Top 10 science stories I wish I’d blogged about in 2013

As 2013 grinds to an end, the internet fills with reminiscence of the year’s top stories and moments. I, for one, especially can’t resist ruminating about the past, especially when packaged in a brain-tickling, “top n”  list form. Without further ado, here is my Top 10 list of the year: Science Stories I Wish I’d Blogged About.

Bonus. A List of Reasons Why Our Brains Love Lists. By Maria Konnikova.

To start off, why are we drawn to lists anyway? Is it due to the clean, structured organization that helps us navigate the material efficiently? Or is it more a product of our current “bite-sized” information culture? Maria has the answers.

10. Can we lessen the effects of fearful memories while we sleep?

Sleep therapy can change bad memories. By Helen Shen (original paper here)

Spontaneous activation of memories during sleep is generally thought to strengthen them. However, when researchers in Northwestern University repeatedly brought up a recently learned fear memory in their sleeping participants by presenting a fear-associated odour, the participants showed a smaller fear reaction to the odour after they awoke. According to the researchers, this is the first time emotional memories have been successfully manipulated in humans.

Similar: A gene for forgetting. MIT researchers identified a gene Tet1 that is critical for memory extinction in mice. Original paper in Neuron.

9. Men and women’s brains are wired differently. Is THAT why men can read maps better (or so the cliché goes)?

Here‘s one cover of the study that would let you believe that (gasp) it is indeed so!

Here are a few level-headed analyses that tackle the nitty-gritty of the study and how its conclusions got blown out of proportion. The bottom line? Brain scans don’t tell us anything about behaviour. Here’s the original paper for reference.

Are men better wired to read maps or is it a tired cliché? By Tom Strafford.

Men, Women and Big PNAS Papers. By Neuroskeptic.

Getting in a Tangle Over Men’s and Women’s Brain Wiring. By Christian Jarrett.

8. Mice inherent fears of their fathers. (And update) By Virginia Hughes.

You know how you are what your grandpa ate? Epigenetics offers an answer to how our interactions with the environment can influence the expression of our and our offspring’s DNA. However there is little evidence that stress and fear can directly change the germline, so that offsprings inherit the fear memory (or something akin to it) of their parents. (There was this interesting report earlier in the year on how cocaine-addicted sires lead to cocaine-resistant male pups through a purely epigentic means, though I remain skeptical.)

Virginia Hughes broke this story at the 2013 Society for Neuroscience conference. Since then, it has garnered plenty of attention from media and neuroscientists alike, with opinions from “deep scepticism” to “awe-inspiring”. Here’s the original paper if you’d like all the juicy details.

7. From Club to Clinic: Physicians Push Off-Label Ketamine as Rapid Depression Treatment. By Gary Stix

Ketamine, the clubbing sweatheart and horse tranquillizer, is now being repurposed as a fast-acting antidepressant; this is perhaps THE most breakthrough new treatment for depression in the last 50 years. In this 3-part series, Gary Stix explains the uprising of grassroots ketamine prescriptions, big pharma interest in the drug and how ketamine is directly the development of next-generation antidepressants.

6. Computer Game-Playing Shown to Improve Multitasking Skills. By Allison Abbott.

Rejoice, gamers of 2013! Not only has the year given us PS4 and Xbox One, this study from Nature has also given us an excuse to game (uh, or not): in subjects aged 60-85, playing a 3-D race car-driving video game reduced cognitive decline compared to those who didn’t.

Commercial companies have claimed for years that brain-training games help improve cognition; yet whether their games actually work is hotly debated (I’m looking at you, Luminosity!). In this new study, researchers from UCSF show that a game carefully tailored to a specific cognitive deficit can be useful, even months later. Unfortunately this doesn’t mean any ole’ video game will do. Shame.

5. 23andme versus the FDA.

I’m sure by now you’ve heard about the fight of the year.

David Dobbs has a full page of links over the 23andme and FDA food fight. What’s the big deal? Why did the FDA issue a cease and desist order? Is it simply a clash of cultures between the company and government department? Or are we selling out our own genetic data to the next-generation Google, and should we fear the services the company offers?

4. Sleep: The Ultimate Brainwasher? By Emily Underwood (Here’s another cover by Ian Sample).

Why do we sleep? Reasons range from learning and memory, metabolism and body-weight regulation, physiology, digestion, everything. A study this year proposes that sleep has another function: nightly cleaning, in which the cerebral spinal fluid washes a day’s worth of brain waste down the sewers. That is, if you’re a rat.

3. Death by sugar? by Scicurious.

With fat making a come-back, sugar and/or carbs are the devil this year. This study in Nature Communications says yes: when mice consumed a diet that has an equivalent amount of sugar to that of many people in the US, the animals’ health and reproductive ability declines.

