Underlying sources of cognitive-anatomical variation in multi-modal neuroimaging and cognitive testing.

Healthy adults have robust individual differences in neuroanatomy and cognitive ability not captured by demographics or gross morphology (Luders, Narr, Thompson, & Toga, 2009). We used a hierarchical independent component analysis (hICA) to create novel characterizations of individual differences in our participants (N=190). These components fused data across multiple cognitive tests and neuroanatomical variables. The first level contained four independent, underlying sources of phenotypic variance that predominately modeled broad relationships within types of data (e.g., "white matter," or "subcortical gray matter"), but were not reflective of traditional individual difference measures such as sex, age, or intracranial volume. After accounting for the novel individual difference measures, a second level analysis identified two underlying sources of phenotypic variation. One of these made strong, joint contributions to both the anatomical structures associated with the core fronto-parietal "rich club" network (van den Heuvel & Sporns, 2011), and to cognitive factors. These findings suggest that a hierarchical, data-driven approach is able to identify underlying sources of individual difference that contribute to cognitive-anatomical variation in healthy young adults.

Cognitive and anatomical data in a healthy cohort of adults.

We present data from a sample of 190 healthy adults including assessments of 4 cognitive factor scores, 12 cognitive tests, and 115 MRI-assessed neuroanatomical variables (cortical thicknesses, cortical and sub-cortical volumes, fractional anisotropy, and radial diffusivity). These data were used in estimating underlying sources of individual variation via independent component analysis (Watson et al., In press) [25].

Water versus DNA: new insights into proton track-structure modelling in radiobiology and radiotherapy.

Water is a common surrogate of DNA for modelling the charged particle-induced ionizing processes in living tissue exposed to radiations. The present study aims at scrutinizing the validity of this approximation and then revealing new insights into proton-induced energy transfers by a comparative analysis between water and realistic biological medium. In this context, a self-consistent quantum mechanical modelling of the ionization and electron capture processes is reported within the continuum distorted wave-eikonal initial state framework for both isolated water molecules and DNA components impacted by proton beams. Their respective probability of occurrence-expressed in terms of total cross sections-as well as their energetic signature (potential and kinetic) are assessed in order to clearly emphasize the differences existing between realistic building blocks of living matter and the controverted water-medium surrogate. Consequences in radiobiology and radiotherapy will be discussed in particular in view of treatment planning refinement aiming at better radiotherapy strategies.

Sleep during acute dopamine D1 agonist SKF 38393 or D1 antagonist SCH 23390 administration in rats.

The effect of the D1 dopamine (DA) receptor agonist SKF 38393 was compared with that produced by the D1-receptor antagonist, SCH 23390, in rats implanted with electrodes for chronic sleep recordings. SKF 38393 (0.1 to 4.0 mg/kg) significantly suppressed rapid-eye-movement sleep (REMS) after the highest dose. SCH 23390 (0.1 to 2.0 mg/kg) increased slow-wave sleep (SWS), whereas wakefulness (W) and REMS were decreased. Pretreatment with SKF 38393 (0.5 mg/kg) prevented the effects of SCH 23390 (0.25 mg/kg) on W and SWS. However, REM sleep showed a further depression. Pretreatment with SKF 38393 (2.0 mg/kg) or SCH 23390 (0.25 mg/kg) failed to modify the increase of SWS and decrease of W induced by D2 receptor agonist bromocriptine (0.5 mg/kg) in a dose that selectively stimulates DA autoreceptors. On the other hand, SCH 23390 (0.25 mg/kg) failed to prevent REMS depression induced by bromocriptine (6.0 mg/kg) in a dose that preferentially acts at postsynaptic sites. Pretreatment with SCH 23390 (0.25 mg/kg) prevented the increase of W and decrease of SWS induced by the 5-HT2 receptor agonist DOI (0.25 mg/kg). Given the "fragility" of REMS in the rat, nonspecific factors could be contributing to its depression after SKF 38389 or SCH 23390 administration. Inhibition of D1 receptors could be responsible for SCH 23390-induced increase of SWS and decrease of W. However, a blockade of 5-HT2 receptors could be partly involved in these effects. Neither SKF 38393 nor SCH 23390 exerted activity on the sleep-wake cycle, which could be considered to reflect effects at DA autoreceptors.

