The majority of functional neuroscience studies have focused on the brain's response to a task or stimulus. However, the brain is very active even in the absence of explicit input or output. In this Article we review recent studies examining spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal of functional magnetic resonance imaging as a potentially important and revealing manifestation of spontaneous neuronal activity. Although several challenges remain, these studies have provided insight into the intrinsic functional architecture of the brain, variability in behaviour and potential physiological correlates of neurological and psychiatric disease.

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Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging.

### A. Overview

Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface receptors termed purine receptors. In this review particular emphasis is placed on the discrepancy between the

/pdf/receptors-for-purines-and-pyrimidines-56f78tnpew.pdf

Receptors for Purines and Pyrimidines

http://dept.wofford.edu/neuroscience/NeuroSeminar/pdfSpring2010/MolecularGenetics.pdf

Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation

Caffeine is the most widely consumed behaviorally active substance in the world. Almost all caffeine comes from dietary sources (beverages and food), most of it from coffee and tea. Acute and, especially, chronic caffeine intake appear to have only minor negative consequences on health. For this

Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

A series of findings over the past decade has begun to identify the brain circuitry and neurotransmitters that regulate our daily cycles of sleep and wakefulness. The latter depends on a network of cell groups that activate the thalamus and the cerebral cortex. A key switch in the hypothalamus shuts off this arousal system during sleep. Other hypothalamic neurons stabilize the switch, and their absence results in inappropriate switching of behavioural states, such as occurs in narcolepsy. These findings explain how various drugs affect sleep and wakefulness, and provide the basis for a wide range of environmental influences to shape wake-sleep cycles into the optimal pattern for survival.

Hypothalamic regulation of sleep and circadian rhythms

D THC), an exogenous Cannabinoid type 1 and type 2 (CB1 and CB2) receptor agonist in patients with Obstructive Sleep Apnea (OSA). Design and Setting: Proof of concept; single-center dose-escalation study of dron- abinol. Participants: Seventeen adults with a baseline Apnea Hypopnea Index (AHI)15/h. Baseline polysomnography (PSG) was performed after a 7-day washout of Continuous Pos- itive Airway Pressure treatment. Intervention: Dronabinol was administered after baseline PSG, starting at 2.5 mg once daily. The dose was increased weekly, as tolerated, to 5 mg and finally to 10 mg once daily. Measurements and Results: Repeat PSG assessments were performed on nights 7, 14, and 21 of dronabinol treatment. Change in AHI (DAHI, mean ± SD) was significant from baseline to night 21 (14.1 17.5; p = 0.007). No degra- dation of sleep architecture or serious adverse events was noted. Conclusion: Dronabinol treatment is safe and well-tolerated in OSA patients at doses of 2.5-10 mg daily and sig- nificantly reduces AHI in the short-term. These findings should be confirmed in a larger study in order to identify sub-populations with OSA that may benefit from cannabimimetic pharmacologic therapy.

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Proof of concept trial of dronabinol in obstructive sleep apnea

The effects of N6-L-(phenylisopropyl)adenosine, cyclohexyladenosine and adenosine-5'-N-ethylcarboxamide on sleep were examined in rats. These effects consist of 1) increased slow-wave sleep2 from 6.6 to 45.7%, in all doses used for cyclohexyladenosine and adenosine-5'-N-ethylcarboxamide and for 0.1 and 0.3 mumol/kg of N6-L-(phenylisopropyl)adenosine and 2) increased values for rapid-eye-movement-sleep, amounting to 56.2 and 51.6% for 0.1 mumol/kg of cyclohexyl-adenosine and 0.3 mumol/kg of N6-L-(phenylisopropyl)adenosine, respectively. Slow-wave sleep1 decreased but values for wakefulness and total sleep were unchanged for 0.03, 0.1 and 0.3-mumol/kg doses of the drugs. Only 0.9-mumol/kg dose of cyclohexyladenosine and N6-L-(phenylisopropyl)adenosine increased wakefulness and decreased total sleep, whereas the same dose of adenosine-5'-N-ethylcarboxamide increased total sleep during the 0- to 3-hr time interval. All three agents reduced rapid-eye-movement sleep at the 0.9-mumol/kg dose. The results indicate that the effect on sleep of all three adenosine analogs was obtained with nanomolar doses of the drugs and that it diminished or disappeared when the drug dose reached micromolar range (0.9 mumol/kg). It appears, therefore, that activation of A1 rather than A2 receptors contributed to the sleep effects of the drugs because adenosine and adenosine analogs activate A1 receptors in nanomolar quantities whereas activation of A2 receptors requires micromolar concentration of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine analogs and sleep in rats.

