Journal of Negative Results in BioMedicine

The Journal of Negative Results in BioMedicine is an open access journal publishing negative data sets, that encourage discussions on ambiguous, unanticipated or provocative results with regard to currently accepted concepts. 
Thereby, the journal wants to challenge present scientific models and dogmas. In particular, the publication of work demonstrating that standard methods and techniques are sometimes inapplicable to some studies is of a great advantage to other researchers in their respective fields. Also, scientists and physicians are invited to publish clinical trials that do not show a higher efficacy in therapy than current treatments. This can eventually lead to the improvement of experimental design and treatment strategies.
As traditional journals infrequently publish negative studies, valuable information often becomes inaccessible to other researchers to evaluate and analyze. In particular, negative or controversial results contradicting prevalent theories aren't easily published - although they might be innovative.
Of course, not all null results and controversial data would necessarily be groundbreaking. In short, the journal believes that the publication of such results is an important influence on the scientific community to consider and improvise upon in their own research.

Check this out: http://www.jnrbm.com/

by Nicole Hentschel
This article originally appeared on June 1, 2011 in  Volume 4 - Issue 2, "Good Scientific Practice"

The Journal of Unsolved Questions (JUnQ)

PhD students from the Graduate school of Material Science (MAINZ) launched a scientific journal to publish negative results.
In the journal of Unsolved Questions (JUnQ), scientific projects gain interest that would never be published in traditional scientific journals: those with negative or inconclusive results. As most of the research projects fail to show positive results with clear conclusions, many results are not published. Accordingly, a lot of information is not available to the scientific community and gets lost.
This Journal provides a platform to exchange data on projects which did not work and are unfinished. Thereby, JUnQ wants to establish the publication of negative results as an important milestone for scientific communication especially among different disciplines to overcome biases and fraud. In addition to these articles, JUnQ also publishes short essays about open scientific questions which have not been solved yet but are important to the science community. According to good scientific practice, the articles are peer-reviewed by independent referees of the respective scientific field. Furthermore, the essays about open questions will be broadly reviewed in order to only publish scientific questions that do not contain false facts.

PUBLICATION OF NEGATIVE DATA AS AN IMPORTANT MILESTONE

Beyond that, JunQ wants to reflect about the day-to-day business in science from a meta-perspective. This will be achieved through different formats. Thus, this summer semester, JUnQ organized a lecture series with the topic "Publish or Perish...?" which discusses the influence of prevalent publication practices in natural sciences.
The first issue of JUnQ was published on January,1^st, 2011 and contained two articles and 4 open questions. To get a copy and more information about JUnQ, go to http://junq.info. Articles and Open Questions can be submitted to JUnQ@uni-mainz.de.

by Nicole Hentschel
This article originally appeared on June 1, 2011 in  Volume 4 - Issue 2, "Good Scientific Practice"

Of the Importance to Publish Negative Results

I had a rough time during my PhD with many experiments that did not support a common hypothesis in my field of research. However, I was able to successfully submit a manuscript describing my negative data. Recently I even won a prize for publishing them.

When scientists embark on a new study, they formulate a hypothesis that they want to test. Sometimes the experiments do not support the hypothesis the researchers set out to test. If the obtained data are unable to confirm a hypothesis or replicate previous results, they are called negative results. Sometimes they are also called NULL results, as the Null hypothesis H₀ (the hypothesis that there will be no difference between experimental and control group) was not rejected. Most of the time, negative results are more accurate and give more informative than results that support a new hypothesis. 

If a test of experimental data comes up significant with p < 0.05, we reject H₀ and accept H₁ (the hypothesis that the results show an effect). Notably, we only tested H₀ and the p-value says nothing about the probability of H₁ being true. However, a non-significant p-value means that H₀ is true (or the data didn’t have enough power to reject it). In a Bayesian sense, data underlying a non-significant p-value can be strong evidence for the H₀. 

Negative data are obviously not very spectacular, because we want to find out what is true, not what isn’t. Positive results seem more interesting and more important than NULL results. The latter are often not submitted for publication, because they are believed to generate less value to scientists and academic publishers. Indeed, they are less likely to open new avenues of research that generate funding opportunities. Manuscripts reporting negative data are also more likely to get rejected, because they appear less exciting. Traditionally it is difficult to publish negative data, unless they refute a spectacular claim. Studies that do not confirm a new hypothesis often get literally filed away in a drawer. Therefore this is also called the “file drawer phenomenon”.

PUBLISH ALL RESULTS TO FIGHT THE PUBLICATION BIAS! 