However, as Scicurious astutely asked, can we really directly translate conclusions derived from mice to humans? Is sugar really that evil?

Here is another article on the topic by Ferris Jabr that’s well worth a read.

2. False memories implanted in mouse’s brain by linking portions of two real memories together. Wow. Just, wow.

False memory planted in mouse’s brain. By Alok Jha

Scientists Plant False Memories in Mice–and Mice Buy It. By Joel N. Shurkin

This is one paper I REALLY wish I had the time to cover when it first came out. An MIT group artificially connected the memory of a safe box and the memory of a footshock in another box to generate a new hybrid memory. This is not “implanting” a de novo memory – that is, researchers didn’t use electrical stimulation (or something similar) to generate a memory from scratch. The study also can’t tell us how false memories are generated biologically in our brains (ie linking imagined material to actual memories), but the study is genuinely fascinating all the same.

Here is a link to the paper, and here is the lead author doing an “ask me anything” interview on Reddit.

1. Knockout blow for PKMzeta, the long-term memory molecule. 

Single protein can strengthen old faded memories, Exposing the memory engine: the story of PKMzeta, and Todd Sacktor talks about the memory engine by Ed Yong

In a nutshell, previous studies have identified a single protein called PKMzeta that helps maintain long-term memory. Unlike other kinases (a type of protein involved in many cellular processes, including memory) PKMzeta is always active, and seems to help sustain the strengthening of connections between neurons during memory formation. Inhibit PKMzeta, and the memory’s gone.

These results spurred HUGH interest in the “memory molecule”, often with references to Eternal Sunshine of the Spotless Mind. However, things went for a downward spiral at the 2012 Society for Neuroscience conference, when researchers presented the first evidence that mice without PKMzeta had no impairments in LTP (long-term potentiation, widely considered a cellular mechanism for learning and memory) could still form memories. The two groups published their findings in early January 2013 in Nature (here and here).

These observations don’t necessarily mean that PKMzeta is not a memory molecule – it very well could be one of the MANY memory-associated proteins. Given the redundancy that often comes with evolution, it’s hard to believe that one particular molecule would be the sole guardian of our memories. The question remains whether PKMzeta is a MAJOR player, but overall, the debate is a cautionary tale against putting one molecule on the pedestal. So if (or when) you see another article with the headline “erasing a bad memory”, remember there’re plenty of other players in memory that you haven’t been told about.

Advertisements

The forgotten case of the sleepy virus

I spent last night rewatching the Steven Soderbergh classic “Contagion“. Halfway through I realized that a story of an unidentified, mind-bending infectious brain disease would make the perfect neuroscience halloween tale. This is not “based” on a true story. It IS a true story.

The year is 1917. Dr. Constantin Economo sat deep in thought, staring through the pages of his half-finished manuscript as he remembered his last patient of the day. She was a young woman, no more than 30, sitting immobile in an armchair lids-half closed, indifferent to the surrounding like a wax doll. Her face masked all expression, moulded into an eternal state of apathy.

“Please get up.” He had asked her. Following a brief pause, she complied; her movements were slow and depressed; her gait tilted. She often paused, holding a position as if frozen in time. Soon, without further probing, she fell back into a stupor. All the while, she was aware of her surroundings.

In stark contrast, the doctor recalled solemnly, was that 15-year-old boy with paranoia. His mother took him in due to sleep complaints – his sleep pattern had completely inverted. 3 days later, his gaze became permanently slanted; his tongue and limbs contorted into uncomfortable positions. An equally macabre shift occurred in his mind: he became increasingly paranoid and anxious, mixed with bouts of agitation. He developed a vocal tick and an obsession with compulsively touching his body. 8 months later, he showed no signs of remission.

The two patients share one thing in common. Von Economo thought as he wrote down the title of his manuscript, “Die Encephalitis lethargica”. An infection by an unidentified virus, transmitting in an unknown manner across continental Europe.

Little did he know that by the end of the epidemic in 1927, the virus would had spread across the globe, taking the lives of at least half a million people. Those spared from death were left in broken bodies, trapped in their shattered minds.

The disease stages of a “sleepy” brain

Encephalitis lethargica (EL) literally translates to “brain inflammation with lethargy”. Reports of the virus can be dated back to the age of Aristotle; however, the virus’ most ferocious rampage occurred between 1917-1926.

The disease is commonly known as “sleepy sickness”. Don’t be fooled by the innocent sounding name: one-thirds of those infected die, another third develop Parkinson’s-like symptoms that haunt them for life. Only one third may recover relatively unscarred.

