The DESIRE Project for Epilepsy: Is Collaboration in Science More Efficient Than Competition?

700 million people will have a seizure in their life - that means 1 out 10 human beings. Epilepsy, which can only be diagnosed after a minimum of two seizures (more than 24h apart) is the third most common neurological condition in the European Union following Alzheimer’s disease and stroke.

Despite these facts, the disease is still widely misunderstood and often stigmatizing.  On September 15th 2011, a new piece of legislation entitled the EU Written Declaration on Epilepsy was approved by the European Parliament after being signed by a strong majority of 459 members (out of 751) [1]. The Declaration initiated a change in the funding strategies of the EU: new funds were allocated, and several research projects were created. Today, the EU is handing out 173 million euros that fund a dozen or so European research projects [2]. Among them: the DESIRE project [3].

Epilepsy : a Misunderstood Disease
This enticing acronym stands for “Development and Epilepsy - Strategies for Innovative Research to Improve Diagnosis, Prevention and Treatment in Children with Difficult-to-Treat Epilepsy”. Now that I’m re-reading this I do not think it’s an acronym- if you take the initials of all important words, then remove half of them, you’ll get „DESIRE“. Anyway, the important words here are “children”, and “hard to treat epilepsy”. Epilepsy can hijack the life of people of all ages and it can have many causes [4]. DESIRE focuses on abnormal early (intrauterine) development of the cerebral cortex and its association with epilepsy [4,5]. During neurodevelopment, precursor cells formed in the periventricular region migrate to their correct location where synapses are made and later edited to produce a mature brain. Any interruption of these processes can create cortical abnormalities [5-7]. Most of these malformations have genetic underpinnings, however, environmental factors such as lack of oxygen or intrauterine infection also play a role [4]. These types of epilepsy are difficult to treat because the underlying pathology varies substantially and patients often have severe comorbidities. 

'DESIRE'  FUNDS MORE THAN 250 RESEARCHERS FROM 11 COUNTRIES

The DESIRE project funds the research activities of more than 250 researchers from 25 universities in 11 countries [3]. Since the Charité is one of the partners and DESIRE funds my PhD, I have attended the last four yearly meetings of the project. The last one was in Valetta (Malta) mid-october. I know what you’re wondering and yes, the weather in Malta is beautiful this time of the year. More seriously, it has been fascinating to see the projects evolve over the years. Researchers don't necessarily need a big European project to collaborate and exchange information, but I have personally never seen cooperation between researchers on this scale before.

DESIRE Leads to Scientific Collaboration
Let me explain. One of the eight work packages within the DESIRE project aims to “Identify genetic causes and pathomechanisms of epileptogenic brain malformations”. The first step is to pin down germinal or somatic mutations in patients with a specific type of malformation. Once you have identified a new interesting mutation in a patient you need at least one more patient to be able to claim a possible causality. Since these malformations are extremely rare this can be nearly impossible. In 2014, during the first meeting that I attended, 20-30 researchers and group leaders sat around a table and started exchanging genetic mutations. The amount of information exchanged in one afternoon was overwhelming. In the following years, databanks were created, pools of interesting genes were selected, and samples were sent across Europe to be systematically tested. Today, 150 patients with malformations of the cortical development and 450 with encephalopathies have been included in the project. This led to the identification or confirmation of several mutations (notably in the PIK3/mTOR pathway and in different types of voltage gated sodium channels) [8-10]. In the meantime, samples were analysed in Erlangen (DE) and a pattern of methylation in a specific type of malformation was identified. Epigenetics were previously known to have a role in epilepsy [11] but this was a breakthrough.

Once a mutation is identified, it needs to be tested. Using in-utero electroporation, these mutated gene sequences were introduced into mice, rat, or ferret embryos to create better models for cortical malformations (the latter is a good model for cortical development because it is convoluted like higher mammals [12]). In many cases, the models showed malformations comparable to those observed in patients, and the pathomechanisms could be studied [7], [13].
Every meeting is extremely dense, each member presents the advancement of their project within their work package, even negative results, often before they are published. There is a sense of community; even competitive teams exchange tips and comment on each other’s data. DESIRE ends in September 2018 and it will certainly meet most of the objectives set in 2013. One of the concluding remarks in Malta by Prof Jeffrey L. Noebels member of the Scientific Advisory Committee was that the most impressive work had been done by collaborations between teams within DESIRE. Let us hope this spirit of collaboration will continue on after the end of DESIRE.

by Aliénor Ragot, PhD student AG Holtkamp
This article originally appeared December 2017 in CNS Volume 10, Issue 04, Sleep 

[1] http://bit.ly/2zfet2n/ 
[2] http://bit.ly/2yAAqaU
[3] http://bit.ly/2Am5jBq
[4] http://bit.ly/1wgpTup
[5] Romero DM, Semin Cell Dev Biol, 2017
[6] Fernandez V, EMBO J, 2016
[7] Khalaf-Nazzal R, Hum Mol Genet,2017
[8] Alcantara D, Brain, 2017
[9] Parrini E, Hum Mutation, 2017
[10] Møller RS, Neurol Genet, 2016
[11] Kobow K, Neurosci Lett,2017
[12] Neal J, J Anat, 2007 
[13] Martinez-Martinez MA, Nat Commun, 2016

From Sleep Researcher to Consultant to Entrepreneur

Meet Els van der Helm the ‘Sleep Geek’; Neuroscientist and founder of Shleep - the sleep company

You hold a Master and a PhD in Neuroscience. Would you tell us more about your background?

I’ve always been fascinated by sleep. I read a book by Prof. Bill Dement from Stanford when I was in high school which taught me about the magic of sleep and also the taboo around it: that we associate it with being lazy or less ambitious. That really inspired me to study clinical neuropsychology and neuroscience. So during my Master on these topics, I started to do sleep research, first at the Netherlands Institute of Neuroscience in Amsterdam and then at Harvard, looking at the effect of sleep in emotional processing. And then I went on to do my PhD at UC Berkeley, looking at the effect of sleep on our brain.

