Altered Activity in the Central Medial Thalamus Precedes Changes in the Neocortex during Transitions into Both Sleep and Propofol Anesthesia

How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing “top-down” inhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some neuronal circuits are affected before others, we used Morlet wavelet analysis to obtain high temporal resolution in the time-varying power spectra of local field potentials recorded simultaneously in discrete brain regions at natural sleep onset and during anesthetic-induced loss of righting reflex in rats. Although we observed changes in the local field potentials that were anesthetic-specific, there were some common changes in high-frequency (20–40 Hz) oscillations (reductions in frequency and increases in power) that could be detected at, or before, sleep onset and anesthetic-induced loss of righting reflex. For propofol and natural sleep, these changes occur first in the thalamus before changes could be detected in the neocortex. With dexmedetomidine, the changes occurred simultaneously in the thalamus and neocortex. In addition, the phase relationships between the low-frequency (1–4 Hz) oscillations in thalamic nuclei and neocortical areas are essentially the same for natural sleep and following dexmedetomidine administration, but a sudden change in phase, attributable to an effect in the central medial thalamus, occurs at the point of dexmedetomidine loss of righting reflex. Our data are consistent with the central medial thalamus acting as a key hub through which general anesthesia and natural sleep are initiated.

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Sleep twitches light up the brain

A University of Iowa study has found twitches made during sleep activate the brains of mammals differently than movements made while awake.

Researchers say the findings show twitches during rapid eye movement (REM) sleep comprise a different class of movement and provide further evidence that sleep twitches activate circuits throughout the developing brain. In this way, twitches teach newborns about their limbs and what they can do with them.

“Every time we move while awake, there is a mechanism in our brain that allows us to understand that it is we who made the movement,” says Alexandre Tiriac, a fifth-year graduate student in psychology at the UI and first author of the study, which appeared this month in the journal Current Biology. “But twitches seem to be different in that the brain is unaware that they are self-generated. And this difference between sleep and wake movements may be critical for how twitches, which are most frequent in early infancy, contribute to brain development.”

Mark Blumberg, a psychology professor at the UI and senior author of the study, says this latest discovery is further evidence that sleep twitches— whether in dogs, cats or humans—are connected to brain development, not dreams.

“Because twitches are so different from wake movements,” he says, “these data put another nail in the coffin of the ‘chasing rabbits’ interpretation of twitches.”

For this study, Blumberg, Tiriac and fellow graduate student Carlos Del Rio-Bermudez studied the brain activity of unanesthetized rats between 8 and 10 days of age. They measured the brain activity while the animals were awake and moving and again while the rats were in REM sleep and twitching.

What they discovered was puzzling, at first.

“We noticed there was a lot of brain activity during sleep movements but not when these animals were awake and moving,” Tiriac says.

The researchers theorized that sensations coming back from twitching limbs during REM sleep were being processed differently in the brain than awake movements because they lacked what is known as “corollary discharge.”

First introduced by researchers in 1950, corollary discharge is a split-second message sent to the brain that allows animals—including rats, crickets, humans and more—to recognize and filter out sensations generated from their own actions. This filtering of sensations is what allows animals to distinguish between sensations arising from their own movements and those from stimuli in the outside world.

So, when the UI researchers noticed an increase in brain activity while the newborn rats were twitching during REM sleep but not when the animals were awake and moving, they conducted several follow-up experiments to determine whether sleep twitching is a unique self-generated movement that is processed as if it lacks corollary discharge.

The experiments were consistent in supporting the idea that sensations arising from twitches are not filtered: And without the filtering provided by corollary discharge, the sensations generated by twitching limbs are free to activate the brain and teach the newborn brain about the structure and function of the limbs.

“If twitches were like wake movements, the signals arising from twitching limbs would be filtered out,” Blumberg says. “That they are not filtered out suggests again that twitches are special—perhaps special because they are needed to activate developing brain circuits.”

The UI researchers were initially surprised to find the filtering system functioning so early in development.

“But what surprised us even more,” Blumberg says, “was that corollary discharge appears to be suspended during sleep in association with twitching, a possibility that – to our knowledge – has never before been entertained.”

No sedative necessary: Scientists discover new “sleep node” in the brain

A sleep-promoting circuit located deep in the primitive brainstem has revealed how we fall into deep sleep. Discovered by researchers at Harvard School of Medicine and the University at Buffalo School of Medicine and Biomedical Sciences, this is only the second “sleep node” identified in the mammalian brain whose activity appears to be both necessary and sufficient to produce deep sleep.