The initial stages of EL infection seem like that of any other nasty bug: fever, sour throat, headache and general lethargy. The infected, unaware of the pathogen’s true nature, battles flu symptoms with bed rest and water, thus giving EL virus ample time to spread across the brain.

Autopsies have confirmed that the virus first and foremost causes infection in the hypothalamus, a small region at the base of the brain. This region controls our vital functions, including breathing, body temperature, hunger and sleep. Viral multiplication causes severe inflammation in the hypothalamus leading to its dysfunction. The EL virus then jumps to other areas of the brain, including the thalamus, cortex, and midbrain (striatum and substantia nigra), which play a role in reward, addiction and movement.

encephalitis-rmn

MRI of a patient with EL. Arrows point to areas of inflammation. Source: Ref 3

Infected adults quickly develop extreme daytime lethargy, unwilling to move for even basic bodily needs such as bathroom runs. To the observer, they seem either completely asleep or caught in the “twilight” zone between sleep and wakefulness. The chilling truth is that they’re completely aware of their surroundings – it just takes them incredible effort to talk or to move, perhaps due to the destruction of their basal ganglia. Most never survive this stage of acute infection – when the hypothalamus shuts down, so do basic survival functions. Unable to breathe, victims suffocate in a mockery of “peaceful sleep”.

Those who survive the initial attack are changed for life. Victims often seem like a shadow of their former selves, unable to concentrate and uninterested in life. Then, years or even decades later, they’re barraged by an onslaught of motor problems. Patients are unable to freely initiate movement; when they do its painfully slow. They’re plagued by tremors, speech and vision problems and abnormal limb movements. The most unfortunate victims managed to retain their hearing, cognition and reasoning but are left in a state of constant stupor. This untreatable, irreversible parkinsonism condemned younger survivors to decades of disability.

40 years after the discovery of post-encephalitic parkinsonism, neurologist Dr. Oliver Sacks famously tried to treat these motor symptoms with L-dopa (used for Parkinson’s Disease). At first it worked, but tolerance grew fast and soon the required dosage exceeded what the body could process. When drug treatment stopped due to toxicity, most patients soon slipped back into a catatonic state. Only a lucky few remained awake.

Infected young children fared even worse. Following a brief stint of lethargy, the virus quickly took over the developing brain, causing rapid changes in personality. At first the child may seem irritable or anxious, often unable to concentrate. As they grew, approximately one third become explosively violent; they “annoy strangers on the street… abuse them; they tramp, beg, lie, steal… indulge in sexual misbehaviour of every kind (at a young age) and make other dangerous acts.” In extreme cases, children self-mutilate to the point of extracting their own teeth; some display malicious cruelty toward others, coupled with feigned friendliness in a psychopathic manner. Their memory and intelligence remained intact; the virus just ate away any sense of morality.

Not much could be done. Many children were arrested or placed into mental institutions; some were subjected to frontal leucotomy. The procedure did not alleviate their destructiveness.

How did EL cause these changes in personality and behaviour? Some doctors propose it stems from direct lesions to the cortex and striatum, resulting in lowered cortical inhibition and skewed motivation. Others believe that dysfunction in the sensorimotor system in turn disrupted the thalamus and emotion-related circuits, increasing a child’s mental and physical sensitivity to any external stimuli. A few doctors opted for a psychoanalytic explanation, in which delinquent behaviours “represented a deep wounding of the ego.”

We still don’t know.

The face of an enigmatic killer virus

What is the true identity of Encephalitis lethargica? Von Economo famously proposed the cause to be a virus, much to the chagrin of Freudian scholars who preferred a psychoanalytical explanation.

Early on, scientists noticed something peculiar: EL almost always trailed behind flu outbreaks; the 1920 epidemic, for example, partially overlapped with the Spanish Flu pandemic, which took more than 20million lives. This overlap in time has led to scientists to speculate that the flu virus may directly be responsible for EL. Although some clinicians and epidemiologists rejected the idea from the get-go, they could not directly study the virus due to its rapid disappearance in the late 1920s.

Almost a century later, in 2001, scientists reopened the case. They obtained brain samples collected from victims of the epidemic and meticulously analyzed them with modern molecular biology techniques. The samples were well preserved, yet scientists could not find any traces of the flu’s genetic material. This may indicate that the flu operated in a “hit-and-run” manner, lingering in the body just long enough to lower its immune defences, allowing EL to “swoop in”. On the contrary, the flu may have triggered the body to produce autoantibodies, which viciously attacked the brain during subsequent EL infection. Or it could mean the two viruses were completely unrelated; a horrendous coincidence.