Els van der Helm, sleep expert and founder of Shleep

 How was your transition from the PhD to becoming a McKinsey consultant?

I really enjoyed doing sleep research and learning about it, but at the same time I realized that doing neuroimaging is very technical and not necessarily my passion. I also missed working in a team and having a more direct impact. I really wanted to help people and the slow pace of academia didn’t fit me. So I decided to make a change and go into business and learn more about the rest of the world, beyond academia.

How was your experience as a business consultant for almost 3 years?

The beginning was quite rough in some ways and quite easy in others. Starting with the roughness: there is much more time pressure on what you are doing. I remember having meetings with my manager and instead of saying ‘I’ll see you in a week’, which was kind of the pace in academia, the answer would be ‘OK, let’s see in two hours where you are’. So, suddenly, you’re doing everything under time pressure. And for me it really meant that I still had a lot to learn about time management and organizational skills. I also had to share my documents with the rest of the team and the clients, whereas in academia it was much more individual: I could make a mess, as long as I could understand it. So the biggest changes for me were the change in pace and the level of focus that it required. It was much more intense. Also, I was at the client’s site the whole day and couldn’t for example go work out in the middle of the day if I wanted to, as I was able to do during my PhD. That was quite rough, to be honest. It was a very different way of working that I needed to learn. Different skills were required and these weren’t skills that you just get within 2 or 3 weeks. I would say I really got the hang of it when I was doing the work for about 9 to 12 months. And that’s quite normal, but coming in after a PhD or a post-doc as opposed to after a Master or a Bachelor’s degree, you expect more of yourself. So for me it was a humbling journey, having to develop all of those new skills, basically a 'consultant's toolbox'. This toolbox is not just critical in consulting, but helpful in any type of job. I also enjoyed the fact that you work in a team, you get so much feedback, training and support around you, which I didn’t really experience during my PhD. So my learning curve was a lot steeper than it had been in academia. I felt like I was using my time better. It was always a different project, team, manager, client, and industry. In consulting, every year feels like a ‘dog year’: it’s worth 7 years! (laughs) So it’s a rough transition but I’d say well worth it. You develop yourself very quickly and it’s a unique experience. There were things I loved and things I was less happy about, but overall, a very positive experience.

What motivated you to make the career change of leaving consulting in a big firm to starting your own company?

It was never really my goal to stay in consulting forever. For me, it was all about purpose. I really wanted to focus more on something I’m really passionate about. The funny thing is that when I joined McKinsey I didn’t think I would ever do anything with sleep again, but not working on sleep anymore made me realize how much I missed it, and how passionate I was about the topic. Perhaps in academia I wasn’t working on the topic in the right way: it was very technical and very slow, which I didn’t really enjoy. When I started as a consultant, I also quickly realized that, for me, business problems are really not as interesting as neuroscience and the brain. But I did really love being in the business world and interacting with people who are really smart, care about their own performance and are very ambitious. In McKinsey, we received a lot of training: in time management, stress, leadership... But never ever did the word ‘sleep’ come up. Knowing how critical sleep is for learning, attention, stress reactivity and developing new insights, I felt that was a major topic missing. 

 'IT STARTED AS MY HOBBY AND THEN GREW INTO A COMPANY'

That really inspired me to start giving sleep workshops for my colleagues and McKinsey clients. It was so much fun and there was so much interest. Giving these workshops made me realize how I could work with the topic of sleep in a way that fits me much better: translating science into practical advice (which I wasn’t really doing in academia) and seeing a direct impact on the people I was working with. That was something I cared about much more than being a consultant. It started as my hobby while at McKinsey but I really made that grow and carved out a space for myself, as the internal sleep expert. It was almost like a testing ground for me, or an incubator, where I could test my ideas, get feedback, and grow my network and skill set. So I decided to leave and started my own business, called Shleep, in 2016.

Can you please tell us more about Shleep? What are its products and who are its clients?

Our mission is to help the world sleep better. We help organizations improve their performance by improving the sleep of their leaders and employees. For this, we offer a number of products and services. We design sleep programs for companies, which means that we help them develop approaches to put sleep on the map and really embrace it in their culture, so that all employees know how important sleep is and can prioritize it better. This way, they perform better, are happier and healthier. Some other services we offer are online assessments, in-person workshops, one-on-one coaching, webinars, and we’ve developed a digital sleep coaching app that will be launched soon in the App Store, so it will also be available for individual consumers. Examples of our corporate clients are McKinsey, Deloitte, Spotify, social network companies, pharmaceutical companies, law firms, startups, amongst others. Our startup team is quite international. The office is based in Amsterdam, along with our marketing guru, Tom, and myself. My co-founder, Jöran Albers (the ‘business guy’), is based in Munich, our developer is from Switzerland but lives in the Netherlands, and Elena, a circadian rhythms PhD, is based in Canada.

http://www.shleepbetter.com/

What advice would you give to current Master and PhD students in Neuroscience who would like to leave academia?

Join our company for an internship! (laughs) I’m laughing, but I’m actually serious! What is great about our startup is that we have experience in management consulting (two people in our team) and we really use these skills in the way we run our company and develop our employees, which we are very much focused on. At the same time, you can get the startup experience, where things change very quickly, we re-prioritize all the time, things are up and down, exciting, moving fast. And we’re translating science into practical advice and products on a daily basis.

 'YOU REALLY HAVE TO DO SOMETHING THAT YOU CARE ABOUT'

Other types of advice: you really have to do something that you care about, that you’re happy to wake up for in the morning. Figure out what it is that drives you. It’s not easy. It took me a while to figure out that for me it was sleep. But look back at your life and think about some of the key moments when you were really happy, inspired or content with what you were doing. Pinpoint moments when you really enjoyed or didn’t enjoy doing something, instead of trying to imagine what you would enjoy doing, because a lot of things aren’t really like what they seem to be. And focus on your own strengths. Ask people around you what you’re good at, what they think is special about you, so you can leverage those strengths. And reach out to people in different jobs, ask if you could meet them for a coffee or talk to them for a few minutes on the phone to ask some career questions. It can be incredibly helpful to get some inside information. I wish you all the best figuring it out!

by Mariana Cerdeira, PhD Student AG Harms

This article originally appeared December 2017 in CNS Volume 10, Issue 04, Sleep 

One Night in the Sleep Lab

It is five o’clock in the morning. The stars and moon have faded away in the slowly brightening dark blue sky. An early bird’s song is drifting in through the open window of the control room. A couple more hours and then it is Feiermorgen, as the Germans say. 

