally administered ANGII (400 μg) or placebo after ANGII type 1 receptors had been blocked by pretreatment with valsartan (80 mg; 12 and 6 hours before intranasal administration). Plasma levels of ANGII, aldosterone, renin, vasopressin, and norepinephrine were measured; blood pressure and heart rate were recorded continuously. Intranasal ANGII acutely decreased blood pressure without altering the heart rate. Plasma levels of vasopressin and norepinephrine remained unaffected. Plasma ANGII levels were increased throughout the recording period. Aldosterone levels increased despite the peripheral ANGII type 1 receptor blockade, indicating an aldosterone escape phenomenon. In conclusion, intranasal ANGII reduces blood pressure in the presence of selective ANGII type 1 receptor blockade. Intranasal ANGII administration represents a useful approach for unraveling the role of this peptide in blood pressure regulation in humans. (Hypertension. 2014;63:762-767.) • Online Data Supplement
The positive impact of sleep on memory consolidation has been shown for human subjects in numerou... more The positive impact of sleep on memory consolidation has been shown for human subjects in numerous studies, but there is still sparse knowledge on this topic in rats, one of the most prominent model species in neuroscience research. Here, we examined the role of sleep in the object-place recognition task, a task closely comparable to tasks typically applied for testing human declarative memory: It is a one-trial task, hippocampus-dependent, not stressful and can be repeated within the same animal. A test session consisted of the Sample trial, followed by a 2-h retention interval and a Test trial, the latter examining the memory the rat had for the places of two objects presented at the Sample trial. In Experiment 1, each rat was tested twice, with the retention interval taking place either in the morning or evening, i.e., in the inactive or active phase, respectively. Rats showed significantly (p < 0.01) better memory for object place after the Morning session. To control for confounding circadian factors, in Experiment 2 rats were tested four times, i.e., in the morning or in the evening while sleep was or was not deprived. Sleep during the retention interval was recorded polysomnographically. Rats only showed significant memory for the target object place in the Test trial after the Morning retention interval in the absence of sleep deprivation, and recognition performance in this condition was significantly superior to that in the three other conditions (p < 0.05). EEG recordings during spontaneous morning sleep revealed increased slow oscillation (0.85-2.0 Hz) and upper delta (2.0-4.0 Hz), but reduced spindle band (10.5-13.5 Hz) activity, as compared to evening sleep. However, spindle band power was increased in the Morning retention interval in comparison to a Morning Baseline period (p < 0.05). We conclude that consolidation of object-place memory depends on sleep, and presumably requires NonREM sleep rich in both slow wave and spindle activity.
As an indicator of cortical excitability, direct current (DC) potentials were recorded from thirs... more As an indicator of cortical excitability, direct current (DC) potentials were recorded from thirsted subjects before, during and after drinking 400 ml of water. Self-rated thirst was distinctly reduced after drinking. Compared with control conditions in which the subjects remained thirsty, during drinking a widespread negative potential shift occurred averaging over -70 microV at Cz. At the transition from the consumatory phase to the postconsumption phase, a slow positive potential shift commenced that was most pronounced over the anterior cortex (averaging over +40 microV at Fz) and persisted for more than 3 min after drinking. Control conditions excluded muscle activity, ocular movements, and changes in body fluid and serum osmolality as possible non-neuronal sources of the DC-potential changes. The sequence of negative and positive potential shifts associated with drinking indicates a coordinate regulation of cortical excitability that may facilitate consumatory behavior and its context-dependent encoding into memory.
Journal of Clinical Psychopharmacology, Feb 1, 1999
Disturbed sleep is common in the elderly and is characterized by disordered sleep architecture wi... more Disturbed sleep is common in the elderly and is characterized by disordered sleep architecture with reduced time spent in slow wave sleep (SWS) and in rapid eye movement (REM) sleep. At present, no treatments are available to fully compensate for these disorders. In the elderly, vasopressin content is decreased at various brain sites. Investigating the effects of a 3-month intranasal vasopressin administration on sleep and cognitive functions in two elderly subjects in a foregoing pilot study, the authors found that the most pronounced influence of the peptide was a marked increase in SWS. This placebo-controlled, double-blind, randomized study examined the influences of a 3-month period of daily intranasal vasopressin treatment (20 IU before bedtime and after awakening) on nocturnal sleep in 26 healthy elderly subjects (mean age, 74.2 years). Intranasal treatment of vasopressin increased (1) the total sleep time, on average, by 45 minutes (p &lt; 0.002); (2) time spent in SWS by 21 minutes (p &lt; 0.025); and (3) time in REM sleep in the second half of the night by 10 minutes (p &lt; 0.01). Vasopressin promotes sleep time and improves sleep architecture after prolonged intranasal administration in elderly subjects, although scores of subjective sleep quality did not change. Results suggest that age-related deterioration of sleep architecture can benefit from intranasal treatment with vasopressin. But a potential use in clinical settings will also depend on demonstrating improved subjective sleep quality, which remained unaffected by vasopressin in this study of elderly subjects.