A study from 2012 further unmasked the EL virus. Scientists obtained brain samples of EL victims from both the epidemic age and from several modern cases. Studies using electron microscopy found virus-like particles in brain cells of EL victims (below).

1471-2334-12-136-3

Endoplasmic Reticulum membrane (normal cell protein factory) embedded in viral particles. Electron microscopy. Source: Ref 3

Surprisingly, these particles also appeared in the cell nucleus, where genomic DNA is stored. Hunkering down in the nucleus is a trait of the Enterovirus – the most notorious of which causes polio – leading scientists to suspect that EL may belong to the genus. Using fluorescent-tagged protein probes specific for poliovirus protein, researchers found proteins similar to that of poliovirus; genetic studies also found ~93% similarity in the genes of EL virus and various Enteroviruses. Unless samples were contaminated, these data strongly suggest that EL is a type of Enterovirus.

Encephalitis lethargica: the case continues

As quickly as it came, the EL virus vanished in 1927, leaving behind hundreds of thousands with broken bodies and shattered minds. Why are scientists interested in a seemingly obsolete virus, quarantined between the pages of history long gone?

The truth is that EL is far from eradicated. Like the boogyman, the virus occasionally rears its ugly head, infecting both adults and children alike. Modern case studies show that EL virus often shadows common “sore throat” bacterium* like Strep or Diplococcus, taking a second, brutal swing at already-infected patients. We still don’t know where it comes from, how it transmits or who is most vulnerable.

Scattered outbreaks are occurring to this day. As of now there is no cure.

* Edit: Thanks @aetiolgy for pointing out that I called Strep a “virus”. It’s a bacterium.

Case descriptions at the beginning of the article are based on Von Economo’s description of patients – nothing made up.

Final word: So…research is “non-essential”, huh?

ResearchBlogging.org

Vilensky JA, Foley P, & Gilman S (2007). Children and encephalitis lethargica: a historical review. Pediatric neurology, 37 (2), 79-84 PMID: 17675021

Dourmashkin RR, Dunn G, Castano V, & McCall SA (2012). Evidence for an enterovirus as the cause of encephalitis lethargica. BMC infectious diseases, 12 PMID: 22715890

Dale RC, Church AJ, Surtees RA, Lees AJ, Adcock JE, Harding B, Neville BG, & Giovannoni G (2004). Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Brain : a journal of neurology, 127 (Pt 1), 21-33 PMID: 14570817

Circadian clock out of whack? Go sleep under the stars!

TL;DR: A week away from artificial light shifts back your out-of-whack circadian rhythm so that you wake at dawn and sleep at dusk. 

CircadianRhythm

Are our circadian clocks running too fast? Source: http://www.kevincredible.com/

Artificial lighting is, for lack of a better word, a godsend. Unfortunately, our circadian rhythms don’t quite agree. Evolved over several millennia, circadian clocks are exquisitely entrained to natural light-dark cycles and allow our bodies to run “on optimal time”. During the bright-lit day, our internal clock tells us to increase energy intake and expenditure and cognition; after sundown, it promotes sleep by increasing the levels of melatonin. Since a major driving force of the circadian clock is light, how much can artificial electrical lighting drive it out of whack (I’m looking at you, iPad)? And is there any way to get our internal circadian rhythm back?

Kenneth P Wright Jr et al (2013) Entrainment of the Human Circadian Clock to the Natural Light-Dark Cycle. Current Biology. Doi: 10.1016/j.cub.2013.06.039

Picture this. In the busy streets of Colorado, 8 people, aged 20-30 years old, are going about their busy lives (and sleep) as usual. What’s out of the norm is that they are participating in an experiment: all of them wore wrist activity monitors to measure their average activity levels, sleep start time, wake time and sleep duration and efficiency. A week later, researchers took these participants into a dim-lit lab, and measured their “natural” circadian rhythms by quantifying the levels of melatonin in their saliva (which, according to the authors is the most accurate way to track circadian clocks). Participants were also asked about their usual sleeping habits.

The group then ditched the city for the Rocky Mountains, where only natural light was permitted. So no flashlights, no iPhones/Androids, only sunlight and campfires. Participants still slept as they pleased, and went back into the lab for a second measuring a week later.

And the results? During the week of camping out, participants experienced more than 400% the amount of total light than in the city, and this increase was seen throughout the day at several light intensities – expect in the evening between sunset and sleep, where participants were exposed to more (artificial) light normally. This bump in light exposure before bed is bad news as the human circadian clock is most sensitive to light-induced delays in the evening. In other words, the circadian clock thinks it’s earlier in the day than it actually is, and holds off on producing melatonin to promote sleep.