Unfortunately, the negative data get lost to the scientific community. If ever another group of researchers has a similar hypothesis, they are likely to tap into the same dead end. The fact that such negative data are rarely published, leads other scientists to waste time and effort by unnecessarily repeating experiments. It is estimated [1] that this costs the US economy alone, $28bn each year, similar in scale to the total $35bn National Institute of Health annual budget [2]. Moreover, the bias towards positive results can lead to an overestimation of biological phenomena or efficacy of drugs. It is devastating and frustrating, if the biased representation of preclinical work compromises the outcome of drug trials. Thus, publishing more negative results will have a positive impact on the development of new drugs and healthcare solutions. 

by Maklay 62 via pixabay

Another current problem is reproducibility. Even though it is fundamental to scientific progress, replication of studies carries little prestige in academic research. Especially in neuroscience, reproducibility has come under particular focus due to some spectacular cases, where data could not be reproduced [3]. Recently, systematic studies demonstrated that current biomedicine has a serious replication problem. It is shocking that more than half of the published biomedical data could not be reproduced [1]. This led to the declaration of a reproducibility crisis. It is necessary to value the effort to reproduce and publish studies regardless of their outcome.

 SCIENCE IS MOST EFFECTIVE WHEN BOTH POSITIVE AND NEGATIVE RESULTS ARE PUBLISHED

Fortunately, many journals now publish reproduction studies and negative data; for example PeerJ, PlosONE, J Neg Res Biomed, Scientific reports and others. Furthermore the necessity to reproduce experiments and publish negative results gets now also recognized by funding agencies that award publications that do not confirm the expected outcome or original hypothesis. The prizes aim to emphasize the value in publishing all the results, as science is most effective when both positive and negative results are published. Another way to fight publication bias and focus on the scientific process and soundness are “Registered Reports”. For this type of journal article, methods and proposed analyses are pre-registered prior to research being conducted. Thereby the results are accepted for publication before data collection commences and without regard to their positive or negative outcome.  
These efforts show, that the recognition to publish negative results and replication studies is growing. Hopefully this will contribute to the soundness of science and retrieve research from the reproducibility crisis.

QUEST is giving away 15 awards of € 1,000  to first/last/corresponding authors (BIH, MDC or Charité affiliation) of preclinical or clinical research papers in which the main result is a NULL or ‘negative’ or in which the replication of own results or the results of others is attempted. Futher information can be found here.

The ECNP’s Preclinical Data Forum created the “ECNP Preclinical Network Data Prize”, a prize for published “negative” scientific results, of €10,000. Aimed initially at neuroscience research, it encourages publication of data where the results do not confirm the expected outcome or original hypothesis. The ECNP’s Preclinical Data Forum is a mixed industry and academic group which aims to improve the replicability and reliability of scientific data, especially in drug development. Futher information can be found here.

by Claudia Willmes, PhD Alumna AG Eickholt / AG Schmitz  

[1] sciencemag, 2015 http://bit.ly/2E5ho01
[2  sciencemag, 2017 http://bit.ly/2uWuFTt
[3] nature news, 2014 http://go.nature.com/2rAME4b

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

Age and Aging Societies

It is common knowledge that Western societies are facing demographic change. But why is it a problem everyone is concerned about?

Germany's Demographics 
Demography is the social science dealing with statistical measures of populations, including humans. It analyzes several features of populations (including age, health, reproduction as well as migration, education and religion) in order to extrapolate future development. In Germany, the Federal Statistical Office which monitors demographics, estimated the number of inhabitants in 2014 to be more than 80 million people (the 16^th most populous country in the world). The estimated average life expectancy is 81 years and the fertility rate is 1.4 children per woman [1] (in contrast to Somalia where life expectancy is less than 50 years and the fertility rate is 6.4 [2]).

Paying it Backward? 
These numbers summarize what the demographic change looks like: higher life expectancy with fewer births. People live longer due to better hygiene and medical care. In addition, the more young people are educated and socio-economically situated, the fewer children they have. This is called the demographic-economic paradox [3]. Especially in Germany, the demographic change is critical as the social and health insurance systems are based on an idea called the intergenerational contract (Generationenvertrag). This system, implemented after the Second World War, required jobholders to pay taxes into a pay-as-you-go system to provide financial security for a limited number of elderly retirees [4].
Back then, considering the shape of Germany's population pyramid, the system made sense. People born in these years (1945 -1965) are today commonly referred to as baby boomers [5], which justifies this concept. However, birth rates dropped steadily by 1967, plateauing since 1990 to their current levels. But, low birth rates do not keep people from aging, they only lead to fewer people taking care of an increasing number of older people. Thus, aging of the population is a socio-economic problem, which has to be addressed by significant changes in the financing of social pension programs.