Scalp-recorded direct current (DC) potentials and their topographical distribution (F3, F4, C3, C... more Scalp-recorded direct current (DC) potentials and their topographical distribution (F3, F4, C3, C4 and pz) were investigated at the transition from wakefulness to sleep, and during NREM-REM sleep and REM-NREM sleep transitions in 11 healthy men during normal sleep. Changes in endexpiratory CO 2 partial pressure (ETC0 2), scalp temperature and polysomnographic data were simultaneously measured. The transition to sleep was associated with a negative potential shift reaching significance bilaterally at frontal and central sites 5 to 10 minutes after sleep onset (p < 0.05). Largest shifts were found at frontal locations 10 to 15 minutes after sleep onset averaging (mean ::t SEM)-512 ::t 103 fL V. Negative DC potential shifts also occurred at the transitions from NREM to REM sleep and from REM to NREM sleep, but were, however, less pronounced. The negative DC shift at NREM-REM sleep transitions prcccdcd the REM sleep onset (assessed conventionally by pulysumnographic criteria) by about 1.5 minutes. Changes in temperature, ETC0 2 and eye movements were ruled out as factors significantly contributing to the generation of these shifts. Assuming a neuronal origin of the DC potential, the negative shifts at the wakesleep transition and between NREM and REM sleep suggest a temporary phase of increased cortical excitability.
Electroencephalographic activity at the transition from wakefulness to sleep is characterized by ... more Electroencephalographic activity at the transition from wakefulness to sleep is characterized by the appearance of spindles (12-15 Hz) and slow wave rhythms including delta activity (1-4 Hz) and slow oscillations (0.2-1 Hz). While these rhythms originate within neocortico-thalamic circuitry, their emergence during the passage into slow wave sleep (SWS) critically depends on the activity of neuromodulatory systems. Here, we examined the temporal relationships between these electroencephalogram rhythms and the direct current (DC) potential recorded from the scalp in healthy men (n)01؍ using cross-correlation analyses. Analyses focused on transitions from wakefulness to SWS in the beginning of the sleep period, and from SWS to lighter sleep and rapid eye movement (REM) sleep at the end of the first sleep cycle. For spindle, delta and slow oscillatory activity strong negative correlations with the DC potential were found at the transition into SWS with peak correlation coefficients (at zero time lag) averaging r,18.0؊؍ ؊0.88 and ؊0.88, respectively (P<0.001). Though slightly lower, distinct negative correlations between these measures were also found at the transition from SWS to REM sleep (؊0.78, ؊0.77 and ؊0.77, respectively, P<0.001). Fast oscillatory activity in the beta frequency band (15-25 Hz) was correlated positively with the DC potential (r,57.0؉؍ P<0.05, at the passage to SWS). Data indicate close links between increasing spindle, delta and slow oscillatory activity and the occurrence of a steep surface negative cortical DC potential shift during the transition from wake to SWS. Likewise, a DC potential shift toward surface positivity accompanies the disappearance of these oscillatory phenomena at the end of the non-REM sleep period. The DC potential shifts may reflect gradual changes in extracellular ionic (Ca 2؉) concentration resulting from the generation of spindle and slow wave rhythms, or influences of neuromodulating systems on cortical excitability thereby controlling the emergence of cortical spindle and slow wave rhythms at SWS transitions.
This chapter discusses various levels of interactions between the brain and the immune system in ... more This chapter discusses various levels of interactions between the brain and the immune system in sleep. Sleep-wake behavior and the architecture of sleep are influenced by microbial products and cytokines. On the other hand, sleep processes, and perhaps also specific sleep states, appear to promote the production and/or release of certain cytokines. The effects of immune factors such as endotoxin and cytokines on sleep reveal species specificity and usually strong dependence on parameters such as substance concentration, time relative to administration or infection with microbial products, and phase relation to sleep and/or the light-dark cycle. For instance, endotoxin increased SWS and EEG SWA in humans only at very low concentrations, whereas higher concentrations increased sleep stage 2 only, but not SWS. In animals, increases in NREM sleep and SWA were more consistent over a wide range of endotoxin doses. Also, administration of pro-inflammatory cytokines such as IL-6 and IFN-alpha in humans acutely disturbed sleep while in rats such cytokines enhanced SWS and sleep. Overall, the findings in humans indicate that strong nonspecific immune responses are acutely linked to an arousing effect. Although subjects feel subjectively tired, their sleep flattens. However, some observations indicate a delayed enhancing effect on sleep which could be related to the induction of secondary, perhaps T-cell-related factors. This would also fit with results in animals in which the T-cell-derived cytokine IL-2 enhanced sleep while cytokines with immunosuppressive functions like IL-4 and L-10 suppressed sleep. The most straightforward similarity in the cascade of events inducing sleep in both animals and humans is the enhancing effect of GHRH on SWS, and possibly the involvement of the pro-inflammatory cytokine systems of IL-1 beta and TNF-alpha. The precise mechanisms through which administered cytokines influence the central nervous system sleep processes are still unclear, although extensive research has identified the involvement of various molecular intermediates, neuropeptides, and neurotransmitters (cp. Fig. 5, Section III.B). Cytokines are not only released and found in peripheral blood mononuclear cells, but also in peripheral nerves and the brain (e.g., Hansen and Krueger, 1997; März et al., 1998). Cytokines are thereby able to influence the central nervous system sleep processes through different routes. In addition, neuronal and glial sources have been reported for various cytokines as well as for their soluble receptors (e.g., Kubota et al., 2001a). Links between the immune and endocrine systems represent a further important route through which cytokines influence sleep and, vice versa, sleep-associated processes, including variations in neurotransmitter and neuronal activity may influence cytokine levels. The ability of sleep to enhance the release and/or production of certain cytokines was also discussed. Most consistent results were found for IL-2, which may indicate a sleep-associated increase in activity of the specific immune system. Furthermore, in humans the primary response to antigens following viral challenge is enhanced by sleep. In animals results are less consistent and have focused on the secondary response. The sleep-associated modulation in cytokine levels may be mediated by endocrine parameters. Patterns of endocrine activity during sleep are probably essential for the enhancement of IL-2 and T-cell diurnal functions seen in humans: Whereas prolactin and GH release stimulate Th1-derived cytokines such as IL-2, cortisol which is decreased during the beginning of nocturnal sleep inhibits Th1-derived cytokines. The immunological function of neurotrophins, in particular NGF and BDNF, has received great interest. Effects of sleep and sleep deprivation on this cytokine family are particularly relevant in view of the effects these endogenous neurotrophins can have not only on specific immune functions and the development of immunological memories, but also on synaptic reorganization and neuronal memory formation.