Screen Shot 2013-08-01 at 1.13.42 PM

This is indeed the case. As you can see in the graph above, when engaged in their normal schedules (“Electrical Lighting”), the participants’ melatonin levels rose long after sunset, about 2 hrs before bedtime (12:30am), and remained high even AFTER wake time at ~8:00am. Since a drop in the hormone’s levels contributes to wakefulness, this could explain the “morning drowsiness” that many night-owls feel after crawling out of bed.

After a week of natural light, things seemed to “reset”. As you can see in the part of the graph labelled “Natural Light”, the participants’ circadian clocks shifted ~2hrs earlier on average, so that now melatonin levels rise near sunset and lower at sunrise. This correlated with a shift towards earlier sleeping and waking times, so that the participants “naturally” awoke at dawn and fell asleep at dusk; however, total sleep time did not change.

Perhaps it’s not surprising that a week away from artificial lighting can put you back “in tune” with your natural circadian rhythm. Nevertheless, this study does raise some questions. Would artificial lighting also influence circadian rhythms of people living near the equator, where there’s naturally much more sun exposure? What about people living in the arctic or Antarctic? This study was done in healthy people – would a similar effect occur in people with sleeping disorders, like insomnia? Can avoiding artificial light – on its own or with therapy – reset their circadian clocks and help them sleep?

A wonky circadian clock is linked to MANY diseases, such as sleep disorders, obesity, diabetes and heart problems. Maybe the best way to enjoy the rest of summer is to go out in the woods, sleep under the stars, and get your body back on the right “time” track.

ResearchBlogging.org
Kenneth Wright Jr. (2013). Entrainment of the Human Circadian Clock to the Natural Light-Dark Cycle Current Biology DOI: 10.1016/j.cub.2013.06.039

Sleep waxes and wanes through the lunar cycle

A group of sleep-scientists walk into a bar… and start asking how a full moon can change your nightly snoozing after a drink or two*. Funny how science works sometimes.

Christian Cajochen et al (2013) Evidence that the Lunar Cycle Influences Human Sleep. Current Biology. doi: 10.1016/j.cub.2013.06.029

scan0002_large

Sleep lab? Eh, not quite. Source: http://www.realityrn.com/

Lucky for the scientists, the data was already available. Roughly a decade ago, the scientists recruited 33 volunteers – both male and female, and young and old – and put them in a sleep lab for a couple of nights. Back then they wanted to study how circadian rhythms changes the body’s physiological functions. The volunteers were kept in a room with constant temperature and light levels, ate regular light snacks and had absolutely no indication of time. (Sounds a little like solitary confinement to me, eek!)

While they snoozed, scientists recorded the electrical activity of their brains with electroencephalogram (EEG). During sleep, the brain does not completely shut down – instead the ebb and flow of various neurotransmitters switches the brain from awake to unconscious and back again. EEG monitors different stages of electrical activity, which occurs in ~90min cycles, and gives information on sleep structure (see graph below). Scientists also checked for eye movement, which occurs during rapid-eye movement (REM) sleep –often associated with dreaming – and the levels of two hormones, melatonin and cortisol. Melatonin helps regulate the sleep-wake cycle by inducing drowsiness (hence their reputation as an OTC sleep aid), while cortisol is associated with the stress response. Scientists also asked the volunteers to rate their sleep quality after the experiment.

497S2a-f2.2

Stages of sleep. Source: Nature Outlook Special Issue on Sleep. http://www.nature.com/nature/journal/v497/n7450_supp/full/497S2a.html

Fast-forward a decade. Data in hand, scientists went ahead to see what they could find (ie they didn’t have an a priori hypothesis). As you can see below, regardless of age or gender, sleep latency correlated beautifully with the lunar cycle, with volunteers requiring roughly 5 MORE minutes to fall asleep during the full moon. On nights close to a full moon, the volunteers also experienced 20 min LESS total sleep time, WORSE sleep quality, and ~30% DECREASE in deep-sleep. The level of melatonin also tanked around full moon, while cortisol didn’t significantly change.

Screen Shot 2013-07-30 at 3.54.51 PM

Figure 1 from the paper. Sleep latency = time it takes to fall asleep. Lovely correlation!

Does our sleep ebb and slow with the moon then? Since the scientists didn’t think of their hypothesis until years after the experiment, the volunteers were in essence “blinded” to the lunar phase. Even if some volunteers were keen on observing the moon, there’s arguably little possibility that they might think that a full moon would affect their sleep negatively and generate placebo effects. The volunteers were kept in a room with constant levels of ambient light – hence the difference in sleep cannot be explained by different levels of light from the moon. It’s possible that ambient evening light might “prime” the volunteers to subconsciously alter their sleeping patterns before they enter the lab – but there’s no evidence for this.