Sleep and waking during acute histamine H3 agonist BP 2.94 or H3 antagonist carboperamide (MR 16155) administration in rats.

The present study evaluated the effects of histamine H3 receptor agonist BP 2.94 or H3 receptor antagonist carboperamide (MR 16155) given by oral route on sleep and waking in rats surgically prepared for long-term recordings. BP 2.94 produced a significant increase of slow-wave sleep (SWS) that was related to slight decreases of waking, light sleep, and REM sleep. Carboperamide significantly increased waking and decreased SWS and REM sleep. Pretreatment with carboperamide prevented the effect of BP 2.94 on SWS. It is suggested that the effects of BP 2.94 or carboperamide on sleep and waking could depend on changes in the availability of histamine at the postsynaptic H1 receptor. Alternatively, activation or blockade of the H3 heteroreceptors found in the central catecholamine, indolamine, and acetylcholine nerve endings could inhibit or increase the release of noradrenaline, serotonin, dopamine, and acetylcholine. This would secondarily result in changes of sleep variables.

Stereoselective antagonism by the pindolol enantiomers of 8-OH-DPAT-induced changes of sleep and wakefulness.

The effects of 5-HT1A receptor agonist 8-OH-DPAT were compared with those of the mixed beta-adrenoceptor and 5-HT1A receptor antagonist (-)pindolol, and the selective beta-adrenoceptor antagonist betaxolol in rats implanted for chronic sleep recordings, 8-OH-DPAT (0.375 mg/kg) significantly increased wakefulness and decreased slow wave sleep (SWS) and REM sleep (REMS). At 2.0-4.0 mg/kg (-)pindolol reduced REMS. Betaxolol in doses of 1.0 and 2.0 mg/kg did not significantly modify sleep variables. Pretreatment with (-)pindolol (2.0-4.0 mg/kg) reversed the effect of 8-OH-DPAT on waking and SWS, while (+)pindolol (4.0 mg/kg) and betaxolol (2.0 mg/kg) were ineffective in this respect. The stereoselective antagonism by the pindolol enantiomers supports the proposal that 8-OH-DPAT-induced increase of waking and decrease of SWS depends on the activation of 5-HT1A receptors. The absence of antagonism by betaxolol tends to indicate that prevention by (-)pindolol of waking increase did not involve beta-adrenoceptors.

Effects of selective activation of the 5-HT1B receptor with CP-94,253 on sleep and wakefulness in the rat.

The effects of the 5-HT1B receptor agonist CP-94,253 were compared with those of the mixed beta-adrenoceptor and 5-HT1A/B receptor antagonist (+/-)pindolol in rats implanted for chronic sleep recordings. CP-94,253 (5.0-10.0 mg/kg) significantly increased waking and reduced slow wave sleep (SWS) and REM sleep (REMS). At 2.0-4.0 mg/kg (+/-)pindolol reduced REMS. Pretreatment with (+/-)pindolol (2.0-4.0 mg/kg) reversed the effect of CP-94,253 on waking and SWS, while REMS remained suppressed. It is suggested that the 5-HT1B receptor together with other 5-HT receptor subtypes may have a direct regulatory action on sleep and waking in the rat.

The effects of neuroleptics with central dopamine and noradrenaline receptor blocking properties in the L-DOPA and (+)-amphetamine-induced waking EEG in the rat.

