An overview of sleep after talking with Dr. Datta

Sleep is a "neurocratic" process. If democracy is rule by the people for the people and because of the people, then sleep is a neurocracy because it is done by the brain for the brain and because of the brain. Sleep is broken down into 5 main stages in humans with 5 distinct cortical EEG readings.

1. First, complete wakefulness involves sensory responses and high frequency, low amplitude neural activity.
2. Stage I sleep is the drowsy state right before sleep. The neural signal is slowing down, but the person may still have their eyes open (and in my case make basic responses to stimuli).
3. The start of stage II sleep is considered sleep onset by many polysomnograph technicians. In this type of sleep, the cortex makes sleep spindles and K-complexes. K-complexes are named for their distinctive shape in the EEG and they indicate a sensory response. A loud clap during a deeper stage of sleep will oftentimes show up as a K-complex in the EEG. Humans may also have a tS-R, or transition-to-REM sleep,  stage that looks just like stage II sleep without the K-complexes. Rats and cats have a distinctive tS-R which is distinguished because of pontine EEG readings from animals. If we could record EEG from the pons of humans without doing surgery, there is a good chance that humans also display this stage distinctively, too.
4. Slow wave sleep, or delta wave sleep is considered deeper sleep. Stage III and Stage IV sleep in humans are functionally equivalent; the only difference between the two stages is the prevalence of delta waves. In stage III sleep, delta waves make up 20-50% of the cortical activity. In stage IV sleep, the delta waves make up >50% of the cortical activity. These delta waves are extremely low frequency, high amplitude waves when measured by the EEG. 
5. REM sleep, called paradoxical sleep in France, makes up only ~20% of the sleep cycle. The rest (sometimes called NREM) is spent in the first 4 stages of sleep.  At the beginning of REM, people will move their heads before their body becomes paralyzed. REM is characterized by rapid eye movements, parasympathetic activation, autonomic disregulation, muscle atonia and cortical activation. Each of the sleep signs is regulated by a different nuclei in the mesencephalon. 

This is all information as I remember it from 2 hours ago, so the facts need to be checked. Look forward to the overview of Datta and Maclean 2007. That will reveal all!

Sleep and Brain Development: The Critical Role of Sleep in Fetal and Early Neonatal Brain Development

In paper citation (Graven & Browne, 2008)

Note: Human infants are born around 40 gestational weeks.

Normal Sleep in Development

• Sleep & sleep cycles are essential for sensory system development in the fetus and young infant. 
• As early as the end of the first trimester, fetuses begin to show circadian rhythms, periods or rest and activity, and rhythmic hormone production. These circadian rhythms are regulated by the mother's hormones (Rivkees & Hao, 2000)
• Between 20 and 28 weeks' gestation, the human fetus shows irregular and immature brain activity. As the preterm infant approaches 28 weeks' gestation, cell firing becomes regular and starts to occur as synchronous waves. This is organized by the ganglion cell firing. (Lai, et al., 1999).
• By 30 weeks gestation, the EEG patterns of REM and nREM occur, but not continuously. The EEG patterns become continuous between 36 and 38 gestational weeks (Davis, et al., 1999).
• In the fetus and young infant the brain is more active during REM than during wakefulness (Mizhari, et al, 2004).
• At 28 weeks gestation, the sleep cycle is mostly REM sleep. 
• By term at 40 weeks, the sleep cycles are about equal REM and NREM.
• By 8 or 9 months, the sleep cycle is about 80% NREM, 20% REM. This is reflective of adult sleeping patterns (Mizhari, et al., 2004)
• Rapid eye movement deprivation between 30 weeks' gestational age and 4-5 months postterm results in delayed or disordered development. 

Preservation of Brain Plasticity

• 3 cellular components of plasticity:
• nerve growth factor
• BDNF
• ubiquitin
• All three components repond to the stimulation and activation of CREB ( cyclic AMP responsive element binding protein) that regulates gene transcription.