I store the saliva sample in the fridge and quickly hurry back to my test subject. God forbid he should fall asleep - that would really mess up my data! But the worst hours are just behind us now and even though my human guinea pig has not slept for over twenty hours, he is getting livelier again, able to finish a sentence without dozing off. I re-enter the room where the poor guy is chained to the bed in an environment of eternal twilight and total isolation. Apart from contact with me, that is, and without real chains, of course - only my stern reprimand when his eyelids drop. 

All in a Night's Work
Welcome to the sleep lab. Keep your eyes open at all times! This is the motto in this room. The patients down the hall are encouraged to sleep. Yet some of them are also wide awake judging by the squiggly lines on the monitors in the control room. They are here because they can’t sleep. My subject is here to stay awake and I am a PhD student who does research on the biological clock. This means that I know very well that doing too many of these night shifts increases my risk of ending up as a patient myself, always tired yet unable to get a good night’s sleep. 

KEEP YOUR EYES OPEN AT ALL TIMES!

The irony is not lost on me. But to truly understand something, especially things that are bad for you, there is no better teacher than personal experience, right? So I take another sample and count down the hours. Not aloud of course - the subject has long before lost track of time and thinks it is the early afternoon. If he were to learn that he has many more hours still to go, it might affect his motivation and thereby his performance on the cognitive tests, which are another part of the torture regiment I expose him to. And did I mention his scalp is plastered with electrodes and that he wears a rectal probe? But don’t feel bad for him, he is here voluntarily and gets paid, too. The things students are willing to do for money, right? The sun is coming up and the experiment is drawing to an end. Soon I can go to sleep myself.  

by Jan de Zeeuw, PhD Student AG Kunz
This article originally appeared December 2017 in CNS Volume 10, Issue 04, Sleep 

Case Study: A new study from Caltech suggests jellyfish may need sleep too.

Researchers at the California Institute of Technology have found evidence that at least one type of jellyfish engages in a very unexpected behavior: sleep. The study, published by Ph.D. candidate Ravi Nath and his fellow researchers in Current Biology [1] in September, showed that Cassiopea jellyfish passed several criteria established in their lab to demonstrate they were engaging in a behavior that could be considered sleep.

The finding comes as a surprise to the scientific community, as previously sleep was thought to be an activity performed only by more complex organisms with central nervous systems: humans, dogs, fish, even worms. Now, adding to the mystery of why organisms sleep, there is one without a brain that does it too.

SLEEP: A BASIC REQUIREMENT IN THE ANIMAL KINGDOM

To establish that the jellyfish were sleeping rather than engaging in other behavior, the researchers set up three criteria: a regular period of diminished activity, decreased responsiveness to stimuli during this period and an increased need for the hypothesized sleep behavior when it was not getting enough. The jellyfish passed all three.

Sleep - it's a NO-brainer!
Formal testing revealed that the jellyfish pulsed 30% less during this period of diminished activity and could be “awoken” with food or prodding, ruling out other possible states such as coma. The researchers tested responsiveness by removing the floors from under the jellyfish at random times; in the hypothesized sleeping phase, they would float around before swimming to their preferred place on the floor of the tank. A need for sleep was operationalized by shooting water through the tank every 20 minutes, keeping the jellyfish from attaining this restful state; during the wakeful period the following day, the jellyfish engaged in lower levels of activity than usual.

Image source: prilfish via Flickr

Cassiopea, the “upside-down jellyfish” have a non-centralized radially symmetric nerve net, a diffused organization of nerve cells throughout the body with no large centralized concentration (a brain) [1]. However, like organisms with central nervous systems, theirs functions using action potentials, synaptic transmission, neuropeptides and neurotransmitters. This commonality suggests maintenance of the nervous system at a very basic level may be a reason organisms need to sleep.
Cnidaria, the phylum of Cassiopea, branched early on from the evolutionary line of human beings. The researchers suggest that this signifies “sleep is rooted in basic requirements that are conserved across the animal kingdom.” [1] More research however, will need to be done to determine whether this behavior evolved in Cnidaria separately, or whether it is truly an early behavior in our evolutionary history.

By Alex Masurovsky, MSc Student Berlin School of Mind and Brain
This article originally appeared December 2017 in CNS Volume 10, Issue 04, Sleep 



[1] Nath et al., Curr Biol, 2017; 
[2] http://nyti.ms/2fE9JuC
[3] http://bit.ly/2hF7bgC

Sleep Deprivation: One-way ticket to a speedy death?

Calm down: If you could actually die of moderate sleep deprivation (SD), PhD students would be an endangered species. So you can put your fears to rest. Severe SD, however, is an entirely different matter…

We all know what a missing night of sleep (or two!) feels like: concentration problems, aching joints, short temper. All unpleasant but manageable. SD, both in acute and chronic forms is a common feature of modern life. But several individuals have taken it to the extreme: the longest scientifically-confirmed voluntary period without sleep was 264 hours (11 days), completed by Randy Gardner in 1977 [1]. Towards the end of the study, Mr. Gardner experienced dramatic memory loss, and experienced florid psychosis, on par with other less systematic reports of SD. Beyond this, there is not much that scientists know about the effects of extreme sleep loss in a controlled setting. However, we do know this: if you prevent an animal from sleeping long enough, it will die. The strange thing is, we don’t know why.

