By M Stewart
Editor: B Davies
It’s a commonly held belief that you can’t grow new brain cells as adult; you’re born with one hundred billion neurons and that’s as many as you’re getting. However, this isn’t quite the case. While new neurons don’t form in most parts of the human central nervous system (the brain and spinal cord), there are two special areas where new neurons do indeed arise after birth. These areas are found in specific parts of the brain with rather complicated names: the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle. These two areas (which we call the ‘SGZ’ and ‘SVZ’ for short) contain what we call ‘neural stem cells’ (NSCs), which are able to produce new neurons throughout adult life. This production of new neurons from stem cells is called ‘neurogenesis’.
Figure 1: Neurogenesis in the rodent (A) and human (B) brains. The final destinations of newly born neurons are shown in green. In both man and rodent one site is the dentate gyrus (DG). Neurons from the subventricular zone of the lateral ventricle (LV) end up in the olfactory bulb (OB) in rodents and in a part of the brain called the striatum in man. From Ernst et al 20153.
Interestingly, there’s a link between neural stem cell activity and exercise. Increased levels of physical activity have been shown to increase neurogenesis, and even restore it in mice who have stopped producing new neurons due to genetic manipulation1. Importantly, this increased neurogenesis has been associated with increased learning ability2. While we know quite a lot about what happens to neural stem cells when we move more, we don’t know much about what happens to neurogenesis when we move less. This gap in our knowledge actually rather important when we consider that prolonged reductions in movement are increasingly common. Lack of muscle activity occurs inn prolonged bed rest or neurological diseases which affect motor function, like spinal cord injury, multiple sclerosis or potentially DCM. Alternatively, effects equivalent to reduced movement can occur in prolonged stays in space, where there the reduced gravity means that muscles aren’t placed under load.
As patients survive longer with neurological diseases and as we expect longer stays in space, it becomes more and more important to understand any links between immobility and neurogenesis for two reasons. Firstly, changes to neurogenesis could affect brain health – it may be that changes to neural stem cells following reduced mobility feed back into disease like MS or DCM and actually become part of the cause. Adult neurogenesis is greatly decreased in Huntington’s disease patients when compared to healthy people, suggesting that there could be a link between reduced neurogenesis may play a role in the disease3. Secondly, exploring the link may help us understand the effects of exercise on the brain. Reduced movement has been shown to impair memory function and learning4 and to change the chemical environment of the brain5. We may also be able to better understand the link between exercise and prevention of neurodegenerative conditions like Alzheimer’s disease, which is associated with degeneration in neurogenic areas6.
For all the above reasons, a team from Italy lead by Rafaella Adami recently set out to explore whether reduced movement lead to changes in neural stem cells7.
The study was done in mice. While mice do have some notable differences to humans in terms of the neural stem cells (see below), these experiments require the dissection of large amounts of brain tissue and immediately after death and so are practically impossible to do in humans.
How was this study done?
The researchers wanted to recreate the conditions seen in situations (e.g. neurological diseases) where people can’t move very much. In these situations limbs are ‘unloaded’ – people aren’t using their arms or legs to move their weight around. in something called the ‘hindlimb unloading model’8 (HU) mouse model. Mice are suspended by their tales from the ceiling of a cage, taking the load off their hind legs, but leaving them free to walk on their front legs. Thus the hind legs don’t bear the mouse’s weight and are ‘unloaded’ (see figure 2). Adami et al put a group of mice in this position for 14 days, over which time their back leg muscles shrank significantly, as they would if they were unable to move them due to neurological disease (or if they were in space and carrying no weight!). After 14 days the mice were killed and their brains where dissected to examine the neural stem cells in the SVZ. Brains from mice which had been allowed to run around their cages freely where used for comparison (control).
It’s important to stress that the mice were well looked after during the experiment. They always had access to as much food and water as the wanted and were visited by a vet 3 times during the 14 days of suspension. The showed the same key mouse behaviours as the free (control) mice and showed no increased levels of stress hormones. Taken together, all these factors strongly suggest that the mice suffered “little” stress during the experiment.
What were the results of the study?
Firstly the researchers looked at the number of proliferating (dviding/reproducing) cells found in the SVZ. In this case, proliferating cells were the stem cells that were dividing to make neurons, so more proliferation suggests more neurogenesis. Adami et al found that there were 70% fewer proliferating cells in the HU mice compared to controls – so neurogenesis was reduced.