Published online in August in Nature Neuroscience, the study demonstrates that fully half of all of the brain’s sleep-promoting activity originates from the parafacial zone (PZ) in the brainstem. The brainstem is a primordial part of the brain that regulates basic functions necessary for survival, such as breathing, blood pressure, heart rate and body temperature.

“The close association of a sleep center with other regions that are critical for life highlights the evolutionary importance of sleep in the brain,” says Caroline E. Bass, assistant professor of Pharmacology and Toxicology in the UB School of Medicine and Biomedical Sciences and a co-author on the paper.

The researchers found that a specific type of neuron in the PZ that makes the neurotransmitter gamma-aminobutyric acid (GABA) is responsible for deep sleep. They used a set of innovative tools to precisely control these neurons remotely, in essence giving them the ability to turn the neurons on and off at will.

 “These new molecular approaches allow unprecedented control over brain function at the cellular level,” says Christelle Ancelet, postdoctoral fellow at Harvard School of Medicine. “Before these tools were developed, we often used ‘electrical stimulation’ to activate a region, but the problem is that doing so stimulates everything the electrode touches and even surrounding areas it didn’t. It was a sledgehammer approach, when what we needed was a scalpel.”

“To get the precision required for these experiments, we introduced a virus into the PZ that expressed a ‘designer’ receptor on GABA neurons only but didn’t otherwise alter brain function,” explains Patrick Fuller, assistant professor at Harvard and senior author on the paper. “When we turned on the GABA neurons in the PZ, the animals quickly fell into a deep sleep without the use of sedatives or sleep aids.”

How these neurons interact in the brain with other sleep and wake-promoting brain regions still need to be studied, the researchers say, but eventually these findings may translate into new medications for treating sleep disorders, including insomnia, and the development of better and safer anesthetics.

“We are at a truly transformative point in neuroscience,” says Bass, “where the use of designer genes gives us unprecedented ability to control the brain. We can now answer fundamental questions of brain function, which have traditionally been beyond our reach, including the ‘why’ of sleep, one of the more enduring mysteries in the neurosciences.”

Speech processing while unconscious: Sleep inhibits action but not preparation and meaning

In a team effort between the Medical Research Council Cognition and Brain Sciences Unit (Cambridge, UK) and the Laboratory of Cognitive and Psycholinguistics Sciences, Ecole Normale Superiore (Paris), part of what we are capable of while sleeping has been unravelled.

People were asked to classify words belonging to one of two categories – animals or objects – by pressing buttons with the left or the right hand, and continued to do so until they have fallen asleep. Their brain activity indicated that they were able to decode the meaning of the words and intended to act but the unconscious state during sleep prevented them from responding (no movement of the fingers).

This result indicates that once a rule (animals press left/objects press right) is established during wakefulness it can still be implemented even during sleep. This means that the decoding networks in the brain process the spoken words and that information (if it is an animal or an object for instance) is passed to a motor plan signaling the intention and subsequent action. During sleep that action is inhibited (we do not purposefully move during sleep) but this study has found that the meaning extraction and subsequent action preparation remained but was slower and lasted longer.

To confirm this result a second study tested whether people could classify word or nonwords (like boat or foat). A similar pattern emerged, showing appropriate brain preparation activity for left or right button presses even if responses were inhibited by the sleep mechanisms.

Research helps explain why elderly have trouble sleeping

As people grow older, they often have difficulty falling asleep and staying asleep, and tend to awaken too early in the morning. In individuals with Alzheimer’s disease, this common and troubling symptom of aging tends to be especially pronounced, often leading to nighttime confusion and wandering.

Now, a study led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and the University of Toronto/Sunnybrook Health Sciences Center helps explain why sleep becomes more fragmented with age. Reported online today in the journal Brain, the new findings demonstrate for the first time that a group of inhibitory neurons, whose loss leads to sleep disruption in experimental animals, are substantially diminished among the elderly and individuals with Alzheimer’s disease, and that this, in turn, is accompanied by sleep disruption.

"On average, a person in his 70s has about one hour less sleep per night than a person in his 20s," explains senior author Clifford B. Saper, MD, PhD, Chairman of Neurology at BIDMC and James Jackson Putnam Professor of Neurology at Harvard Medical School. "Sleep loss and sleep fragmentation is associated with a number of health issues, including cognitive dysfunction, increased blood pressure and vascular disease, and a tendency to develop type 2 diabetes. It now appears that loss of these neurons may be contributing to these various disorders as people age."