The Case of The Sleepless Rats
In the lab, there are several rather nasty experimental paradigms to prevent animals from getting either deep REM sleep, or sleep at all. For example, animals are placed on a small platform in a tank of water. Whenever they start showing signs of relaxing, sometimes visualized by EEG of EMG changes, they are gently handled by experimenters or simply allowed to fall into the water [2].
If you prevent a rat from having any sleep at all, they die within 2-3 weeks [2]. But what if you only block periods of deep, REM sleep? Well, they still die, but manage to hold out just over a month.
What happens to the animals during this time? Rats’ mental states are not so easily queried as humans’, so we can only judge their cognitive health based on (decreasing) performance on behavioral tests [3]. But after a short period, the animals start exhibiting a range of physical and physiological changes, too. Body temperature drops, as does the animals’ weight (despite increased appetite), and they start exhibiting skin lesions. Bacteria flood the intestine, and the immune system becomes overburdened. Then… they die [2,4]. There are several theories about why this happens, for example, that animals have irreversible hypothermia, or severe sepsis. However, rats that are kept warm or given antibiotics still succumb [4].

IF YOU PREVENT A RAT FROM SLEEPING, IT DIES WITHIN 2-3 WEEKS

It’s not entirely clear whether death in this experimental setting is most easily ascribed to severe stress from the environment, total immune failure, brain damage, or some combination of the three [4]. For example, pigeons and mice subjected to the same paradigm have much better physiological outcomes [5], though it seems that the animals in these studies were euthanized before they became as ill as the rats above. Nowadays, researchers seem to be more interested in the subtler effects of SD on things like metabolism and cancer resistance (which are worth a full article [or issue of the newsletter] in their own right) [4, 6].

Image source: Alyssa L. Miller via flickr

The Case of the Unlucky Insomniacs
There is one final type of death-by-SD worth considering, though it leaves open just about as many questions as it answers: Fatal Familial Insomnia (FFI) [7]. This is an exceedingly rare disorder which, yes, affects (and kills) humans. 26 families worldwide carry an autosomal dominant gene variant which causes the condition, while only 9 sporadic cases have ever been recorded [9]. This mutation causes changes on PrP, the gene responsible for prion protein and the devastating effects of Creutzfeld-Jakob (aka Mad Cow) disease (CJD). Patients begin exhibiting anxiety and behavioral changes around age 50, which quickly transitions to ever-decreasing periods of sleep and eventually total insomnia. Dementia follows, and patients usually die within a year from complications such as pneumonia [8,9].

YOU ARE EXTREMELY UNLIKELY TO DIE DIRECTLY BY SLEEP DEPRIVATION

Thus, patients with FFI don’t really die of SD per se, rather of generalized brain atrophy accompanied by approximately 6 months without sleep [8,9]. Much like CJD, this disease causes the brain to become riddled with mutant prions and causes atrophy in several areas, notably the frontal cortices and thalamus (the most likely candidate for sleep-related problems) [7,8]. Due to the extremely low number of cases worldwide, there is not a great deal more information, although a mouse model was produced in the late 2000s that recapitulates many features of the human condition [9].

Something to Keep You Up At Night
I’ve been writing for the newsletter for about 4 years now, covering more than a dozen topics. And this article was far and above one of the most grim to research. Real SD is truly the stuff of nightmares (and legally-sanctioned torture [4]). But I digress! The good news here is that most humans are extremely unlikely to die directly by SD. However, there are a host of dangers associated with SD. First and foremost, accidents caused by nodding off or being distracted while doing things like driving. There is also a growing body of evidence linking SD to metabolic problems like obesity and diabetes.
To put it bluntly, SD will catch up with you. It’s just a question of how quickly…

by Constance Holman, PhD Student AG Schmitz
This article originally appeared December 2017 in CNS Volume 10, Issue 04, Sleep 



[1] http://bit.ly/1GWPboW
[2] http://bit.ly/1ccEe6e
[3] Alhola and Pola-Kantola, Neuropsychiatr Dis Treat20017
[4] http://slate.me/1WTz4Oe
[5] Newman et al., Physiol Behav 2008
[6] Knutson et al., Sleep Med Rev 2007
[7] http://bit.ly/2z8wwHB
[8] Schenkein and Montagna, MedGenMed 2006
[9] http://bit.ly/2z73PL1

Eat Well and Sleep Soundly, in These Two Good Health Abounds

Can Food Intake Influence Our Sleeping Pattern? There are few facts in life that are rock solid: food and sleep are among them. Everyone has to sleep - and obviously everyone has to eat. However, do these two fundamental pillars of bodily existence influence each other and if yes, in what way?

The WHY and WHEN of sleep is well studied and is known as the two-process-model of sleep-wake regulation. Process S is defined as a homogenic sleep drive which is generated by sleep inducing substances in the brain (WHY). Process C is the circadian clock, which serves as an internal time keeping device. It controls the timing of most of the processes in our body and by regulating “alertness”, it can influence WHEN we get tired.
The master clock in our brain (suprachiasmatic nucleus – SCN) can convey time cues (e.g., light-dark cycle) to the peripheral clocks which are ticking in almost every cell of our body. These in turn are thought to regulate local tissue physiology [1]. Now, this is where it gets interesting, since various metabolites can feed back onto the peripheral clocks and onto the SCN [2].
For instance, if food resources are restricted to a certain time of day, animals can go from being nocturnal to diurnal or vice versa on a behavioral level. This is also mirrored on the molecular level in tissues such as the liver [3, 4].

CHRONIC SLEEP DISRUPTION CAN LEAD TO OBESITY

 
Knowing how a system works means we can also trick it. For example, after a trans-continental flight, almost everyone suffers from jet lag. One way to adapt quicker is to eat meals corresponding to the local time, therefore already resetting our organ clocks to local time.
Conversely, if sleep rhythms and therefore eating rhythms are chronically disrupted, such as in shift workers, this can lead to obesity and other metabolic diseases [5].
All in all, in the hectic pace of modern life, we often neglect our body clocks concerning sleeping and food intake, thereby seriously endangering our health. As the medical psychologist Till Roenneberg said: "Time really is of the essence".