Tiagabine Increases Slow Wave Sleep but not Memory-Feld et al INTRODUCTION There exists ample evi... more Tiagabine Increases Slow Wave Sleep but not Memory-Feld et al INTRODUCTION There exists ample evidence that memory traces acquired during wakefulness rely on strengthening during sleep. 1 This consolidation process is essentially supported by slow wave sleep (SWS). SWS enhances declarative memory (for episodes and facts) 2,3 as well as procedural skill memories. 4 The enhancing effect on memory consolidation appears to be mediated in particular by the neocortical < 1 Hz slow oscillation that is the hallmark of the EEG during SWS; it synchronizes the neuronal reactivation of newly acquired memory representations occurring during SWS in distributed networks to the excitable depolarizing up-state of these slow oscillations. 5 This allows the redistribution of the reactivated memory representations and their stabilization for the longer term. 1 Recent evidence suggests that procedural memory can also benefit from reactivation during NREM sleep and that this effect is related to sleep spindles. 6 The memory-consolidating effect of the slow oscillations appears to additionally result from the fact thatin parallel with reactivations-they also synchronize thalamocortical spindles (12-15 Hz) to the depolarizing slow oscillation up-state. 7,8 Post-learning spindle activity has been consistently SLOW WAVE SLEEP INDUCED BY TIAGABINE AND MEMORY CONSOLIDATION
This study examined the effects of ACTH 4-10, a fragment of adrenocorticotropin (ACTH) with known... more This study examined the effects of ACTH 4-10, a fragment of adrenocorticotropin (ACTH) with known central nervous system (CNS) activity, on the dimensional complexity of the ongoing electroencephalographic (EEG) activity. Stressful stimuli cause ACTH to be released from the pituitary, and as a neuropeptide ACTH may concurrently exert adaptive influences on the brain's processing of these stimuli. Previous studies have indicated an impairing influence of ACTH on selective attention. Methods: Dimensional complexity of the EEG, which indexes the brain's way of stimulus processing, was evaluated while subjects performed tasks with different attention demands. Sixteen healthy men (23 to 33 years) were tested once after placebo and another time after administration of ACTH 4-10 (1.25 mg intravenously (IV), 30 minutes before testing). The EEG was recorded while subjects were presented with a dichotic listening task (consisting of the concurrent presentation of tone pips to the left and right ear). Subjects either a) listened to pips in both ears (divided attention), or b) listened selectively to pips in one ear (selective attention), or c) ignored all pips. Results: Dimensional complexity of the EEG was higher during divided than selective attention. ACTH significantly increased the EEG complexity during selective attention, in particular over the midfrontal cortex (F z , CJ. Conclusions: The effects support the view of a de-focusing action of ACTH during selective attention that could serve to improve the organism's adaptation to stress stimuli.
Systemic administration of growth hormone-releasing hormone (GHRH) has been found to improve huma... more Systemic administration of growth hormone-releasing hormone (GHRH) has been found to improve human sleep in previous studies. Here we examined effects of GHRH on endocrine function and sleep after intranasal administration, a method which based on previous studies appears to enable a direct effect of peptides on brain function. Also, it was hypothesized that elderly humans displaying deficient GH release and sleep, benefit from GHRH administration more than young subjects. A study was performed according to a double-blind cross-over design. Each of 12 young and 11 old healthy men were intranasally administered with 300 mg GHRH (vs. placebo) 30 min before bedtime at 23:00 h. Sleep was recorded polysomnographically until 07:00 h and blood was collected in 15 min intervals for determination of cortisol and GH. Apart from the well-known age-related changes of hormonal secretion and sleep, intranasal GHRH reduced cortisol nadir concentrations in the beginning of sleep (PB0.05), and also reduced the sleep-induced elevation in GH concentrations during early sleep. Moreover, results indicated that after intranasal administration GHRH increased rapid-eye-movement (REM) sleep and slow wave sleep (SWS), with this influence concentrating on the second half of sleep time. Effects of GHRH did not depend on the subject's age. We conclude that there is a coordinate influence of intranasal GHRH on the central nervous regulation of sleep processes and of hypothalamic-hypophysiotropic
Processing of hedonic stimulus quality is assumed to be accompanied by a tuning of cortical arous... more Processing of hedonic stimulus quality is assumed to be accompanied by a tuning of cortical arousal and excitability. In this pilot study in 11 healthy humans scalp-recorded DC potentials were assessed during application of a sweet (sucrose) and bitter (quinine hydrochloride) taste, i.e., primary reinforcers of positive and negative quality. Muscular, ocular, and skin potential activity were controlled. Application of sucrose induced a widespread positive DC-potential shift with an amplitude of 40 ± 50 mV and persisting for more than 120-s post-stimulus onset. Following administration of quinine hydrochloride, this positive shift was reduced, most distinctly between 48-and 88-s post-stimulus onset. The reduction appeared to be most consistent at anterior midline recording sites (Fz, Cz). It is assumed that the higher DC-potential positivity during sweetness than during bitterness points to a differential tuning of cortical excitability by a widespread decrease in depolarization of apical dendrites.