1 A study was carried out in rats (prepared for chronic sleep recording) of the effects of pretreatment with neuroleptics differing in their relative antinoradrenaline and antidopamine receptor potencies, on the L-DOPA and (+)-amphetamine-induced increase in waking EEG. 2 Haloperidol (0.6 mg/kg), which blocks central dopamine and noradrenaline (NA) receptors, reversed the EEG desynchronizing actions of L-DOPA and (+)-amphetamine. 3 Low doses of pimozide (0.4 to 0.8 mg/kg) which block dopamine receptors exclusively, were not able to modify the pharmacologically induced disruption of the sleep-awake cycle. However, at 1 mg/kg, a dose which also produces blockade of NA receptors, pimozide counteracted the increase in waking elicited by (+)-amphetamine. 4 Spiroperidol (1 to 4 mg/kg) which is devoided of NA receptor blocking properties, failed to reverse the L-DOPA or (+)-amphetamine-induced arousal. 5 Our results suggest that the increased waking time observed after the catecholamine agonists is related to an increased availability of NA rather than dopamine.

Effects of oxolinic acid on the sleep-wakefulness cycle of the rat.

1 A study was carried out in rats (prepared for chronic sleep recording) of the effects of oxolinic acid on the sleep-wakefulness cycle.2 In addition, the actions of oxolinic acid on the sleep-wake cycle were assessed after pretreatment with drugs interfering with central catecholamine mechanisms or facilitating central gamma-aminobutyric acid (GABA) activity.3 Oxolinic acid (8-32 mg/kg) induced a significant and dose-related increase of waking EEG, while slow wave and REM sleep were decreased.4 The effects of oxolinic acid on waking, slow wave and REM sleep were antagonized by alpha-methyl-p-tyrosine (50-100 mg/kg) which interferes with the synthesis of catecholamines.5 FLA-63 (25 mg/kg) which is a specific inhibitor of noradrenaline synthesis, was effective in blocking oxolinic acid-related increase of waking and decrease of slow wave sleep.6 Haloperidol (0.4-0.6 mg/kg) which blocks central dopamine and noradrenaline receptors, reversed oxolinic acid-induced actions on waking and slow wave sleep. Spiroperidol (2-4 mg/kg) which interferes with dopamine and 5-hydroxytryptamine mechanisms, only antagonized the effect of oxolinic acid on light slow wave sleep. REM sleep was further decreased by both neuroleptic agents.7 gamma-Hydroxybutyrate (25-50 mg/kg), which acts as a GABA agonist and amino-oxyacetic acid (20 mg/kg), which considerably increases central GABA levels, were ineffective in blocking oxolinic acid-related disruption of the sleep-wake cycle.8 Our results suggest that the catecholamines are involved in the arousing effect of oxolinic acid.

The actions of dihydroxyphenylalanine and dihydroxyphenylserine on the sleep-wakefulness cycle of the rat after peripheral decarboxylase inhibition.

1. The actions of dihydroxyphenylalanine (DOPA) and dihydroxyphenylserine (DOPS) were assessed on the sleep-wakefulness cycle of male Wistar rats. 2. In comparative studies the extracerebral decarboxylase was inhibited with serinetrihydroxybenzylhydrazide (RO 4-4602) before injection of DOPA or DOPS. 3. DOPA (80-160 mg/kg, i.p.) with or without previous inhibition of the peripheral decarboxylase gave rise to an initial significant increase of slow wave activity, which may be related to a release of 5-hydroxytryptamine. 4. During the subsequent 8 h sessions, DOPA significantly decreased slow wave sleep and rapid eye movement sleep (REM) and increased wakefulness. 5. DOPS (80-160 mg/kg, i.p.) did not significantly modify the sleep-wakefulness cycle apart from a decrease of the latency for the first REM episode after 160 mg/kg in the RO 4-4602 pretreated animals.

Conventional and power spectrum analysis of the effects of zolpidem on sleep EEG in patients with chronic primary insomnia.