[1] Dibner et al, Annu Rev Physiol, 2010
[2] Morris et al, Mol Cell Endocrinol, 2012
[3] Damiola, Genes Dev, 2000
[4] Mistlberger, Eur J Neurosci, 2009
[5] Bass andTakahashi, Science, 2010

by Veronika Lang, PhD Alumna AG Kramer
This article originally appeared 2014 in CNS Volume 7, Issue 3, Nature vs Nurture

Don’t Give Up On Your Dreams. Sleep On!

Sleep is an almost universal behavior throughout the animal kingdom. Humans spend roughly a third of their life sleeping, therefore we can call it a truly integral part of life. However, is sleep just a uniform state of unconsciousness opposite to being awake? 

Like most animals, humans' sleep and wakefulness are modeled by inner circadian rhythms and external cues, so-called zeitgebers (see also the article on chronotherapeutics on page 10), to a period of roughly 24 hours. In particular, sunlight is able to reset our inner clocks, thereby enabling us to adjust our daily rhythm, e.g. after intercontinental flights. Not sleep itself, but rather when we sleep is regulated by the suprachiasmic nucleus in the anterior hypothalamus, which functions like an internal clock and is affected by environmental inputs (again, especially sunlight, which reaches the hypothalamus via the retinohypothalamic tract) [1].

sleep well; source:  http://bit.ly/2yFBDBZ

Is sleep just a consequence of the brain being less active because it's tired? Although this explanation might appeal to many fellow PhD students, sleep is characterised by a complex pattern of brain activity! Key aspects of sleep are: little motor activity, little response to stimulation, typical postures (like lying down curled up) and the state being quite easily reversible (distinguishing sleep from coma, for example) [1]. These features can be monitored by conventional electrical recordings, including electromyography and electroencephalography (EEG). When people (and animals) fall asleep, EEG recordings show a drastic change in neuronal activity.

Sleep = Brain Activity?!
Broadly speaking, sleep comes in two flavors: REM (rapid eye movement) sleep and non-REM sleep, which consists of four stages of characteristic brain activity patterns. Wakefulness typically comprises approximately 20 Hz waves. When people fall asleep, this frequency falls to 10 Hz and entering sleep stage 1 is characterized by mixed frequency patterns, light muscle activity and slow rolling eye movements. Likewise, body temperature and metabolism slow down. The next stage (stage 2) is characterized by 12-14Hz activity sleep spindles and K complexes, biphasic high-voltage waves. The sleep stages 3 and 4 are also referred to as slow-wave sleep, as EEG recordings of these phases are dominated by delta waves of only 0.5-2Hz frequencies. In contrast to the characteristics of the four stages of non-REM sleep, brain activity in REM sleep resembles wakefulness, with some populations of neurons being even more active when you are in REM sleep than when you are awake. REM sleep is accompanied by an increase of body temperature and metabolic rate but an almost complete loss of muscle tone, except for the eyes which characteristically move rapidly [1].

Sleep phases; source: http://bit.ly/2zp9M61

Interestingly, it is easier to wake a person up during REM sleep than stage 3-4 of non-REM [2]. As brain activity during REM sleep pretty much resembles EEG patterns during wakefulness, it may not seem surprising that most dreaming occurs during these phases of a night’s sleep. Dreaming can also occur during non-REM sleep, although with a much lower incidence and slightly different characteristics [2].

Sleep is not a uniform State!
Each sleeper moves through REM and the 4 stages of non-REM sleep several times a night in cycles of 90-110 minutes. During a night’s sleep, the stages do not succeed eachother in a particular order and also change in length. For example, phases of REM sleep can take 1-60 minutes and may be accompanied by brief periods of waking [3]. The cycles through the different phases of sleep, the sleep “architecture”, differ between subjects, single nights, and also change with age. In early childhood, much more time sleeping is speny in deeper sleep stages 3 and 4 whereas in older age stage 2 sleep dominates [4]. (See also our article in "The Aging Brain")

How you sleep changes with age

But what's the point of such a complicated sleep architecture? As also discussed in the articles “Evolutionary basis of sleep” on page 5 and “Sleep and learning ” on page 6 of this issue, sleep serves important functions for the body and thus is necessary. However, being unresponsive to potential threats is a significant problem, which is in part circumvented by the fact that we alternate between periods of deeper and lighter sleep [3].
As you can see sleep is much more than just the most unproductive period between two days. It is quite complex and interesting and science still needs a lot of effort to unravel all its mysteries. Therefore, everyone should spend more time in personal field studies. For example, at home - sleeping.

Good Night!

[1] Kandel, Schwarz, Jessel. Principles of Neural Science, 2003
[2] Staunton, Naturwissenschaften, 2005
[3] Voss, Rev Neurosci. 2004
[4] Zepelin et al., J Gerontol, 1983


by Bettina Schmerl, PhD Student AG Shoichet
This article originally appeared Dedcember 2017 in CNS Volume 10, Issue 04, Sleep 

„Mum, how do dolphins sleep?“: Sleep throughout the animal kingdom

Have you ever wondered whether your dog sleeps like you – and yaps because he is probably dreaming about the mailman? Do all animals need sleep as much as we do? And how on Earth do they continue swimming or even flying during sleep?

Smart because of Mattresses?

First of all, we should define what we are talking about: Sleep can be characterized in many ways, but without electroencephalography with wild animals, we should focus on the behavioral definition: Sleep is when the animal exhibits a rapidly reversible state of immobility and reduced responsiveness to external stimuli. Furthermore, an increased drive for sleep (rebound effect) is expected after sleep deprivation [1].

Lets start with our closest relatives: Great apes exhibit monophasic sleep (like humans and unlike the majority of other mammals), meaning that they concentrate their sleep in one period per day. Theories claim the reason for this is that they are (like us) capable of building a comfortable and safe sleeping platform - allowing them to sleep more safely and therefore more deeply. Maybe our cognitive abilities just came from very comfy beds [2]?