Theory of memory consolidation

• Short term memory circuits in the neocortex.
• Consolidation phase during NREM for novel information.
• Neocortex communicates with hippocampus via theta waves in NREM.
• Hippocampus organizes the information and sends it back to the neocortex using different theta waves in REM. Continued theta waves solidify this memory connection. 
• Stickgold et al., 2008; Yoo, et al., 2007 

Sleep Development in the NICU

• Better sleep organization correlated with improved outcomes in the NICU (Lehtonen & Martin, 2004)
• NICU babies have historically been handled constantly with an average of 100 interventions in 24 hours. 
• NICU babies follow the developmental pattern of their gestational age in terms of sleeping patterns unless they have chronic lung disease (Scher, et al., 1992).
• Kangaroo mother care and breast feeding seem best in establishing sleep-wake patterns in pre-term infants. 

Remaining questions:

What are the established effects of REM deprivation and sleep deprivation?

If SSRIs decrease REM, how does this affect neonatal development? Is there a causal relationship between sleep and cognitive ability or is the correlation deeper?

Tim Vail, my deaf swing-dancing friend

Here is a sweet article about one of the best lindy-hop leaders that I know: http://swungover.wordpress.com/2011/08/16/interview-with-tim-vail-deaf-lindy-hopper/

Tim Vail is a great dancer and a great friend of mine. I am always amazed at how well he can keep to the rhythm even though he is deaf.

New Perspectives on the Neurodevelopmental effects of SSRIs

In paper citation: (Homberg, Schubert, & Gaspar, 2009)

This paper is a review article and therefore is mostly just a collection of useful facts. I will leave citations to be looked up using the paper.

Introduction

• Selective serotonin reuptake inhibitors inhibit the function of the serotonin transporter (5HTT), which is responsible for the high affinity reuptake of serotonin.
• The 5HTT has only one gene and is an identical protein in the peripheral and central nervous system, making it hard to target.
• 10-16% of pregnant women are depressed; 25% of these women continue SSRI use through their pregnancy and another .5% of these women start taking SSRIs while pregnant.
• The SSRIs reach the fetus through the placenta and the newborn through breastmilk. 
• Perinatal administration of SSRIs causes anxiety and depression-like behaviors in rodents (the SSRI paradox)

The SSRI paradox

• In adults the chronic use of SSRIs:
• decrease anxiety/depression
• decrease REM sleep
• cause cardiodepression and vasodilation
• In contrast, perinatal exposure to SSRIs:
• increases anxiety/depression
• increases REM sleep
• blunts pain responses
• improves spatial learning
• increases cocaine-induced conditioned place preference
• causes dilated cardiomyopathy

It is important to note that functional brain maturity at postnatal day 12&13 in rodents are most similar to the day of birth in primates. 

Cellular Targets of SSRIs during development

• At mid gestation (E11) the 5HTT gene is first expressed in the raphe nucleus.
• At birth, the 5HTT gene is expressed in many regions of the frontal cortex.
• 5HTT expression in non-serotonergic neurons ends rapidly during during the second postnatal week.
• Repression of 5HTT expression is controlled by circulating hormones, such as thyroid, that peak in postnatal life.

Signalling Pathways of 5HT

• 5HT1B receptors are similar to the 5HTT and regulate activity dependent axon-remodelling by controlling glutamate release and cyclic AMP production. This in turn is involved in the production of netrins and ephrins. This could result in an altered brain topography.
• 5HTT regulates 5HT levels and thus determine the activation of pre and post synaptic 5HT receptors. 

Lessons from rodent behavioral studies

Embryonic exposure to SSRIs:

• increased neonatal mortality
• reduced body weight
• reduced the receptor density of 5HT2A/2C 
• reduced expression of 5HT and 5HTT
• resulted in depression-like symptoms during adulthood
• reduced exploratory behavior and increased anxiety-related phenotype
• reduced aggression
• reduced sexual behavior
• increased REM sleep and anhedonia
• blunted thermal and tactile responses
• delayed motor development
• improved spatial learning
• reduced impulsivity
• kept the rats from swimming on a forced swim test
• increased sensitivity to cocaine-seeking behaviors

Genetic vs. Pharmacological models of 5HTT downregulation

• 5HT1A affected in knockout mice, but not in mice treated with SSRIs neonatally
• Cognitive effects seem similar, but not enough testing has been done to be sure.