We have examined the effects on sleep and brain temperature of bilateral microinjections of adenosine and adenosine analogs to the preoptic area (PO) of rats. Administration of adenosine (12.5 nmoles), a nonselective adenosine A1/A2 receptor agonist NECA (N-ethyl-carboxamido-adenosine, 1.0 nmole), and the selective adenosine A1 receptor agonist CPA (cyclopentyladenosine, 0.25, 0.5 nmoles) increased total sleep primarily through an enhancement in deep slow-wave sleep (SWS2), while adenosine also increased REM sleep. Administration of 12.5 nmoles adenosine and 0.25 nmoles CPA did not affect brain temperature, while 1.0 nmole NECA and 0.5 nmoles CPA caused a transient and prolonged hypothermia, respectively. Administration of the selective adenosine A2 receptor agonist CV-1808 (2-phenylaminoadenosine, 5, 10 nmoles) had no effect on sleep or brain temperature. The present results demonstrate a site for the central hypnotic action of adenosine, and a functional role for adenosine A1 receptors in the hypothalamus.

Role of adenosine in sleep and temperature regulation in the preoptic area of rats.

Study Objectives: Decreased serotonergic facilitation of upper-airway motor neurons during sleep has been postulated as an important mechanism rendering the upper airway vulnerable to obstruction in patients with obstructive sleep apnea syndrome (OSA). Although serotonin reuptake inhibitors have been shown to produce modest reductions in the apnea-hypopnea index (AHI) during non-rapid eye movement (NREM) sleep, they have not been proven to be generally effective as treatments for OSA. Conversely, antagonists of type 3 (5-HT 3 ) serotonin receptors effectively have been shown to reduce the frequency of central apneas during rapid eye movement (REM) sleep in a rodent model of sleep-related breathing disorder. We sought to determine whether mirtazapine, a mixed 5-HT 2 /5-HT 3 antagonist that also promotes serotonin release in the brain would effectively reduce AHI during both NREM and REM sleep in patients with OSA. Design: A randomized, double-blind, placebo-controlled, 3-way crossover study of mirtazapine in patients with OSA. Setting: Laboratory studies were conducted in the Center for Sleep and Ventilatory Disorders at the University of Illinois Medical Center. Patients: Seven adult men and 5 adult women with newly diagnosed (treatment-naive) and medically uncomplicated OSA were randomized into the study. Interventions: Each subject self-administered oral medications 30 minutes before bedtime each night for 3 consecutive 7-day treatment periods. These treatments comprised (1) placebo, (2) 4.5 mg per day of mirtazapine, and (3) 15 mg per day of mirtazapine. The order of treatments was randomized for each subject, and orders were counterbalanced for the overall study. Measurements and Results: Each subject charted his or her sleep-wake schedule throughout the study and completed the Stanford Sleepiness Scale every 2 hours during the seventh day of each treatment period. Subjects were studied by laboratory polysomnography on the seventh night of each treatment period. With respect to placebo treatment, 4.5 mg of mirtazapine significantly reduced the AHI in all sleep stages to 52%, with 11 of 12 subjects showing improvement over placebo; 15 mg of mirtazapine reduced the AHI to 46%, with 12 of 12 subjects showing improvement over placebo. Sleep fragmentation was reduced only by the higher dose of mirtazapine. Gross changes in sleep architecture were unremarkable. Conclusions: Daily administration of 4.5 to 15 mg of mirtazapine for 1 week reduces AHI by half in adult patients with OSA. This represents the largest and most consistent drug-treatment effect demonstrated to date in a controlled trial. These findings suggest the therapeutic potential of mixed-profile serotonergic drugs in OSA and provide support for future studies with related formulations. Mirtazapine also is associated with sedation and weight gain-2 negative side effects in patients with OSA. In view of the above, we do not recommend use of mirtazapine as a treatment for OSA.

/pdf/efficacy-of-mirtazapine-in-obstructive-sleep-apnea-syndrome-1ju43uvu71.pdf

Miodrag Radulovacki

Papers

Proof of concept trial of dronabinol in obstructive sleep apnea

Adenosine analogs and sleep in rats.

Role of adenosine in sleep and temperature regulation in the preoptic area of rats.

Efficacy of mirtazapine in obstructive sleep apnea syndrome.

N6 (L-Phenylisopropyl)adenosine (L-PIA) increases slow-wave sleep (S2) and decreases wakefulness in rats