Apes build comfy beds

 

But there are other intelligent animals that definitely have no mattress to sleep on. Many dolphins are able to rest one half of their brain while the other one controls breathing, for which marine mammals have to come to the surface. This phenomenon, which some of us would love to do during boring seminars, is called uni-hemispheric slow-waves (USW). It enables dolphins, whales and also many birds to rest one hemisphere at a time with the contralateral eye closed, changing to the other one after about two hours [1]. Brain waves similar to slow-wave sleep and REM sleep in humans have been recorded in flying frigate birds which migrate for several months at a time [3]. Remarkably, when in REM sleep, these birds as well as some other mammals like the sperm whale also show bi-hemispheric sleep. However, this behaviour can only be found on the ground – or in the case of sperm whales while floating vertically in the ocean, holding their breath for a long time [4]. A strategy like this would never work in many sharks, since they need constant flow through their gills to be able to breathe. Some seem to solve this problem by doing “yo-yo diving“: First they swim to the surface to then glide downwards, giving themselves a short period of rest [5].

Different Animals sleep differently

The sleeping behaviour of terrestrial animals can also be very different from ours: Does anyone sleep while standing - No?! Horses and other bigger herbivores often do, with help of their stay apparatus, which consists of ligaments and tendons that lock into place. Still, many of them need to lie down for REM sleep as it comes with strong muscle atonia. Due to this, horses, giraffes and also elephants actually end up having much less sleep than we are used to, getting away with just 2-4 hours per day [6]. Many short naps seem to be more beneficial for these animals, since it enables them to spend more time alert when predators are around.

Who wouldn’t like to be capable of skipping 5-6 hours sleep per day in order to prepare the next lab meeting? New-born orcas outperform us a lot when it comes to little sleep: They stay awake for one full month after birth, and only rest while pressing their body against their mother. Compared to this, big brown bats and hairy armadillos lead a pretty relaxed life, sleeping for roughly 20 hours per day [6]. 

Image Source: http://bit.ly/2B1GiM7

So far we were mostly talking about sleep similar to human non-REM. But do animals also dream? Of course, no one can ask a cat whether it was recently dreaming of mice. Anyway, many mammals, birds and even reptiles show physiological patterns with consistent with REM sleep. Dragonflies have 350 REM cycles per day, each of them lasting 80s [7] and the platypus spends approximately 5.8-8 h/day in REM [8]. REM sleep is sometimes seen as a key feature during evolution of the amniote – the common ancestor of mammals, birds and reptiles that lived more than 300 million years ago [7]. However, octopus also seem to have REM like sleep patterns that go along with changing colours and twitching of their arms [9].

Yet, the animal kingdom consists of more than vertebrates. What about insects, nematodes and porifera (sponges)? While for porifera there is no evidence of sleeping behavior, the fruitfly D. melanogaster has not only been shown to have sleep-like resting patterns but also exhibit cognitive impairment upon sleep depriviation [1]. A fatigue period (lethargus) before moulting in C. elegans suggests that sleep is somehow connected to development and related to neuronal changes [10].

What's the Purpose behind Sleep...?

Of course most sleep studies focused on very few animals from each taxa so far. For instance, just 50 out of 60000 vertebrate species have been tested for all sleep criteria so far and not all of them were found to meet all of the criteria. Nevertheless sleep-like behavior seems to be present in various animals. Can we assume that all these animals sleep for the same reason - and if so what is the reason?

Over years, several theories on the function of sleep have been developed. The original idea that sleep is mainly necessary to conserve energy seems quite unlikely nowadays since it decreases metabolism by very little amounts (5-10%), whereas hibernation saves a lot more energy [11]. Another very prominent idea is that sleep is important for learning and memory consolidation (see article of page 6). Even though there is evidence for a role of sleep in memory, it is still disputed what this role exactly is – ranging from memory deletion during REM sleep to maturation of memory circuits [12]. Recently, sleep has been linked with a restorative function in the central nervous system, leading to a clearance of free radicals and other metabolic waste that accumulates during wakefulness [13]. While many of these processes definitely occur during sleep, they don’t explain the great variation in sleep needs and patterns throughout the animal kingdom. 

Do all animals sleep for the same reason?

Trying to address this, some researchers now regard sleep as a state of adaptive inactivity, optimizing the timing of behavior according to prey/food availability and threats in the environment. In this scenario, continuous wakefulness implies the greatest energy demands but maximizes niche exploitation. This can explain why giraffes sleep so little (they have a very low-caloric diet and a high threat of predators). For bats that feed specifically on insects being active between dusk and initial hours of darkness, on the other hand, a longer period of time awake would be highly maladaptive since it increases their risk of becoming prey [14].

... we don't fully know (yet)!

Exploring sleeping behavior of other animals can, therefore, help to clarify its function in humans. While sleep deprivation in humans and rodents so far suggests that sleep influences cognition, emotion, immunity and memory, the function of sleep can still be substantially different when looking at all animals that exhibit sleep-like resting behavior. We should all be aware that, as put by Michel Jouvet, a famous sleep researcher who just passed away, "it’s not enough to use the brain of your experimental animal, it’s also necessary to use your own”. 