The team then wondered if this reduced proliferation meant that the stem cells themselves had changed in some way. To explore this possibility, they then took NSCs out of the HU and control mouse brains and grew them in a dish, to form a ball of stem cells and neurons. They saw that stem cells from HU mice divded more slowly than in controls, taking 7 days to double in number (the controls only took 2 days). They also checked that this slower rate of growth wasn’t due to cells dying.
Overall, these findings led the team to their first key result: reducing movement reduces the proliferative capacity of neural stem cells.
Adami et al then wondered what caused this reduced proliferation. They discovered that it was because the more of the HU mouse stem cells appeared to have become stuck in the ‘resting state’ when compared to the control mouse stem cells. 69% of HU stem cells were found to be in a resting state, compared to 57% of controls. Far more of the control cells were in a very active, dividing state (21% vs 13% of HU mice).
The researchers then looked at whether the neural stem cells were able to form mature neurons. They found that 6.8% of control stem cells could form mature neurons, whereas only 0.5% of HU stem cells could.
This lead the team to their second key result: reducing movement reduces the maturation capabilities of neural stem cells.
Next, Adami et al explored whether the metabolism (energy production) of neural stem cells in HU mice had changed. Most neural stem cells produce energy by a process called glycolysis, which by produces a byproduct known as lactate. HU stem cells produced significantly less lactate than controls cells, suggesting that reduced movement gives neural stem cells an abnormal metabolism.
Finally, to try and understand what could be underlying these changes, the researchers looked at gene expression in the neural stem cells. They found that expression of 2 genes were significantly different between HU and control samples. A gene known as CDKrap1 was 3.5x lower in HU stem cells than in controls, while a gene known as cdk6 was 2.3x high in HU stem cells. Overall, it appears that reduced movement changes the genes expressed in neural stem cells. Adami et al haven’t commented on what these different levels of cdkrap5 might mean, but they think that the higher levels of cdk6, which helps keep cells in the resting state rather than dividing, could explain the reduced neurogenesis seen in HU mice.
What do these results mean for DCM?
Right now, not a great deal. This work is still very much ‘blue sky research’ intended to see if the neural stem cells are worth further study for neurological disease (or space travel!). While its fascinating to see that that restricting movement leads to change in neural stem, we have to be cautious in how far we extrapolate the results to humans. Firstly, while mice and humans may be similar, they aren’t the same (newly born neurons rom the SVZ actually end up in a totally different places in mice and people). Secondly, while DCM can involve reduction in movement if nerve damage progresses to an extreme stage or pain becomes debilitating, it’s not quite as clear cut as in this mouse model. Therefore it’s hard to say if neural stem cells would undergo the same changes in DCM patients as they do here. Thirdly, it’s difficult to understand the implications of the results when we don’t fully understand how/if reduced neurogenesis contributes to neurological diseases. Furthermore, the consequences of reduced neurogenesis are likely to vary across conditions – changes to neurogenesis might be completely in DCM than they are for something like Huntington’s.
The next step will be to explore the nature of neural stem cells in other mouse models of reduced movement, such as multiple sclerosis, spinal cord injury and DCM to see if neural stem cells undergo similar reductions in neurogenesis. Then we’ll need to determine how/if reduced neurogenesis might contribute to the problems we see in these conditions. If such a contribution was confirmed, this could be a breakthrough in our understanding of how DCM develops. We might even then be able to developing new treatments which target the neural stem cells themselves. However, there are many steps we must take before we reach that stage – for now we’ll have to move slowly. Watch this space for more!
1. Farioli-Vecchioli, S. et al. Running Rescues Defective Adult Neurogenesis by Shortening the Length of the Cell Cycle of Neural Stem and Progenitor Cells. Stem Cells 32, 1968–1982 (2014).
2. van Praag, H., Shubert, T., Zhao, C. & Gage, F. H. Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice. J. Neurosci. 25, 8680–8685 (2005).
3. Ernst, A. & Frisén, J. Adult Neurogenesis in Humans- Common and Unique Traits in Mammals. PLOS Biol. 13, e1002045 (2015).
4. Wang, T. et al. iTRAQ-based proteomics analysis of hippocampus in spatial memory deficiency rats induced by simulated microgravity. J. Proteomics 160, 64–73 (2017).
5. Dupont, E., Canu, M.-H., Stevens, L. & Falempin, M. Effects of a 14-day period of hindpaw sensory restriction on mRNA and protein levels of NGF and BDNF in the hindpaw primary somatosensory cortex. Brain Res. Mol. Brain Res. 133, 78–86 (2005).