One major problem with retrospective studies like this one is that it can sometimes lead to false positive statistical correlations. 33 people is a small sample, especially considering their diversity in terms of age and sex, it’s highly possible that the results would not stand up in a much larger study. (There are also people conducting n=1 “quantified self” experiments across the internet, and while interesting, can’t be counted as stringent scientific studies.)  It would be really interesting to follow up this study with a larger sample designed to directly test this hypothesis, and see if the same phenomenon can be repeatedly detected in different cohorts.

Until the results are repeated and the mechanisms unravelled, I’m still skeptical. But let’s say that human sleep does undulate with lunar phases. How could this work? Although oceanic tidal waves undulate with different lunar phases, the human body (or the water within) does not, so changes in water flow in the body is out of the question. Another long-standing myth is that lunar phases affect people’s mood and behaviour (hence words like “lunacy”), and mood may in turn effect sleep. However, while legends and old wives tales persist, this myth has been rebuked by science.

The authors suggest that perhaps just like daily circadian rhythms, humans also have a “circalunar rhythm”, which has been characterized in certain marine animals like the Galapagos marine iguanas. However, perhaps due to huge individual differences in sensitivity to lunar phases, the idea of a circalunar clock is still controversial.

The idea of a mysterious lunar clock in humans is tantalizing. What does it DO? How much influence does it have on us? How much is it disrupted by our current society of artificial lights and hectic work schedules? What are the neuronal underpinnings of such a phenomenon? Would chronic disruption of the lunar clock lead to various diseases, or vice versa?

* Quote from the methods section of the paper: “Thus, the aim of exploring the influence of different lunar phases on sleep regulation was never a priori hypothesized, nor was it mentioned to the participants, technicians, and other people involved in the study. We just thought of it after a drink in a local bar one evening at full moon, years after the study was completed. ” BOSS!

ResearchBlogging.org
Christian Cajochen (2013). Evidence that the Lunar Cycle Influences Human Sleep Current Biology DOI: 10.1016/j.cub.2013.06.029

Why do some memories fade while others endure?

1-s2.0-S136466131300020X-gr2

The brain doesn’t shut down during sleep – certain memories are reactivated, which may determine their fate. Source: http://www.sciencedirect.com/science/article/pii/S136466131300020X

Ah, the age-old question: why do we remember what we remember? One possible mechanism is selective “memory replay” during sleep, in which the brain reactivates specific patterns of neuronal firing as seen during learning. In other words, memories that are rehearsed during sleep will most likely be retained (“consolidated” in neurojargon) in the long run. Studies in rats imply that not all memories are equal: periods involving reward information or crucial choice-points – “important” memories – are preferentially replayed and consolidated. The same seems to happen in humans – you probably remember your “emotionally salient” first kiss much better than what you had for breakfast that morning. Is replay responsible for this selectivity?  Does replay happen when you’re asleep or awake? Can we manipulate replay to remember what would’ve been forgotten?

Delphine Oudietete et al. (2013) The Role of Memory Reactivation during Wakefulness and Sleep in Determining Which Memories Endure. J. Neurosci. 33(15): 6672-6678.

To answer these questions, researchers worked with 60 young volunteers, and asked them to remember the location of objects on a screen (see figure below). Each object had a value displayed with it to inform volunteers how much money they could make if they recalled the location correctly. A distinctive sound was played for each object (“meow” for cat and “woof” for dog) – as you will see, these sounds are the puppet strings used later to manipulate memory replay.

Screen Shot 2013-04-15 at 4.45.41 PM

After learning, participants were separated into four groups. Groups 1  & 2 went for a 90min power nap. For group 2, researchers played sounds associated with half of the low-value objects during a phase of sleep called slow-wave sleep (e.g. researchers played only “meow” even though both cat (associated) and dog (not associated) are both low-value objects). The idea is those sounds will act as cues to trigger replay of associated low-value memories. Group 1 was left alone to snooze in peace. Groups 3 & 4 stayed awake. Group 3 watched a relaxing nature documentary while group 4 worked through a bunch of difficult memory tasks. During these tasks, researchers played sounds characteristic of half of the low-value objects in the background, similar to group 2. Because the task was so taxing, researchers assumed group 4 would not be able to pay attention to the sounds. In a sense, this design mimics the unconscious perception of sounds during sleep.