In 1996, the Saper lab first discovered that the ventrolateral preoptic nucleus, a key cell group of inhibitory neurons, was functioning as a “sleep switch” in rats, turning off the brain’s arousal systems to enable animals to fall asleep. “Our experiments in animals showed that loss of these neurons produced profound insomnia, with animals sleeping only about 50 percent as much as normal and their remaining sleep being fragmented and disrupted,” he explains.

A group of cells in the human brain, the intermediate nucleus, is located in a similar location and has the same inhibitory neurotransmitter, galanin, as the vetrolateral preoptic nucleus in rats. The authors hypothesized that if the intermediate nucleus was important for human sleep and was homologous to the animal’s ventrolateral preoptic nucleus, then it may also similarly regulate humans’ sleep-wake cycles.

In order to test this hypothesis, the investigators analyzed data from the Rush Memory and Aging Project, a community-based study of aging and dementia which began in 1997 and has been following a group of almost 1,000 subjects who entered the study as healthy 65-year-olds and are followed until their deaths, at which point their brains are donated for research.

"Since 2005, most of the subjects in the Memory and Aging Project have been undergoing actigraphic recording every two years. This consists of their wearing a small wristwatch-type device on their non-dominant arm for seven to 10 days," explains first author Andrew S. P. Lim, MD, of the University of Toronto and Sunnybrook Health Sciences Center and formerly a member of the Saper lab. The actigraphy device, which is waterproof, is worn 24 hours a day and thereby monitors all movements, large and small, divided into 15-second intervals. "Our previous work had determined that these actigraphic recordings are a good measure of the amount and quality of sleep," adds Lim.

The authors examined the brains of 45 study subjects (median age at death, 89.2), identifying ventrolateral preoptic neurons by staining the brains for the neurotransmitter galanin. They then correlated the actigraphic rest-activity behavior of the 45 individuals in the year prior to their deaths with the number of remaining ventrolateral preoptic neurons at autopsy.

"We found that in the older patients who did not have Alzheimer’s disease, the number of ventrolateral preoptic neurons correlated inversely with the amount of sleep fragmentation," says Saper. "The fewer the neurons, the more fragmented the sleep became." The subjects with the largest amount of neurons (greater than 6,000) spent 50 percent or more of total rest time in the prolonged periods of non-movement most likely to represent sleep while subjects with the fewest ventrolateral preoptic neurons (less than 3,000) spent less than 40 percent of total rest time in extended periods of rest. The results further showed that among Alzheimer’s patients, most sleep impairment seemed to be related to the number of ventrolateral preoptic neurons that had been lost.

"These findings provide the first evidence that the ventrolateral preoptic nucleus in humans probably plays a key role in causing sleep, and functions in a similar way to other species that have been studied," says Saper. "The loss of these neurons with aging and with Alzheimer’s disease may be an important reason why older individuals often face sleep disruptions. These results may, therefore, lead to new methods to diminish sleep problems in the elderly and prevent sleep-deprivation-related cognitive decline in people with dementia."

Missing sleep may hurt your memory

Lack of sleep, already considered a public health epidemic, can also lead to errors in memory, finds a new study by researchers at Michigan State University and the University of California, Irvine.

The study, published online in the journal Psychological Science, found participants deprived of a night’s sleep were more likely to flub the details of a simulated burglary they were shown in a series of images.

Distorted memory can have serious consequences in areas such as criminal justice, where eyewitness misidentifications are thought to be the leading cause of wrongful convictions in the United States.

“We found memory distortion is greater after sleep deprivation,” said Kimberly Fenn, MSU associate professor of psychology and co-investigator on the study. “And people are getting less sleep each night than they ever have.”

The Centers for Disease Control and Prevention calls insufficient sleep an epidemic and said it’s linked to vehicle crashes, industrial disasters and chronic diseases such as hypertension and diabetes.

The researchers conducted experiments at MSU and UC-Irvine to gauge the effect of insufficient sleep on memory. The results: Participants who were kept awake for 24 hours – and even those who got five or fewer hours of sleep – were more likely to mix up event details than participants who were well rested.

“People who repeatedly get low amounts of sleep every night could be more prone in the long run to develop these forms of memory distortion,” Fenn said. “It’s not just a full night of sleep deprivation that puts them at risk.”