This study shows that divergent thinking, considered the general process underlying creative prod... more This study shows that divergent thinking, considered the general process underlying creative production, can be distinguished from convergent, analytical thought based on the dimensional complexity of ongoing electroencephalographic (EEG) activity. EEG complexity over the central and posterior cortex was higher while subjects solved tasks of divergent than convergent thinking, and also higher than during mental relaxation. Over the frontal cortex, EEG complexity was comparable during divergent thinking and mental relaxation, but reduced during convergent thinking. Results indicate that the basic process underlying the generation of novel ideas expresses itself in a strong increase in the EEG's complexity, reflecting higher degrees of freedom in the competitive interactions among cortical neuron assemblies. Frontocortical EEG complexity being comparable with that during mental relaxation, speaks for a loosened attentional control during creative thinking.
As an indicator of cortical excitability, direct current (DC) potentials were recorded from thirs... more As an indicator of cortical excitability, direct current (DC) potentials were recorded from thirsted subjects before, during and after drinking 400 ml of water. Self-rated thirst was distinctly reduced after drinking. Compared with control conditions in which the subjects remained thirsty, during drinking a widespread negative potential shift occurred averaging over -70 microV at Cz. At the transition from the consumatory phase to the postconsumption phase, a slow positive potential shift commenced that was most pronounced over the anterior cortex (averaging over +40 microV at Fz) and persisted for more than 3 min after drinking. Control conditions excluded muscle activity, ocular movements, and changes in body fluid and serum osmolality as possible non-neuronal sources of the DC-potential changes. The sequence of negative and positive potential shifts associated with drinking indicates a coordinate regulation of cortical excitability that may facilitate consumatory behavior and its context-dependent encoding into memory.
A previous experiment indicated a greater efficacy of episodic than continuous growth hormone (GH... more A previous experiment indicated a greater efficacy of episodic than continuous growth hormone (GH)-releasing hormone (GHRH) administration in enhancing sleep. The greater efficacy of episodic administration could principally result from two factors, i.e. the greater peak concentration reached after episodic administration or the recurrence of increasing slopes in GHRH concentration. In order to investigate which factor essentially determines the pharmacodynamics of sleep promotion after GHRH, effects after a transient high peak in GHRH concentration were compared with those of repetitive increases in GHRH concentration. Sleep, plasma concentrations of GH, and GHRH were examined in healthy subjects after evening administration of a &#39;single&#39; i.v. bolus of 50 micrograms GHRH, after five &#39;repetitive&#39; boluses of 10 micrograms GHRH, and after placebo. Compared with placebo, single GHRH significantly increased time spent in stage 4 sleep (p &lt; .01) and in stage 2 sleep, reduced time spent in wakefulness and onset latency of stage 4 sleep (p &lt; .05, for each), while repetitive GHRH remained without effects. GH secretory activity also tended to be higher after single than repetitive GHRH. Thus, results suggest the relevance of a transiently high concentration of GHRH in blood as an essential factor in enhancing the central nervous sleep process.