01 - later3

Testing the power-nappers for recall showed that while memory performance decreased in general, high-value object locations were remembered better than low-valued ones after sleep. However, playing sounds associated with low-value objects during sleep “rescued” the memory, to the extent that memory retention was similar for high- and low-valued objects. This seemed to work best when the sounds were played during slow-wave sleep: sound cues presented in another stage of sleep weren’t nearly as helpful. Surprisingly, sound cues helped the participants remember the whole category of low-value object locations better, not just the half directly associated with the sounds. Using our cat/dog example as above, playing “meow” during sleep enhanced memory retainment for both cat AND dog.

A similar trend showed up in the waking groups, with participants showing less error in remembering high-value object locations upon recall. While sound cues also enhanced retention of low-value object memories, further analysis showed that this was specific to the ones directly associated with the sounds, not the entire category.

So what makes us remember what we remember? Well, memories are selectively retained during both wakefulness and sleep, depending on their value. This selectivity seems to be driven by memory reactivation. Memories with a high (monetary) value are (probably) preferentially replayed and consolidated, as seen by the fact that high-valued objects show less memory decline. It’s more than likely that the same advantage holds for other types of salient (striking) memories. In fact, some researchers propose that disrupting replay and consolidation during sleep can weaken traumatic memories and reduce the chance of developing post-traumatic stress disorders.

Conversely, low-value memories can be saved from forgetting by artificially driving their reactivation through an associated cue. Presumably, this is because cues can cause reactivation of associated memories, increasing their replay and subsequent consolidation. Unfortunately, without sticking electrodes into the brain to record neural activity, we can’t be sure the sound cues in this study are triggering memory replay.

Which makes me wonder: What if you give cues corresponding to high-value objects during sleep and wakefulness? Will this strengthen the memory even more? Or will it eventually start interfering with the memory? Does the characteristic of the cue matter? Here it seems that the cues inherently reflect the nature of the object. What if a “baaahhh” is paired with a dog? Would this still strengthen the dog-related low-value memory? Why do sound cues enhance memory retention of the entire category of low-value objects when given during sleep, but increases only cue-associated memories during wakefulness? Can we specifically enhance individual memories during sleep? What happens if the cue is given throughout the entire sleep cycle, instead of just slow-wave sleep?

Finally, this study suggests we may be able to “sleep hack” our way into remembering several different types of memories better.

ch6explicitAs shown above, memories can be explicit (facts, visual memory, abstract knowledge) or implicit (certain motor skills you can do without thinking). A recent study in Nature Neuroscience showed that replaying a newly learned piano melody during sleep helps people perform the melody better upon awakening, demonstrating that sound cue-induced reactivation can enhance motor (implicit) memories.This study suggests that explicit memories may also be open to sleep hacking. While I don’t want to jump to conclusions, maybe next time I’ll try falling asleep to my study playlist and see what happens.

ResearchBlogging.org
Oudiette D, Antony JW, Creery JD, & Paller KA (2013). The Role of Memory Reactivation during Wakefulness and Sleep in Determining Which Memories Endure. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33 (15), 6672-8 PMID: 23575863

A new cure for insomnia?

zombie

From the hilarious and horrifyingly accurate http://www.phdcomics.com If you haven’t seen those yet, GO! If you’re a grad student, do it NOW!

Many a nights I’ve tossed and turned, willing my brain to STFU and let me sleep. I’m not alone in this battle. 10-15% of adults suffer from insomnia, and up to a third take prescription sleeping pills to bring on the snooze – for a heavy cognitive price.

Current sleeping drugs, such as Ambien and Lunesta, target a type of receptor called GABAAR in the brain. GABAAR is not only implicated in sleep; it also regulates mood, learning and cognition, and works to increase inhibitory synaptic transmission. Targeting GABAAR with Ambien is almost like bringing a hammer to the head: it slows down the brain enough to bring on sleep, but at the same time disrupts normal cognition, attention, learning and memory the next day, leading to “hypnotic hangovers” that are hard to shake off. Even worse, GABAA-modulators don’t really mimic the physiological sleep state, and can bring on some seriously weird behaviors, such as walking, eating and even driving while the person is asleep.

Is it time for a new target?

Jason M. Uslaner et. al. (2013) Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition. Science Translational Medicine 5, 179ra44

hypothalamus

The authors in this study have their eyes on the orexinergic system. Along with its role in appetite and energy regulation, orexin (aka hypocretin) is also a predominant arousal signal to parts of the brain controlling the sleep/wake cycle. It is a protein synthesized almost exclusively at the lateral hypothalamus, the brain’s major sleep/wake control centre, and acts to promote wakefulness and vigilance. Unlike the promiscuous GABAAR, orexin’s receptors are scattered in brain areas primarily involved in sleep. Previous studies have shown that blocking orexin can induce sleep, but haven’t looked at potential cognitive side effects. Here, the authors developed a new orexin receptor antagonist called DORA-22, and pitted it against the traditional hypnotics, Valium (diazepam), Ambien (zolpidem) and Lunesta (eszopiclone).