Annika Reinhold, MSc Student MedNeuro

References:

[1] Siegel, 2008, Trends in Neurosciences

[2] Shumaker et al., 2014, American Journal of Physical Anthropology

[3] Rattenborg et al., 2016, Nature Communications

[4] Miller et al., 2008, Current Biology

[5] http://bit.ly/2jd1XfV 

[6] http://bit.ly/2zsCd59 

[7] Shein-Idelson et al., 2016, Science

[8] Siegel et al., 1999, Neuroscience

[9] http://bit.ly/2jmPMc6 

[10] Sing et al., 2013, Sleep

[11] Assefa et al., 2015, AIMS Neuroscience

[12] Diekelmann & Born, 2010, Nature Reviews Neuroscience

[13] Xie et al., 2013, Science

[14] Siegel, 2009, Nature Reviews Neuroscience

Billboard:

New Issue Out Now! SLEEP

“I have too much to do. I can sleep when I’m dead.” Sounds familiar? Why do we even bother spending a third of our lives unconscious? In this issue of the Snoozeletter (sorry for the pun), we drift off to dreamland to explore one of the most mysterious neurological phenomena of all time.

access the full magazine

Have you ever wondered whether your pets dream (about you, hopefully) (pages 4-5)? Or whether skipping a few hours of shuteye is a good idea? Spoiler alert: it’s not! You need it to remember (page 6), to develop (page 11), and work on your fine motor skills (page 13). And with enough sleep deprivation, you will also learn how things go downhill really fast (pages 9 and 14). Think that your sleeping patterns probably don’t match a 9 to 5 schedule? Check out our article on social jetlag (page 7). We cover this year’s Nobel laureates’ work (page 6) and how it could affect treatment of medical illnesses (page 10). So perhaps you shouldn’t feel so guilty for having that session of Napflix & Chill.

Sounds interesting? Well, we also talked to researchers working in a sleep lab (13), as sleep consultants (14), and even studying lucid dreaming (8). From the busiest human to the humble jellyfi sh (page 5), we all need our shuteye. Or perhaps you are dreaming a new collaborative research project? Hear about this year’s exciting DESIRE conference from our correspondent Aliénor Ragot (14).

So put on your pyjamas, crawl into bed with a glass of Glühwein, and get into December hibernation-mode with some great writing from the Berlin neuroscience community. Happy reading, and enjoy the winter holidays!

Constance Holman & Helge Hasselmann

Co-editors-in-chief

Einstein PhD Fellowships

The Einstein Center for Neurosciences Berlin (ECN) calls for applications for its PhD program starting in Fall 2018. 

The ECN member institutions promote cutting-edge neuroscientific research across a wide range of different disciplines and approaches. The ECN provides an umbrella structure that specifically fosters interdisciplinary and collaborative research by facilitating cooperation between institutions and by promoting interaction on all levels. 

With around 100 internationally recognized research groups, the ECN offers outstanding interdisciplinary training and research opportunities for national and international scientists, with research spanning from synapse to behavior, molecule to disease, and brain to mind.

Closing date for applications is January 14th, 2018.

Final interviews will take place in March 2018.

www.ecn-berlin.de/education/phd-fellowships.html

www.ecn-berlin.de/education/phd-fellowships.html

Call for Master’s Applications

The Medical Neurosciences Program invites bright and interested students to apply for our program. 

Ideally,candidates should already have some laboratory work experience, e.g. having worked in a lab for a Bachelor’s project, or other types of work experience such as a residency as a medical doctor.

The program’s rigorous and comprehensively structured education in basic neuroscience provides and trains students to approach questions concerning the central and peripheral nervous system. In addition to the in-depth theoretical training, our program emphasizes state-of-the art practical lab experience, preparing graduates for continued research as PhD students. 

Closing date for applications is January 15th, 2018

https://www.medical-neurosciences.de/en/admission/

Nobel Prize 2017: What Makes Our Cells Tick?

Since Wednesday the Nobel Week in Stockholm is taking place. During one week the Laureates give press conferences and hold their Nobel Lectures. The week culminated in the Nobel Prize Award Ceremony and Banquet yesterday night, December 10. (see the full programme here)

source

In October this year, the Nobel Prize of physiology or medicine was awarded to the three chronobiologists Jeffrey Hall, Michael Rosbash and Michael Young. They received the prize for their discovery of the molecular machinery that controls the biological clock.

1 million euros for telling time

In 1984, Jeffrey Hall and Michael Rosbash in Boston, simultaneously with Michael Young in New York, discovered that they could disrupt the biological clock in fruit flies by mutating a gene. This gene, called period, encodes the protein PER, which happens in a 24-hour (circadian) rhythm. During the night, PER accumulates in cells and during the day it is degraded. They hypothesized that PER could control its own concentrations via an inhibitory feedback loop. However, PER was unable to enter the nucleus... How could it influence its own production? A few years later, Michael Young was able to answer this question. In 1994, he discovered another gene called timeless and its protein TIM which, when coupled with PER, enables both of them to cross the nuclear membrane. Now the only remaining question was how PER achieved its 24-hour rhythm. Michael Young also answered this question with the discovery of a third gene called doubletime. Doubletime encodes the protein DBT that can slow down the accumulation of PER and thus produces circadian oscillations.

Wide Implications
These mechanisms were later shown to be similar in humans. Yet, the importance of the biological clock is still underestimated today, not only by the general public, but also in medicine. From hormone concentrations, functioning of the immune system, to even behavior, the biological clock regulates a vast variety of physiological and psychological functions. Sleep is just one of the things under strong influence of the biological clock. In spite of the importance of sleep, millions of people work nightshifts, thereby desynchronizing their biological clock and jeopardizing their health. This year’s Nobel Prize might provide a leg up for the chronobiologists in their efforts to show the general public how important our internal clock is. It is a win, not only for the three scientists, but for the entire research field.

Zehring, W.A., Wheeler, D.A., Reddy, P., Konopka, R.J., Kyriacou, C.P., Rosbash, M., and Hall, J.C. (1984). P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster. Cell 39, 369–376.

Bargiello, T.A., Jackson, F.R., and Young, M.W. (1984). Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752–754.


by Jan de Zeeuw, PhD Student AG Kunz

Is it True that People Born in Summer Need Less Sleep than People Born in Winter?

Why do some people seem to need less sleep than others? Why is it so easy for some people to get up in the morning and for others it's easier to stay up late at night?