STUDY OBJECTIVE: The purpose of this study was 1) to assess the effect of zolpidem or a placebo on sleep in two groups of insomniac patients with a diagnosis of moderate-to-severe chronic primary insomnia and 2) to determine the effect of zolpidem on sleep structure using spectral analysis. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Sleep laboratory of the Department of Pharmacology and Therapeutics at the Clinics Hospital. PARTICIPANTS: 12 female outpatients with chronic primary insomnia. INTERVENTIONS: Zolpidem was given at a daily dose of 10 mg for 15 nights. RESULTS: The hypnotic drug reduced sleep latency and waking time after sleep onset, and increased total sleep time and sleep efficiency. Values corresponding to visually scored slow wave sleep (stage 3 and 4) showed no significant changes. All-night spectral analysis of the EEG revealed that power density in NREM sleep was significantly increased in the low frequency band (0.25-1.0 Hz) in the zolpidem group during the first 2-h interval. CONCLUSIONS: In agreement with previous findings obtained in patients with chronic primary insomnia, zolpidem significantly improved sleep induction and maintenance. Moreover, zolpidem increased power density in the 0.25-1.0 Hz band during short-term and intermediate-term treatment. Nevertheless, other frequency bands in the delta range showed a relative decrease which was not statistically significant.

Sleep and nighttime pruritus in children with atopic dermatitis.

The number of scratching episodes and average frequency with which they started during each sleep stage as well as the effects of nighttime pruritus on objective sleep parameters in nine children with atopic dermatitis were assessed in the sleep laboratory. Scratching episodes occurred during rapid eye movement (REM) sleep and non-REM (NREM) sleep. The largest average frequency corresponded to stage 1, followed by stage 2, REM sleep, stage 4, and stage 3. Sleep maintenance was markedly altered. Total sleep time decrease was related mainly to smaller amounts of stage 4 NREM sleep. REM sleep percentage of total sleep time was increased as compared with normal children of the same age. Furthermore, in six of nine patients REM sleep latency was found to be decreased.

The effects of ritanserin on mood and sleep in abstinent alcoholic patients.

A trial was carried out to determine the effect of ritanserin or a placebo on sleep and mood in two groups of abstinent alcoholic patients. Their condition was characterized by both alcohol dependence and dysthymia, associated with a personality disorder. They were included in the study after 30 days of sobriety. Ritanserin was given at a daily dose of 10 mg for 28 days and was preceded (10 days) and followed (2 days) by a placebo. Plasma ritanserin concentration after administration of the 28th dose was higher than after the first dose. Peak levels of ritanserin from the first to the 28th dose increased approximately three-fold. In the ritanserin group there was a reduction of total waking time. Total sleep time increase was associated with significantly larger amounts of nonrapid eye movement sleep. Slow wave sleep and rapid eye movement sleep (in minutes or as a percent of total sleep time) were not significantly modified. Patients on ritanserin achieved a progressive improvement of their dysthymia. As compared to the placebo group, a statistically significant decrease of the Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety was found in the ritanserin group after 1 week of treatment. The absence of an effect in the placebo-treated group suggests that the clinical response and sleep improvement were mainly related to ritanserin administration.

Effect of DSP-4, a noradrenergic neurotoxin, on sleep and wakefulness and sensitivity to drugs acting on adrenergic receptors in the rat.

DSP-4, a neurotoxin which produces a marked and long-lasting depletion of norepinephrine (NE) in the central nervous system, was given in a dose of 50 mg/kg by i.p. route to rats prepared for chronic sleep recordings. Light sleep was significantly increased and REM sleep decreased during the first 2 days following DSP-4. Thereafter, REM sleep showed a consistent increase which attained significance on days 5 and 6 postinjection, thus indicating a permissive role for NE on this behavioral state. We examined also whether pretreatment with DSP-4 would modify the effects of clonidine, yohimbine, methoxamine, or clenbuterol on sleep and wakefulness. The sensitivity to alpha 2-agents, methoxamine, and clenbuterol was respectively slightly increased or unchanged, decreased, and clearly increased after DSP-4.