By feeding the drugs to rats and rhesus monkeys, the authors first discovered that at higher doses, DORA-22 was just as effective as GABA-modulating drugs in bringing on the zzzs, while at lower doses it was even more effective than current drugs on the market. (How do you tell when an animal is asleep? Here the authors fitted their test subjects with devices for ECGs to measure their brain waves. A less objective way is to flip a rat over and see if it flips back. Either way, sleepy rats make cute subjects. Not so sure about sleepy monkeys). So DORA-22 seems to work as hypothesized, but what about side effects? The authors went on to test DORA-22’s effect on three aspects of cognition: episodic-like memory, the ability to remember things and events; working memory, the ability to keep information in mind and manipulate it towards a goal; and attention, the ability to focus and keep track.

Novel

Novel Object Recognition Task.   Source: http://www.cedars-sinai.edu/

After inducing sleep with the drugs, researchers rudely awakened their subjects and started the tests. They presented rats with a new object, which the rats eagerly explored. They then took the object away, and returned it one hour later, along with a new object. If the rats remembered the first object, they would explore the newer one more vigorously. This is called the “object recognition task”, and is a measure of memory. Valium, Ambien and Lunesta all disrupted object recognition memory. In fact, the minimum dose that did so was ½ to 1/10 the minimum dose that increased sleep in rats! This means that GABAA modulators induce memory failure BEFORE sleep. In stark contrast, while DORA-22 also decreased memory at high doses, the minimum dose required was 30-fold greater than the dose that increased sleep. In other words, DORA-22 had a much greater therapeutic window. The same trend was observed for the other two tasks: monkeys on GABAA modulators performed much worse on tasks measuring working memory and attention than controls, while those given DORA-22 did just as well.

This is very exciting and encouraging, as DORA-22 signifies an entirely new class of hypnotics. Not every drug works for everyone, and those that do work tend to be less effective over time as tolerance develops. The lack of negative effects on short-term cognition is also a major plus.

HOWEVER, due to the experimental design, it is impossible to tell whether manipulating the orexin system will cause next day “hypnotic hangover”. The conditions used in this study corresponds to situations where the patient is awakened from a short stretch of DORA-22-induced sleep and expected to perform tasks that demands attention, memory and mental flexibility. Think a student popping a pill to power nap for an hour, before being wakened by the alarm to immediately go take an exam. From the available data we don’t know if cognition is disrupted the next day after a full sleep period. We also don’t know if DORA-22 influences the composition of sleep, as in the relative percentage of rapid-eye movement (REM), non-REM and slow-wave sleep. Since each stage of sleep has its own distinct function, maintaining a physiological sleep make-up is crucial. Along the same lines, sleep generally occurs in 90-min cycles, and disrupting the cycle can impair memory processes such as memory reconsolidation. At the moment we also don’t know whether DORA-22 influences cycle duration and/or total sleep time. There is also no information on long-term usage. And finally, while orexin receptors are more specifically distributed than GABAARs, orexins DO have roles outside managing wakefulness, such as increasing food intake and energy expenditure. Whether DORA-22 (and its sons and daughters) will affect these biological processes is anybody’s guess.

Although I wouldn’t call DORA-22 a “drug that can overcome insomnia without leaving users feeling hungover the following day” or “the perfect hypnotic” just yet, overall, targeting the orexin system seems to be a promising strategy for bringing sleep to insomniacs without the cognitive side-effects.

download

Finally, if you haven’t seen Mike Birbiglia’s “Sleepwalk with me” yet, I highly recommend it. From Wikipedia: Sleepwalk with Me is a comedy written by, directed by and starring comedian Mike Birbiglia, based on a true story he told in his one-man off-Broadway show and his first book. The film follows the journey of an aspiring comedian in denial about his girlfriend, his career, and, most significantly, his REM Sleep Behavior Disorder. The more he fails to express his true feelings, the more his anxiety comes out in increasingly funny and dangerous sleepwalking incidents.

ResearchBlogging.org
Uslaner JM, Tye SJ, Eddins DM, Wang X, Fox SV, Savitz AT, Binns J, Cannon CE, Garson SL, Yao L, Hodgson R, Stevens J, Bowlby MR, Tannenbaum PL, Brunner J, McDonald TP, Gotter AL, Kuduk SD, Coleman PJ, Winrow CJ, & Renger JJ (2013). Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. Science translational medicine, 5 (179) PMID: 23552372

Edit: Looks like Merck’s DORA drug in on the brink of approval from the FDA. Exciting!