Neuroanatomical differences in rodents with perinatal SSRI exposure:

• Somatosensory cortex:
• treated rats have thinned terminal clusters and altered dendritic organization in the spiny stellate neurons in layer 4 barrel cortex
• rats have impaired transmission of tactile information in the somatosensory cortex, but do not lose their tactile skills completely
• structural organization of thalamocortical innervations perturbed
• Corticolimbic circuit
• The dorsal raphe nucleus, mPFC and amygdala make up this serotonergic circuit
• in knockout rodents, the PFC and amygdala have pyramidal cells with abnormally increased branching and  abnormally increased dendritic spine density

In humans

• Humans carrying the short allelic variant of the 5HTT promoter have reduced circulating 5HTT in their blood. These people show increased stress responsivity as newborns, and increased amygdala activity as adults.
• This allele also modulates the antidepressant effects of SSRIs.

REM sleep reduction effects on depression syndromes

In paper citation: (Vogel et al., 1975)

New conclusions:

1. N-REM sleep deprivation does not produce REM deprivation and REM rebound on recovery nights, but REM sleep deprivation does. (NREM sleep deprivation was acheived by waking participants up 10 minutes after they finished REM at the same rate as their REM-deprived partner)
2. In both endogenous and reactive depression, REM deprivation treatments caused REM deprivation, but only in the endogenous depressives did it also induce REM rebound on the recovery night.
3. Total sleep time was lower by about 40 minutes for everyone who received REM deprivation treatments  compared to controls.
4. EST did not reduce REM sleep the first two nights after treatment.
5. Endogenously depressed patients showed significant improvement with 3 weeks of REM sleep deprivation, but they did not have a significant difference in self-ratings of psychomotor activity (a symptom of depression)
6. 17 of 34 patients improved sufficiently for a hospital discharge after 7 weeks of increased REM pressure. Of these patients, 3 required rehospitalization within nine months of discharge, and 13 patients showed continued improvement.
7. 7 of 34 patients did not respond to sleep treatments or imipramine and received EST. Of these patients, 3  required rehospitalization within nine months of discharge, one went to a long-term care facility, and two showed consistent improvement. 
8. The unimproved patients were REM deprived, but did not show REM rebound. It may be that REM pressure is the force behind this healing process.

Other Important Information:

• Reactive depression is depression induced by a stimulus. Endogenous depression has a "spontaneous" onset.
• Tricyclics and monoamine oxidase inhibitors suppress REM sleep.
• EST has also been reported to decrease REM sleep. 
• If woken during REM, the patient was woken immediately at the onset of REM and kept awake for 3 minutes.
• If woken during NREM (controls) the patient was woken 10 minutes after the offset of REM so as to not disturb the normal REM sleep.

Remaining Questions:

• Is it REM deprivation, or increased REM pressure that relieves the depression?
• Is this method safe to use as a long term treatment?
• How could this treatment be made more efficient, affordable, and effective?

Single Cell Activity Patterns of Pedunculopontine Tegmentum Neurons Across the Sleep-Wake Cycle in Freely Moving Rats

In paper citation: (Datta & Siwek, 2002)

The new findings in this paper:

• There are three types of cells in the PPT of the rat (from measurements of 70 individual cells):
• ~12.86% of the cells are REM-on cells. These cells are more active during REM sleep than wakefulness or SWS. They start firing 5-10 seconds before the onset of REM and stop firing 5-8 seconds before the end of REM. These cells fire tonically with ISI modes of 90-110ms.
• ~60% of the cells are Wake-REM-on cells. These cells are more active during wakefulness and REM than SWS. They become silent at the onset of SWS and stay silent until 5-8 seconds  before the onset of REM. These cells fire tonically, but their firing rate was lower during REM, dropping from 15Hz (wake) to 10Hz  (REM). 
• ~27.14% of the cells are state-independent.
• There was no evident spatial differentiation within the PPT.
• None of the PPT cells fired in a bursting manner at any time.
• The average duration of spikes was around 1ms for all three types of cells, indicating that they were probably not GABAergic cells (which have spike duration of .5ms) but rather cholinergic cells
• When awake, the 70 cells fired 854 spikes/second. When in SWS, the 70 cells fired 63 spikes/second. When in REM sleep, the 70 cells fired 559 spikes/second. The activity of the cholinergic cells is thus assumed to be about 65% of the wakefulness baseline during REM sleep.