The cytokine IL-6 has been considered to exert neuromodulating influences on the brain, with prom... more The cytokine IL-6 has been considered to exert neuromodulating influences on the brain, with promoting influences on sleep. Sleep enhances the consolidation of memories, and, in particular, late nocturnal sleep also represents a period of enhanced IL-6 signaling, due to a distinctly enhanced availability of soluble IL-6 receptors during this period, enabling trans-signaling of IL-6 to neurons. Thus, a contribution of IL-6 to sleep-dependent memory consolidation is hypothesized. To test this hypothesis, we compared effects of intranasally administered IL-6 (vs. placebo) on sleep-dependent consolidation of declarative (neutral and emotional texts, 2-dimensional object location) and procedural (finger sequence tapping) memories in 17 healthy young men. IL-6 distinctly improved the sleep-related consolidation of emotional text material (P<0.03), which benefits mostly from sleep in the second night-half, in which rapid eye movement sleep (REM) dominates the non-REM-REM sleep cycle. During this second night-half, the amount of electroencephalogram slow-wave activity (0.5-4 Hz) distinctly increased after IL-6 (P<0.01). Other types of memory were not affected. The ability of IL-6 to enhance sleep-associated emotional memory consolidation highlights an example of a functional interaction between the central nervous and immune system.-Benedict, C.,
Slow oscillations originating in the prefrontal neocortex during slowwave sleep (SWS) group neuro... more Slow oscillations originating in the prefrontal neocortex during slowwave sleep (SWS) group neuronal network activity and thereby presumably support the consolidation of memories. Here, we investigated whether the grouping influence of slow oscillations extends to hippocampal sharp wave-ripple (SPW) activity thought to underlie memory replay processes during SWS. The prefrontal surface EEG and multiunit activity (MUA), along with hippocampal local field potentials (LFP) from CA1, were recorded in rats during sleep. Average spindle and ripple activity and event correlation histograms of SPWs were calculated, time-locked to half-waves of slow oscillations. Results confirm decreased prefrontal MUA and spindle activity during EEG slow oscillation negativity and increases in this activity during subsequent positivity. A remarkably close temporal link was revealed between slow oscillations and hippocampal activity, with ripple activity and SPWs being also distinctly decreased during negative half-waves and increased during slow oscillation positivity. Fine-grained analyses of temporal dynamics revealed for the slow oscillation a phase delay of approximately 90 ms with reference to up and down states of prefrontal MUA, and of only approximately 60 ms with reference to changes in SPWs, indicating that up and down states in prefrontal MUA precede corresponding changes in hippocampal SPWs by approximately 30 ms. Results support the notion that the depolarizing surface-positive phase of the slow oscillation and the associated up state of prefrontal excitation promotes hippocampal SPWs via efferent pathways. The preceding disfacilitation of hippocampal events temporally coupled to the negative slow oscillation half-wave appears to serve a synchronizing role in this neocorticohippocampal interplay.
Slow wave sleep, hallmarked by the occurrence of slow oscillations (SO), plays an important role ... more Slow wave sleep, hallmarked by the occurrence of slow oscillations (SO), plays an important role for the consolidation of hippocampus-dependent memories. Transcranial stimulation by weak electric currents oscillating at the endogenous SO frequency (SO-tDCS) during post-learning sleep was previously shown by us to boost SO activity and improve the consolidation of hippocampus-dependent memory in human subjects. Here, we aimed at replicating and extending these results to a rodent model. Rats were trained for 12 days at the beginning of their inactive phase in the reference memory version of the radial arm maze. In a between subjects design, animals received SO-tDCS over prefrontal cortex (PFC) or sham stimulation within a time frame of 1 h during subsequent non-rapid eye movement (NREM) sleep. Applied over multiple daily sessions SO-tDCS impacted cortical network activity as measured by EEG and behavior: at the EEG level, SO-tDCS enhanced post-stimulation upper delta (2-4 Hz) activity whereby the first stimulations of each day were preferentially affected. Furthermore, commencing on day 8, SO-tDCS acutely decreased theta activity indicating long-term effects on cortical networks. Behaviorally, working memory for baited maze arms was enhanced up to day 4, indicating enhanced consolidation of task-inherent rules, while reference memory errors did not differ between groups. Taken together, we could show here for the first time an effect of SO-tDCS during NREM sleep on cognitive functions and on cortical activity in a rodent model.
Intranasal administration of angiotensin II (ANGII) affects blood pressure in a mode different fr... more Intranasal administration of angiotensin II (ANGII) affects blood pressure in a mode different from intravenously administered ANGII via a direct access to the brain bypassing the blood-brain barrier. This clinical study investigated blood pressure regulation after intranasal ANGII administration in healthy humans, whereas systemic, blood-mediated effects of ANGII were specifically blocked. In a balanced crossover design, men (n=8) and women (n=8) were intranasally administered ANGII (400 μg) or placebo after ANGII type 1 receptors had been blocked by pretreatment with valsartan (80 mg; 12 and 6 hours before intranasal administration). Plasma levels of ANGII, aldosterone, renin, vasopressin, and norepinephrine were measured; blood pressure and heart rate were recorded continuously. Intranasal ANGII acutely decreased blood pressure without altering the heart rate. Plasma levels of vasopressin and norepinephrine remained unaffected. Plasma ANGII levels were increased throughout the recording period. Aldosterone levels increased despite the peripheral ANGII type 1 receptor blockade, indicating an aldosterone escape phenomenon. In conclusion, intranasal ANGII reduces blood pressure in the presence of selective ANGII type 1 receptor blockade. Intranasal ANGII administration represents a useful approach for unraveling the role of this peptide in blood pressure regulation in humans. (Hypertension. 2014;63:762-767.) • Online Data Supplement
The positive impact of sleep on memory consolidation has been shown for human subjects in numerou... more The positive impact of sleep on memory consolidation has been shown for human subjects in numerous studies, but there is still sparse knowledge on this topic in rats, one of the most prominent model species in neuroscience research. Here, we examined the role of sleep in the object-place recognition task, a task closely comparable to tasks typically applied for testing human declarative memory: It is a one-trial task, hippocampus-dependent, not stressful and can be repeated within the same animal. A test session consisted of the Sample trial, followed by a 2-h retention interval and a Test trial, the latter examining the memory the rat had for the places of two objects presented at the Sample trial. In Experiment 1, each rat was tested twice, with the retention interval taking place either in the morning or evening, i.e., in the inactive or active phase, respectively. Rats showed significantly (p < 0.01) better memory for object place after the Morning session. To control for confounding circadian factors, in Experiment 2 rats were tested four times, i.e., in the morning or in the evening while sleep was or was not deprived. Sleep during the retention interval was recorded polysomnographically. Rats only showed significant memory for the target object place in the Test trial after the Morning retention interval in the absence of sleep deprivation, and recognition performance in this condition was significantly superior to that in the three other conditions (p < 0.05). EEG recordings during spontaneous morning sleep revealed increased slow oscillation (0.85-2.0 Hz) and upper delta (2.0-4.0 Hz), but reduced spindle band (10.5-13.5 Hz) activity, as compared to evening sleep. However, spindle band power was increased in the Morning retention interval in comparison to a Morning Baseline period (p < 0.05). We conclude that consolidation of object-place memory depends on sleep, and presumably requires NonREM sleep rich in both slow wave and spindle activity.