Bevoelkerungsentwicklung DeutschlandAdapted from Wikipedia bit.ly/1PMBcCr

Healthcare and Aging Populations 
Retirees are getting older: With improved medical care, the life expectancy at birth rose from an average 50 years in 1900 to an average 78 years in 2008, with women living several years longer than men [6]. Unfortunately, most people do not remain healthy in old age, but develop several age-related comorbidities.
This adds to the socio-economic costs of an aging society, as healthcare burdens increase, with rising costs and a lack of staff. To make things worse, the diseases of the elderly will be accompanied not only by an increase in the number of cases, but also an increase in complexity. Although personalized therapy is a promising solution for many diseases, it requires more extensive diagnostics – this eventually leads to imbalances in the ratio of workload to qualified personnel in the medical sector [7].
In addition, the changes in household structure also play a major role in the outbreak and spreading of infections. In the olden days, families were large and infections spread easily, whereas now families are much smaller. Today, however, those opposed to vaccination ("anti-vaxxers") make society susceptible to explosive outbreaks of numerous diseases [8]. 

Bevölkerungspyramide
data source: Statistisches Bundesamt

Familial Trends 
Demographic change does not solely affect societies: it also affects the family by changing its composition. In the 19^th century, only a minor proportion of young adults got to know their grandparents. Today, about 80% of people have at least one living grandparent. This causes an increasing demand to nurse the elderly generation, which threatens individuals’ financial, psychological and physical abilities [6]. Thanks to improvements in gender equality and the education of women, the mean age at first childbirth has increased from 21 years in the 1970s to 25 years today. Together, these factors cause a “crunch” situation for people in their 50s and 60s where raising their children and caring for their own parents compete [6]. 
Demographic change also affects how family members interact and take care of each other: As families become smaller, parents distribute their money and time more equally among their offspring and grandchildren [6].
Demographic change may appear to be a problem of Western countries, but it is definitely a global one. Ten years ago, the WHO reported a global mean age of 27.6 years, with 10% of the population being older than 60 years. By 2050, the United Nations expects the mean age to be 38 years with 22% of people being older than 60. Further, the proportion of children is predicted to decrease from 30% to less than 20% [9]. The socio-economic impact of these changes cannot be ignored.

[1] bit.ly/1ScMbK1 
[2] http://bit.ly/1PSObsc 
[3] bit.ly/1PMdwy2 
[4] http://bit.ly/1KUTobt 
[5] http://bit.ly/1JVUjxq 
[6] Seltzer and Bianchi, Annu Rev Sociol, 2013 
[7] Warth et al., Virchows Arch, 2015
[8] Geard et al., Epidemics, 2015 
[9] http://bit.ly/1Is6Qaq 

by Bettina Schmerl, PhD student AG Shoichet
This article originally appeared 2016 in CNS Volume 9, Issue 1, The Aging Brain

How Old Are We Really?

Comedian Chris Rock once said, “If a woman tells you she's twenty and looks sixteen, she's twelve. If she tells you she's twenty-six and looks twenty-six, she's probably near forty.” 

Funnily, there is some truth in his words. Researchers published a study in July 2015 whose results can basically be summed up as – if you think you look older and you feel older than you are, it is because you probably are older [1]. So what does this actually mean?

 

source: http://bit.ly/1P5YWBG

Researchers followed approximately 1000 individuals from birth up until the age of 38. Eighteen different biological markers such as cholesterol levels, gum health, DNA and body mass index, among others, were monitored over a period of 12 years (from age 26 to 38). The aim was to see the rate of change in these parameters in different people. The results showed that their sample of adults with a 'chronological age' of 38 had 'biological ages' varying from 28 to 61!

UP TO 20 YEARS DISCREPANCY BETWEEN ‘BIOLOGICAL’ AND ‘CHRONOLOGICAL’ AGE

 
In other words, a 38-year-old sometimes had the cholesterol profile and cardiovascular tissue structure of a 61-year-old. The scientists also calculated the ‘pace of aging’, i.e. how much organs changed in one chronological year. While some people showed zero years of biological change per chronological year, others showed three years of biological change in the same time. So people with an older biological age had a more rapid pace of aging. This higher biological age was also associated with feeling less healthy and looking older at age 38 [2].

Unfortunately we do not know yet whether drug treatment or lifestyle changes can impact biological aging, but we certainly now know why some 80-year-old people can still go skiing!