Other important information:

• Glutamate microinjection in the PPT increases the duration of REM sleep in the rat (Datta et al., 2001a)
• Choline microinjection in the PRF induces REM sleep in the rat (Gnadt & Pegram, 1986)
• Thus it is hypothesized that the PPT is a major source of cholinergic input to the PRF that can induce choline agonist-induced sleep
• Aminergic cells in the pons remain silent during REM sleep (Chu & Bloom, 1973; Hobson et al. 1975; (for more see paper))
• The cat has 5 types of neurons. The 2 not seen in the rat are: REM-off and PGO-on (Saito et al, 1977; El Mansari et al., 1989,1990;(for more see paper))
• REM-off cells are aminergic.These were only found in the cat.
• PGO-on cells discharge in bursts just prior to and during PGO wave activity. These are seen in the cat (Koyama & Sakai, 2002)
• The latency from increased PPT activity to REM sleep is longer in the cat (20-60s*) than in the rat (5-10s). However the cat has longer REM sleep episodes (10-30min) than the rat (3-13 min) (Foote, 1973; Datta & Hobson, 2000)
• LDT cholinergic cells are just like the PPT in distribution and action.

Remaining Questions:

• What coordinates the wake-REM-on and REM-on cells so that they both start  firing 5-8 seconds before REM and stop 5-8 seconds before the end of REM?
• Are there no bursting cells inside the PPT or were they just not found?
• What in development determines a W-REM-on from a REM-on from a state independent cell?

Sleep-wake effects of meta-chlorophenyl piperazine and mianserin in the behaviorally depressed rat

In paper citation: (Mavanji, Meti, & Datta, 2002)

All rats in this paper were made depressed using neonatal clomipramine treatments. All rats were male. Controls were treated with saline, but handled in the same manner.

The new findings from this paper are:

1. REM sleep onset latency is significantly shorter in depressed rats than in controls. Rats spend ~25% less time in SWS before their first REM cycle.
2. The total number of REM sleep episodes is significantly (~2X) higher in depressed rats than in controls.
3. The total amount of REM sleep in depressed rats is significantly more than controls (>2X more REM).
4. mCPP, a serotonin agonist, decreased the total amount of REM sleep in the depressed rats by decreasing the total number of REM sleep episodes and increasing the REM sleep onset latency.
5. mianserin, a SSRI, decreased the total amount of REM sleep in the depressed rats by decreasing the total number of REM sleep episodes. 

Other important information:

• REM sleep deprivation in humans alleviates symptoms of depression (Vogel et al., 1975).
• REM sleep deprivation in rats normalizes deficits in sexual activity and aggression, which are symptoms of rat depression (Vogel et al., 1990).
• mCPP is known to increase serotonin release (Bauman et al., 1993) and reduce REM sleep in humans ( Lawlor et al., 1991).
• Clomipramine treated rats have less serotonin in their brain than control rats (Mavanji & Meti, 1999).
• Serotonin inhibits REM sleep (McCarley, 1982) and so serotonin agonists reduce REM sleep (Quattrochi et al., 1992; Stickgold et al., 1993)
• mCPP normally reduces REM in the controls if it is injected systemically because it inhibits acetylcholine release (Vizi et al., 1981) It didn't in this case because it was injected  ICV.
• Mianserin typically reduces REM in both depressive patients and normal subjects (Mendlewicz et al., 1995; Tormey et al., 1980).

Remaining questions:

• How does the clomipramine rat model work? Would this still be the case in social stress depressed rats, or learned helplessness rats?
• The CLI+mianserin group seemed to have low wakefulness and high SWS in my opinion. I'm surprised that it didn't come out significant.