As an indicator of cortical excitability, direct current (DC) potentials were recorded from thirs... more As an indicator of cortical excitability, direct current (DC) potentials were recorded from thirsted subjects before, during and after drinking 400 ml of water. Self-rated thirst was distinctly reduced after drinking. Compared with control conditions in which the subjects remained thirsty, during drinking a widespread negative potential shift occurred averaging over -70 microV at Cz. At the transition from the consumatory phase to the postconsumption phase, a slow positive potential shift commenced that was most pronounced over the anterior cortex (averaging over +40 microV at Fz) and persisted for more than 3 min after drinking. Control conditions excluded muscle activity, ocular movements, and changes in body fluid and serum osmolality as possible non-neuronal sources of the DC-potential changes. The sequence of negative and positive potential shifts associated with drinking indicates a coordinate regulation of cortical excitability that may facilitate consumatory behavior and its context-dependent encoding into memory.
Journal of Clinical Psychopharmacology, Feb 1, 1999
Disturbed sleep is common in the elderly and is characterized by disordered sleep architecture wi... more Disturbed sleep is common in the elderly and is characterized by disordered sleep architecture with reduced time spent in slow wave sleep (SWS) and in rapid eye movement (REM) sleep. At present, no treatments are available to fully compensate for these disorders. In the elderly, vasopressin content is decreased at various brain sites. Investigating the effects of a 3-month intranasal vasopressin administration on sleep and cognitive functions in two elderly subjects in a foregoing pilot study, the authors found that the most pronounced influence of the peptide was a marked increase in SWS. This placebo-controlled, double-blind, randomized study examined the influences of a 3-month period of daily intranasal vasopressin treatment (20 IU before bedtime and after awakening) on nocturnal sleep in 26 healthy elderly subjects (mean age, 74.2 years). Intranasal treatment of vasopressin increased (1) the total sleep time, on average, by 45 minutes (p &lt; 0.002); (2) time spent in SWS by 21 minutes (p &lt; 0.025); and (3) time in REM sleep in the second half of the night by 10 minutes (p &lt; 0.01). Vasopressin promotes sleep time and improves sleep architecture after prolonged intranasal administration in elderly subjects, although scores of subjective sleep quality did not change. Results suggest that age-related deterioration of sleep architecture can benefit from intranasal treatment with vasopressin. But a potential use in clinical settings will also depend on demonstrating improved subjective sleep quality, which remained unaffected by vasopressin in this study of elderly subjects.
Scalp-recorded direct current (DC) potentials and their topographical distribution (F3, F4, C3, C... more Scalp-recorded direct current (DC) potentials and their topographical distribution (F3, F4, C3, C4 and pz) were investigated at the transition from wakefulness to sleep, and during NREM-REM sleep and REM-NREM sleep transitions in 11 healthy men during normal sleep. Changes in endexpiratory CO 2 partial pressure (ETC0 2), scalp temperature and polysomnographic data were simultaneously measured. The transition to sleep was associated with a negative potential shift reaching significance bilaterally at frontal and central sites 5 to 10 minutes after sleep onset (p < 0.05). Largest shifts were found at frontal locations 10 to 15 minutes after sleep onset averaging (mean ::t SEM)-512 ::t 103 fL V. Negative DC potential shifts also occurred at the transitions from NREM to REM sleep and from REM to NREM sleep, but were, however, less pronounced. The negative DC shift at NREM-REM sleep transitions prcccdcd the REM sleep onset (assessed conventionally by pulysumnographic criteria) by about 1.5 minutes. Changes in temperature, ETC0 2 and eye movements were ruled out as factors significantly contributing to the generation of these shifts. Assuming a neuronal origin of the DC potential, the negative shifts at the wakesleep transition and between NREM and REM sleep suggest a temporary phase of increased cortical excitability.