[1] Belsky et al., Proc Nat Acad Sci, 2015
[2] http://1.usa.gov/1UApYET

by Apoorva Rajiv Madipakkam, PhD Alumna AG Sterzer
This article originally appeared 2016 in CNS Volume 9, Issue 1, The Aging Brain

Messing up With Mendel - Genetic Imprinting and Its Effect on Your Life

It was on a summer’s day in the year 1822 when Johann Mendel saw the light of day. He inherited 50% of his genes from his father Anton and 50% from his mother Rosina. But contrary to his postulated rules, the expression of some genes was altered in a parent-of-origin specific manner: Depending on whether the origin of a gene copy is maternal or parental, the gene is active or non-active. This phenomenon is called “genetic imprinting” or “genomic imprinting” [1].

Methylation Is Key to Genetic Imprinting
Helen Course described a “parent-of-origin effect” for the first time in 1960. Experiments with mice in 1980 revealed the first proof of parent-dependent inheritance of some genes. They used nuclear transplantation in mouse embryos with either maternal or parental chromosomes. The embryos could not develop normally, despite a diploid genome [2].
Since this discovery, researchers have tried to answer questions on how imprinting is facilitated, what the evolutionary advantages are, and which diseases are correlated with imprinting. In principle, imprinting is an epigenetic process that leads to monoallelic expression without altering the DNA sequence – a process known as methylation that leads to inactivation of gene expression (see also "Lamarck's Last Laugh" ). In contrast to mutation, imprinting is reversible. During gametogenesis, the imprinting status in germ cells is erased and re-programmed according to the sex of the individual [3].

Mendel’s studies with pea plants established many rules of heredity, known as
"rules or principles of Mendelian inheritance":
1. Segregation: In diploid organisms, chromosome pairs are separated into individual gametes to transmit genetic information to offspring.
2. Independent Assortment: Alleles on different chromosomes are distributed randomly to individual gametes.
3. Dominance: A dominant allele completely masks the effects of a recessive allele. A dominant allele produces the same phenotype in heterozygotes and in homozygotes.

A Parental Tug-of-War
As genetic imprinting diminishes the advantages of a diploid genome, it is unclear why genetic imprinting occurs. The most favored hypothesis is the “parental conflict theory”. It states that genomic imprinting reflects the differing strategies of parents regarding the proliferation of their genes [4].
A classic example is the regulation of fetal growth in mice by imprinting of the insulin-like growth factor 2 gene (Igf2) and the receptor gene Igf2r. Igf2 is a paternally expressed growth factor that enhances fetal and placental growth when it binds to the receptor Igfr1. Therefore, paternal strategy lies in extracting more resources to improve the fitness of their offspring [2].
The maternally expressed receptor Igf2r also binds Igf2 which leads to degradation of the paternally expressed protein. This antagonistic mechanism counterbalances the paternal effect and ensures an equal distribution of nutrients among the offspring [2]. Loss of genetic imprinting in Igf2- or Igf2r-locus in mice leads to either fetal overgrowth (e.g., biallelic expression of Igf2) or reduced fetal growth.

The Shady Side of Genetic Imprinting
In humans, less than 1% of the human genome is modified by parental imprinting [4]. The majority of these genes are related to growth and neuronal development of the embryo [4]. By affecting neurodevelopmental processes, genetic imprinting influences brain function and behavior. This leads to severe dysfunctions if the non-imprinted gene copy is malfunctional.

ACTIVATION OF IMPRINTED GENES IS ORIGIN-DEPENDENT

 
The ubiquitin-protein ligase E3A (UBE3A), for example, is only imprinted in brain tissue where the paternal copy is silenced. This enzyme is a key player in ubiquitin-mediated protein degradation. Children with a malfunctional maternal copy suffer from Angelman’s syndrome, characterized by developmental delay, epilepsy, movement disorders, and a perpetually smiling facial expression.
Other genes located near the UBE3A locus, like the genes SNRPN and NDN, are maternally imprinted. A malfunctional paternal copy leads to Prader-Willi syndrome, characterized by intellectual delay, hypogonadism, and hypotonia [4]. The risk of some neuropsychiatric disorders such as autism spectrum disorders, schizophrenia, Tourette syndrome, and bipolar disorders has also been related to genetic imprinting [4].
It seems that genetic imprinting can influence many aspects of our lives. Further investigation will bring us a better understanding of development, pathologies, and genetic fitness. And though it contradicts with Mendel’s postulated rules, he would probably be fascinated by the strange paths evolution may take.