Effects of methoxamine and alpha-adrenoceptor antagonists, prazosin and yohimbine, on the sleep-wake cycle of the rat.

A study was carried out on the effects of methoxamine, prazosin, and yohimbine on the sleep-wake cycle in rats prepared for chronic sleep recordings. Methoxamine (4-8 mg/kg), an alpha 1-adrenoceptor agonist, induced a dose-related increase in wakefulness (W) and a decrease in slow-wave sleep (SWS) and REM sleep (REMS). Prazosin (0.125-1 mg/kg), which selectively blocks alpha 1-adrenoceptors, modified only slightly the amount of time spent in W and SWS, and consistently decreased REMS values. Prazosin (0.5 mg/kg) reversed the effects of methoxamine, decreasing W and increasing sleep. Yohimbine (3 mg/kg), which blocks alpha 2-adrenoceptors, augmented W and diminished sleep. Methoxamine (4 mg/kg) in animals pretreated with yohimbine (3 mg/kg) induced a further decrease of SWS and REMS and an increase of W. Thus, pharmacological activation of alpha 1- or blocking of alpha 2-adrenoceptors appears to decrease sleep and increase W. Further, blocking of alpha 1-adrenoceptors decreases REMS. Rapid eye movement sleep depression by the alpha 1-agonist or the alpha 1-antagonist is tentatively ascribed to a critical change in noradrenergic transmission in the brain.

Hypnoticlike effects of cannabidiol in the rat.

The actions of cannabidiol (CBD), one of the cannabis constituents, were assessed on the sleep-wakefulness cycle of male Wistar rats. During acute experiments, single doses of 20 mg/kg CBD decreased slow-wave sleep (SWS) latency. After 40 mg/kg SWS time was significantly increased while wakefulness was decreased. REM sleep was not significantly modified. Following the once-daily injections of 40 mg/kg CBD for a period of 15 days, tolerance developed to all the above-mentioned effects.

The actions of dopaminergic and noradrenergic antagonists on conditioned avoidance responses in intact and 6-hydroxydopamine-treated rats.

The actions of various doses of haloperidol, pimozide, clozapine, and phenoxybenzamine were assessed on a conditioned-avoidance response (CAR) in control and 6-hydroxydopamine-treated rats, using a pole-climbing device. Haloperidol proved to be the most potent in disrupting the CAR. Pimozide was about 1.6 times less potent, and clozapine and phenoxybenzamine were approximately 52 and 155 times less potent than haloperidol, respectively. Prior treatment with 6-hydroxydopamine slightly enhanced the sensitivity to some of the doses of the DA and NE antagonists. Significantly lower levels of responding, however, were observed only after the highest dose of primozide. Clonidine was not only ineffective in reverting avoidance decrements, but also induced a further decline of the CAR. Apomorphine produced a partial, but significant, reversal of the haloperidol and pimozide-induced depression of conditioned responses. Regarding the clozapine-pretreated animals, a significant antagonism was observed only with the smaller dose of apomorphine. The highest dose induced a further decline of the CAR. The DA agonist was also ineffective in the phenoxybenzamine-injected rats. Amphetamine was effective in antagonizing the avoidance decrements produced by all the CA antagonists. Our results support the suggestion that CAR depends on both DA and NE mechanisms. DA seems to be more significant that NE, however, since the CAR was more depressed when receptors depending on the former neurotransmitter were blocked.

Depletion of brain serotonin by 5,7-DHT: effects on the 8-OH-DPAT-induced changes of sleep and waking in the rat.