Electroencephalographic activity at the transition from wakefulness to sleep is characterized by ... more Electroencephalographic activity at the transition from wakefulness to sleep is characterized by the appearance of spindles (12-15 Hz) and slow wave rhythms including delta activity (1-4 Hz) and slow oscillations (0.2-1 Hz). While these rhythms originate within neocortico-thalamic circuitry, their emergence during the passage into slow wave sleep (SWS) critically depends on the activity of neuromodulatory systems. Here, we examined the temporal relationships between these electroencephalogram rhythms and the direct current (DC) potential recorded from the scalp in healthy men (n)01؍ using cross-correlation analyses. Analyses focused on transitions from wakefulness to SWS in the beginning of the sleep period, and from SWS to lighter sleep and rapid eye movement (REM) sleep at the end of the first sleep cycle. For spindle, delta and slow oscillatory activity strong negative correlations with the DC potential were found at the transition into SWS with peak correlation coefficients (at zero time lag) averaging r,18.0؊؍ ؊0.88 and ؊0.88, respectively (P<0.001). Though slightly lower, distinct negative correlations between these measures were also found at the transition from SWS to REM sleep (؊0.78, ؊0.77 and ؊0.77, respectively, P<0.001). Fast oscillatory activity in the beta frequency band (15-25 Hz) was correlated positively with the DC potential (r,57.0؉؍ P<0.05, at the passage to SWS). Data indicate close links between increasing spindle, delta and slow oscillatory activity and the occurrence of a steep surface negative cortical DC potential shift during the transition from wake to SWS. Likewise, a DC potential shift toward surface positivity accompanies the disappearance of these oscillatory phenomena at the end of the non-REM sleep period. The DC potential shifts may reflect gradual changes in extracellular ionic (Ca 2؉) concentration resulting from the generation of spindle and slow wave rhythms, or influences of neuromodulating systems on cortical excitability thereby controlling the emergence of cortical spindle and slow wave rhythms at SWS transitions.
This chapter discusses various levels of interactions between the brain and the immune system in ... more This chapter discusses various levels of interactions between the brain and the immune system in sleep. Sleep-wake behavior and the architecture of sleep are influenced by microbial products and cytokines. On the other hand, sleep processes, and perhaps also specific sleep states, appear to promote the production and/or release of certain cytokines. The effects of immune factors such as endotoxin and cytokines on sleep reveal species specificity and usually strong dependence on parameters such as substance concentration, time relative to administration or infection with microbial products, and phase relation to sleep and/or the light-dark cycle. For instance, endotoxin increased SWS and EEG SWA in humans only at very low concentrations, whereas higher concentrations increased sleep stage 2 only, but not SWS. In animals, increases in NREM sleep and SWA were more consistent over a wide range of endotoxin doses. Also, administration of pro-inflammatory cytokines such as IL-6 and IFN-alpha in humans acutely disturbed sleep while in rats such cytokines enhanced SWS and sleep. Overall, the findings in humans indicate that strong nonspecific immune responses are acutely linked to an arousing effect. Although subjects feel subjectively tired, their sleep flattens. However, some observations indicate a delayed enhancing effect on sleep which could be related to the induction of secondary, perhaps T-cell-related factors. This would also fit with results in animals in which the T-cell-derived cytokine IL-2 enhanced sleep while cytokines with immunosuppressive functions like IL-4 and L-10 suppressed sleep. The most straightforward similarity in the cascade of events inducing sleep in both animals and humans is the enhancing effect of GHRH on SWS, and possibly the involvement of the pro-inflammatory cytokine systems of IL-1 beta and TNF-alpha. The precise mechanisms through which administered cytokines influence the central nervous system sleep processes are still unclear, although extensive research has identified the involvement of various molecular intermediates, neuropeptides, and neurotransmitters (cp. Fig. 5, Section III.B). Cytokines are not only released and found in peripheral blood mononuclear cells, but also in peripheral nerves and the brain (e.g., Hansen and Krueger, 1997; März et al., 1998). Cytokines are thereby able to influence the central nervous system sleep processes through different routes. In addition, neuronal and glial sources have been reported for various cytokines as well as for their soluble receptors (e.g., Kubota et al., 2001a). Links between the immune and endocrine systems represent a further important route through which cytokines influence sleep and, vice versa, sleep-associated processes, including variations in neurotransmitter and neuronal activity may influence cytokine levels. The ability of sleep to enhance the release and/or production of certain cytokines was also discussed. Most consistent results were found for IL-2, which may indicate a sleep-associated increase in activity of the specific immune system. Furthermore, in humans the primary response to antigens following viral challenge is enhanced by sleep. In animals results are less consistent and have focused on the secondary response. The sleep-associated modulation in cytokine levels may be mediated by endocrine parameters. Patterns of endocrine activity during sleep are probably essential for the enhancement of IL-2 and T-cell diurnal functions seen in humans: Whereas prolactin and GH release stimulate Th1-derived cytokines such as IL-2, cortisol which is decreased during the beginning of nocturnal sleep inhibits Th1-derived cytokines. The immunological function of neurotrophins, in particular NGF and BDNF, has received great interest. Effects of sleep and sleep deprivation on this cytokine family are particularly relevant in view of the effects these endogenous neurotrophins can have not only on specific immune functions and the development of immunological memories, but also on synaptic reorganization and neuronal memory formation.