[1] http://www.genetics.edu.au
[2] Reik and Walter, Nat Rev Genet, 2001
[3] Philips, Lobo, Nature Edu, 2008
[4] Wilkinson et al, Nat Rev Neurosci, 2007

by Betty Jurek, PhD student AG Prüß
This article originally appeared 2014 in CNS Volume 7, Issue 3, Nature vs Nurture

Our Moods, Our Foods

Have you ever wondered why you sometimes have good days and bad days, or are in good or bad mood? Can there be a connection between the food you eat and how you feel afterwards?

You don’t need a study to tell you the obvious: we see a lot of people all around us who just aren't feeling the love. Such people could be our coworkers, the impatient people in the supermarket, and aggressive and vindictive drivers. In the United States, it is estimated that nearly 21 million adults suffer from mood disorders and about 40 million people have anxiety disorders. Stop for a moment and reflect on how food affects your mood [1].
Do you sometimes feel fuzzy-headed and sleepy after lunch? This is due to the increase in blood sugar level which suppresses orexin; a neuropeptide linked to alertness [1]. On the contrary, when your blood sugar level is low due to hunger, more primitive brain regions take charge and you are more likely to be impatient and easily irritated [2].

Source:  http://bit.ly/1OvEDhe

Eating specific foods affects brain chemicals and eating patterns also affect blood sugar levels, both of which play a role in mood. However, the connection between food and mood not only depends on blood sugar fluctuations, but also on the quality and quantity of nutrients in the diet [1,3]. Our mood is just like our bodies: better enhanced with fresh, whole foods containing proteins, vitamins and minerals. Everything we eat affects the synthesis of neurotransmitters and hormones and the quality of our synaptic connections. These together go a long way to influence how we respond to stress and the demands of daily life [3].

Eating Yourself Happier
Making certain changes in one's diet may help to improve mood: Eating regular meals, especially breakfast and choosing positive mood foods containing tryptophan (essential for the synthesis of serotonin, a neurotransmitter important for a positive affect) can influence one’s mood positively. In addition to eating tryptophan-containing foods, the intake of carbohydrates, vitamins, and minerals which help the uptake of serotonin is also highly recommended. A late night snack can actually help you fall asleep!

WHAT YOU EAT DEFINES YOUR MOOD

 
A study conducted at the University of Otago, Dunedin, New Zealand, shows that fruit and vegetable consumption may contribute to a well-being state and hence positive affect. They reported that there is a correlation between eating more fruits and vegetables to the state of well-being, curiosity, and creativity [3]. One possible biological mechanism underlying the relation between the intake of fruits and vegetables to a greater positive affect and well-being is the fact that vitamins B and C are cofactors for the synthesis of dopamine; a neurotransmitter responsible for motivation and greater engagement. In addition, the antioxidants found in fruits and vegetables are known to lower inflammatory responses. A lower inflammation leads to lower levels of depression and promotes positive affect [4,5].

Happy Fats
Who said all fats are bad? Are you constantly getting rid of fat from your meal? Then stop and think again. Omega-3 fatty acids, although not technically neurotransmitters, are essential for normal brain function and mood regulation. The brain is composed of 70% fat and therefore needs fat for maintaining normal balanced moods throughout life and for moderating aggressive behavior. Omega-3 fatty acids improve the activity of neurotransmitters by assisting the communication between brain cells and thus enhancing plasticity and reducing inflammation which can damage brain cells [6]. By completely eliminating one thing from your diet, even fat, it can have negative consequences on your mood.

Bad Mood Foods
I guess we all want to be in a positive mood most of the time. There are various foods that put us in a bad mood. For example studies show that depression is a symptom of gluten intolerance. Individuals with gluten intolerance have lower levels of serotonin [7,8].
Other examples include soy because it contains proteins that the body finds difficult to digest. The stress on the digestive tract in digesting this protein can equally put us in a state of stress and discomfort. Refined white flour, sugars, vegetable oils can also affect our mood depending on their quantity [9]. Therefore go ahead, eliminate the sad mood foods and eat yourself happier.

[1] http://bit.ly/1U1JOth
[2] http://bit.ly/1DIut7g
[3] http://bit.ly/1IABMp9
[4] Wurtman et al, Am J Clin Nutr, 2003
[5] Girbe et al, Neuroreport, 1994
[6] Appleton et al, Am J Clin Nutr, 2006
[7] Coleman NS et al., Clin Gastroenterol Hepatol, 2006
[8]  http://bit.ly/1H1YizV
[9] http://bit.ly/1fz7OVa 

by Priscilla Koduah, PhD Student AG Meisel
This article originally appeared 2015 in CNS Volume 8, Issue 3, Food for Thought.