As far as we know, there is no data on the association between sleep patterns and birth dates. I even asked an expert on the topic: Prof. Dr. Till Rönneberg from LMU Munich. However, he told me that this has not been investigated in depth. What has been thoroughly investigated though is why some people are early birds and some are night owls. This has to do with our inner clock that has evolved to help us anticipate the daily changes in our environment, such as light-dark cycles or temperature cycles. Almost everyone’s inner clock is happily ticking away with an approximately 24-hour period (that is why it is termed “circadian clock”- circa dias - almost a day). However, the ticking speed varies. Imagine you have a fast inner clock. This means that you would be too early for everything: you wake up early, eat early and get tired early; you would be an early bird, or as the scientific community terms it - an early chronotype. The opposite is also true; late chronotypes have a slow inner clock, so they are “late” for everything.
The interesting thing is that our chronotype varies throughout our life; we all start off as very early chronotypes, our clocks become gradually slower until puberty and then getting earlier again during the rest of our lives. Not only is our chronotype age-dependent, but also sex-dependent.
These differences in individual chronotypes are definitely something which we have to keep in mind when discussing school hours or office hours. These are often much too early especially for school children in the midst of puberty.
Last but not least, I want to mention an important feature of our inner clock, and that is that it is able to synchronize to our environment through light. This means that it can entrain the 24-hour day-night cycle provided it receives enough light input. To cut it short, the more light we get, the easier it is for night owls to get up in the morning and the longer early birds can stay up at night.

Reference

Rönneberg and Merrow, Cold Spring Harb Symp Quant Biol, 2007

by Veronika Lang
this article originally appeared 2013 in CNS Volume 6, Issue 4, Integrative Medicine

Do you also sometimes wonder about the simple neuroscientific questions in everyday life, but don’t really feel like looking them up right away? For questions like this, just mail us your question (cns-newsletter@charite.de) and Dr. Harebrained will give us his explanation in the next issue!

Little Einsteins-In-The-Making: Brain Development in Newborns

The fertility rate in Germany has risen to a 33-year high after years of decline in the rate of births. How will life be for this new generation? How will they percieve the world ? Time to have a look at a newborn's brain!

The emergence of new life, the creation of a little human being, is one of the most fascinating events in this world. Of all organs, the development of the brain is one of the first to start and one of the last to end (although it never really ends). The first structure, the neural tube, forms within the first weeks after conception. The first movements of the fetus can be detected by ultrasound after only 7 weeks and are probably because the first neurons and synapses have already developed in the spinal cord. Although a very basic functional brain is present at birth, many aspects of brain development are nowhere near complete yet.

The Birth of Consciousness
Future parents often wonder how much of the outside world their fetus experiences consciously. For example, is it beneficial to play piano music or speak to the little one in the uterus? Although fetuses can open their eyes after some months, they are mainly asleep and can hardly be woken up. Consciousness is defined as awareness of the body, the self and the outside, and is linked to the condition of being awake. Consequently, the process of birth initiates the development of consciousness by waking the fetus. When a newborn is touched by another person, it reacts differently compared to when it touches itself, indicating it has awareness of its own body.

Sleeping newborn infant with an EEG net.
Fifer, William P., et al. "Newborn infants learn during sleep."  
Proceedings of the National Academy of Sciences 107.22 (2010)

Furthermore, the awareness of smell allows the newborn to pursue the mother's milk. In addition, the ability to discriminate between the mother's voice and that of a stranger develops early on. The effort to reach the mother's breast right after birth also indicates purposeful behavior. Together with other signs such as the sense of pain, language, and short-term memory, newborns fulfil the criteria of basic consciousness and are perfectly equipped to explore the new world [1].

Explosion of Synapses and Glial Cells
Interestingly, the brain of an infant at birth already contains almost the same number of neurons as an adult brain. Now they only have to form their various connections to form mature neuronal circuits. Therefore, an extremely high number of synapses is built during the first months in a process called synaptogenesis, which requires the selection and elimination of synapses. This process, known as pruning, is highly delicate and, therefore, it is not surprising that early life stress can result in the development of behavioral dysfunctions and mental disorders in adulthood [2].

A NEWBORN'S BRAIN 

DEPENDS ON OUTSIDE STIMULI

 

In the past, it was believed that the selection is mainly dependent on the activity of neuronal connections, while the help of glial cells is only required for removing synapses by phagocytosis. However, more recent evidence supports the important role of glial cells in all stages of pruning. A stepwise removal of low-activity synaptic contacts is achieved by a fine-tuned interplay between neurons, astrocytes, microglia and oligodendrocytes that communicate with each other by secreting molecules [3]. For example, during postnatal development, neurons express the chemokine Cc3cl1 (fractalkine) whose receptor is expressed by microglia. As reported first by Paoliceli et al., the lack of this chemokine leads to fewer microglia and delayed synaptic pruning [4].

Sleep, Baby, Sleep…
When one considers the numerous events taking place in the newborn brain – and I've only mentioned a few here – it is not surprising that sleep is absolutely essential for flawless neuronal development. All this learning and processing of environmental stimuli, with their accompanying reorganization of nascent neuronal circuits sounds extremely exhausting for such a fragile organism. Intuitively, one would thus think that the phase of sleep linked to physical rest would be most important for newborns. But quite the contrary. It's actually active sleep, also referred to as rapid eye movement (REM) sleep, which seems crucial for postnatal brain development. Newborns spend about 50% of their sleep in REM (compared to 20% in adults). Indeed, it has been shown that twitching during REM sleep leads to increased activity of Purkinje cells in the cerebellum of rat neonates, indicating that active sleep is important for sensorimotor development [5].

Impact on Our Future Minds
Since the development of a newborn's brain is highly dependent on environmental stimuli, these bewitching creatures should be protected from any harmful influences – beginning already at pregnancy. Everything we experience in our first years after birth will somehow shape our mind for the rest of our lives. This thought is amazing and terrifying at the same time because at that stage these poor little creatures are dependent on how responsible the outside world is …

[1] Langercrantz and Changeaux, Semin Perinatol, 2010
[2] Bock et al., Front Neurosc, 2014
[3] Terni et al., Brain Res Bull, 2016
[4] Paoliceli et al., Science, 2011
[5] Sokoloff et al., Dev Neurobiol, 2014

by Eileen Schormann, PhD Student, AG Krüger

This article was voted "best contribution of the December 2016 issue"