Tiagabine Increases Slow Wave Sleep but not Memory-Feld et al INTRODUCTION There exists ample evi... more Tiagabine Increases Slow Wave Sleep but not Memory-Feld et al INTRODUCTION There exists ample evidence that memory traces acquired during wakefulness rely on strengthening during sleep. 1 This consolidation process is essentially supported by slow wave sleep (SWS). SWS enhances declarative memory (for episodes and facts) 2,3 as well as procedural skill memories. 4 The enhancing effect on memory consolidation appears to be mediated in particular by the neocortical < 1 Hz slow oscillation that is the hallmark of the EEG during SWS; it synchronizes the neuronal reactivation of newly acquired memory representations occurring during SWS in distributed networks to the excitable depolarizing up-state of these slow oscillations. 5 This allows the redistribution of the reactivated memory representations and their stabilization for the longer term. 1 Recent evidence suggests that procedural memory can also benefit from reactivation during NREM sleep and that this effect is related to sleep spindles. 6 The memory-consolidating effect of the slow oscillations appears to additionally result from the fact thatin parallel with reactivations-they also synchronize thalamocortical spindles (12-15 Hz) to the depolarizing slow oscillation up-state. 7,8 Post-learning spindle activity has been consistently SLOW WAVE SLEEP INDUCED BY TIAGABINE AND MEMORY CONSOLIDATION
This study examined the effects of ACTH 4-10, a fragment of adrenocorticotropin (ACTH) with known... more This study examined the effects of ACTH 4-10, a fragment of adrenocorticotropin (ACTH) with known central nervous system (CNS) activity, on the dimensional complexity of the ongoing electroencephalographic (EEG) activity. Stressful stimuli cause ACTH to be released from the pituitary, and as a neuropeptide ACTH may concurrently exert adaptive influences on the brain's processing of these stimuli. Previous studies have indicated an impairing influence of ACTH on selective attention. Methods: Dimensional complexity of the EEG, which indexes the brain's way of stimulus processing, was evaluated while subjects performed tasks with different attention demands. Sixteen healthy men (23 to 33 years) were tested once after placebo and another time after administration of ACTH 4-10 (1.25 mg intravenously (IV), 30 minutes before testing). The EEG was recorded while subjects were presented with a dichotic listening task (consisting of the concurrent presentation of tone pips to the left and right ear). Subjects either a) listened to pips in both ears (divided attention), or b) listened selectively to pips in one ear (selective attention), or c) ignored all pips. Results: Dimensional complexity of the EEG was higher during divided than selective attention. ACTH significantly increased the EEG complexity during selective attention, in particular over the midfrontal cortex (F z , CJ. Conclusions: The effects support the view of a de-focusing action of ACTH during selective attention that could serve to improve the organism's adaptation to stress stimuli.
Systemic administration of growth hormone-releasing hormone (GHRH) has been found to improve huma... more Systemic administration of growth hormone-releasing hormone (GHRH) has been found to improve human sleep in previous studies. Here we examined effects of GHRH on endocrine function and sleep after intranasal administration, a method which based on previous studies appears to enable a direct effect of peptides on brain function. Also, it was hypothesized that elderly humans displaying deficient GH release and sleep, benefit from GHRH administration more than young subjects. A study was performed according to a double-blind cross-over design. Each of 12 young and 11 old healthy men were intranasally administered with 300 mg GHRH (vs. placebo) 30 min before bedtime at 23:00 h. Sleep was recorded polysomnographically until 07:00 h and blood was collected in 15 min intervals for determination of cortisol and GH. Apart from the well-known age-related changes of hormonal secretion and sleep, intranasal GHRH reduced cortisol nadir concentrations in the beginning of sleep (PB0.05), and also reduced the sleep-induced elevation in GH concentrations during early sleep. Moreover, results indicated that after intranasal administration GHRH increased rapid-eye-movement (REM) sleep and slow wave sleep (SWS), with this influence concentrating on the second half of sleep time. Effects of GHRH did not depend on the subject's age. We conclude that there is a coordinate influence of intranasal GHRH on the central nervous regulation of sleep processes and of hypothalamic-hypophysiotropic
Processing of hedonic stimulus quality is assumed to be accompanied by a tuning of cortical arous... more Processing of hedonic stimulus quality is assumed to be accompanied by a tuning of cortical arousal and excitability. In this pilot study in 11 healthy humans scalp-recorded DC potentials were assessed during application of a sweet (sucrose) and bitter (quinine hydrochloride) taste, i.e., primary reinforcers of positive and negative quality. Muscular, ocular, and skin potential activity were controlled. Application of sucrose induced a widespread positive DC-potential shift with an amplitude of 40 ± 50 mV and persisting for more than 120-s post-stimulus onset. Following administration of quinine hydrochloride, this positive shift was reduced, most distinctly between 48-and 88-s post-stimulus onset. The reduction appeared to be most consistent at anterior midline recording sites (Fz, Cz). It is assumed that the higher DC-potential positivity during sweetness than during bitterness points to a differential tuning of cortical excitability by a widespread decrease in depolarization of apical dendrites.
This study shows that divergent thinking, considered the general process underlying creative prod... more This study shows that divergent thinking, considered the general process underlying creative production, can be distinguished from convergent, analytical thought based on the dimensional complexity of ongoing electroencephalographic (EEG) activity. EEG complexity over the central and posterior cortex was higher while subjects solved tasks of divergent than convergent thinking, and also higher than during mental relaxation. Over the frontal cortex, EEG complexity was comparable during divergent thinking and mental relaxation, but reduced during convergent thinking. Results indicate that the basic process underlying the generation of novel ideas expresses itself in a strong increase in the EEG's complexity, reflecting higher degrees of freedom in the competitive interactions among cortical neuron assemblies. Frontocortical EEG complexity being comparable with that during mental relaxation, speaks for a loosened attentional control during creative thinking.
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