The effect of 5-HT1A receptor agonist 8-OH-DPAT on sleep and wakefulness was studied in rats with selective serotonin depletion after ICV administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Injection of 8-OH-DPAT to vehicle-treated animals induced biphasic effects, such that low doses (0.010 mg/kg) which act perferentially on the somatodendritic autoreceptor decreased wakefulness (W) and increased slow wave sleep (SWS), while higher doses (0.375 mg/kg) which stimulate postsynaptic receptors caused opposite effects. REM sleep was suppressed irrespective of the dosage given. Injection of the 0.010 mg/kg dose in the 5,7-DHT-treated rats did not result in significant changes in sleep or W. On the other hand, the 0.375 mg/kg dose produced changes in sleep variables which were similar to those described in the vehicle-treated animals. Our findings tend to indicate that increased SWS after low doses of 8-OH-DPAT depends upon the activation of inhibitory somatodendritic 5-HT1A receptors, while increased W after higher doses of the compound is related to stimulation of postsynaptic receptors.

Biphasic effects of dopamine D-2 receptor agonists on sleep and wakefulness in the rat.

The effects of the dopamine (DA) receptor agonists apomorphine, bromocriptine and pergolide were compared with those produced by a DA receptor antagonist, haloperidol, in rats implanted with electrodes for chronic sleep recordings. Apomorphine (0.025-2.0 mg/kg) and bromocriptine (0.25-6.0 mg/kg) induced biphasic effects such that low doses decreased wakefulness (W) and increased slow wave sleep (SWS) and REM sleep (REMS), while large doses induced opposite effects. The effects of pergolide (0.05-0.5 mg/kg) on W and SWS were also biphasic, while REMS was suppressed over the range of dosages given. At 0.040 mg/kg, haloperidol increased W, while at 0.160 mg/kg it produced the opposite effect. Pretreatment with haloperidol (0.020 mg/kg) in a dose which preferentially acts at presynaptic sites reversed the effects of low doses of apomorphine, bromocriptine or pergolide on sleep and W. However, the compound differed substantially in its ability to block agonist effects. The increase in sleep after low doses of apomorphine, bromocriptine or pergolide could be related to activation of presynaptic D-2 receptors located on DA axons of mesolimbic and mesocortical systems. In addition, inhibition of norepinephrine and acetylcholine neurons having inhibitory D-2 receptors could contribute to the increase of sleep after small doses of the DA agonists.

Increase of waking and reduction of NREM and REM sleep after nitric oxide synthase inhibition: prevention with GABA(A) or adenosine A(1) receptor agonists.

The effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of enzyme nitric oxide synthase (NOS), on spontaneous sleep during the light period, was studied in adult rats implanted for chronic sleep recordings. L-NAME was injected by subcutaneous (s.c.) route or was infused directly into the dorsal raphe nucleus (DRN). Subcutaneous (46.0--185.0 micromol/kg) administration of L-NAME increased waking (W), slow wave sleep (SWS) and rapid-eye-movement sleep (REMS) latency, whereas SWS, REMS and the number of REM periods were reduced. Direct application of L-NAME into the DRN (0.37--1.1 micromol) induced an increment of W and a reduction of SWS and REMS. Values corresponding to SWS and REMS latency, and the number of REM periods remained within control levels. Subcutaneous administration of the GABA(A) receptor agonist muscimol (1.7--3.5 micromol/kg) or the adenosine A(1) receptor agonist L-PIA [L(-)N(6)-(2-phenylisopropyl)adenosine] (0.1--0.3 micromol/kg) induced slight but inconsistent changes of W, light sleep (LS), SWS and REMS that did not attain significance. Pretreatment with muscimol (1.7--3.5 micromol/kg, s.c.) or L-PIA (0.1--0.3 micromol/kg, s.c.) antagonized the increase of W and reduction of SWS and REMS induced by s.c. (92.0 micromol/kg) or intra-DRN (0.74 micromol) administration of L-NAME. However, neither muscimol nor L-PIA prevented the increase of REMS latency induced by L-NAME 92.0 micromol/kg, s.c. Our findings tend to indicate that the change of behavioral state observed after systemic or intra-DRN administration of L-NAME is partly related to the reduction of GABA and adenosine at critical sites in the CNS.