6. Guure, C. B., Ibrahim, N. A., Adam, M. B. & Said, S. M. Impact of Physical Activity on Cognitive Decline, Dementia, and Its Subtypes: Meta-Analysis of Prospective Studies. Biomed Res. Int. 2017, 1–13 (2017).
7. Adami, R. et al. Reduction of Movement in Neurological Diseases: Effects on Neural Stem Cells Characteristics. Front. Neurosci. 12, 336 (2018).
8. Barbosa, A. A. et al. Bone mineral density of rat femurs after hindlimb unloading and different physical rehabilitation programs. Rev. Ceres 58, 407–412 (2011).
By Timothy Boerger
Reviewed by B.Davies
Reason for the study
The number of times a paper is cited is a common metric of how meaningful that paper is to the scientific community. Generally, papers that are highly cited have a profound impact on their field. If scientists look at the trends of which papers are most cited, it can give us an idea of what topics within a scientific discipline are experiencing the most interest over time.
The prominent journals publishing research related to the spine were first identified from a database of journals. This list of journals including: Spine, Journal of Spinal Disorders, European Spine Journal, Journal of Spinal Cord Medicine, Spinal Cord, Spine Journal, Journal of Spinal Disorders & Techniques, and Journal of Neurosurgery: Spine were searched using the database Web of Science which provides all articles ever published from the selected journals. Articles were then sorted by most citations and the top 100 cited articles were analysed. Articles were then sorted by topic including,
By far the most articles were published in the journal Spine (84/100 articles). This suggests that the journal is publishing a substantial body of the spine research which is both impactful and broadly of-interest to clinicians and researchers of spinal conditions. Ranked according to most articles by topic, low back pain was 1st and had over 2x as many articles represented as any other topic area (22/100 articles). Ranked according to most articles by topic, Cervical myelopathy/Cervical fusion was tied-9th with 3/100 articles. Of these 3, all were on operative techniques for different aspects of cervical myelopathy. The most recent of these 3 articles was published in 2001 (the other 2 were published in 1983 and 1981). Neck pain was 12th.
Why is this important?
The number of times an article was cited is often an indicator of how popular a topic is. This suggests that cervical myelopathy, despite its prevalence and impact upon a person, has received relatively little impactful research. Impactful is an important caveat here; a terrible study, or one that only marginally advances the field, will probably not receive a lot of citations in the future. This means that researchers that look at myelopathy need to produce impactful research that helps us understand mechanisms of the disease, its impact, etc. that may help drive more interest and produce more highly impactful work and better treatments.
It isn’t all doom and gloom, however. On Aug 1, 2018 I searched pubmed (another database of research articles) for all research containing the keywords:
and got 24,107 results. Similarly if you search “low back pain, one would get 34,002 results in the same database. This suggests that there is a decent amount of research compared to low back pain, but not nearly in the ball park as other disabling conditions such as multiple sclerosis (~80,000 articles). This suggests that more research is needed in all facets of the disease, but this research also needs to be well designed, rigorous, and impactful. It also means that more publicity is needed for this disease to generate more interest in the scientific community.
By Iwan Sadler
Words can be powerful when spoken or in thought. Words are used on so many different levels from the expression of your thoughts to the decision you will make within the moment.Peace is delivered with words but also wars are started by the spoken or written word.
We choose our life choices on words. The average person can speak between 125 and 150 words a minute, but the rate of "expanded inner speech! (word-for-word) is slightly faster than verbal speech. That puts into perspective how many words enter our train of thought on a daily basis. Some decisions can sometimes be made in seconds - other decisions take a lot longer. One thing is for certain: they are all decided with words.
With the technological development of the internet and mobile phones, words are used more now than ever. The average person uses their mobile phone for approximately four hours per day and around 18.7 billion text messages are sent around the world on a daily basis. And we can’t forget the amount of words we use on our social media platforms. I think you’ll agree that’s a great quantity of words.
This just shows how important words are for our social integration and how powerful words can be. They say that concurring thoughts will eventually become your actions so should we be careful at what we think? Many people think that words, once spoken, cannot be taken back and the action of those words, even if they were delivered within seconds, will last and echo for a lot longer.
So should we be more careful with what we choose to say? Do words really cut deeper than a knife and leave longer lasting invisible scars? Could our words to a situation decide the overall reactive decision to a situation? Can our words totally change a decision within a scenario? The answer is “Yes!” Our action will always lead to a reaction and the outcome will always depend on our words.
“Where are you going with all this?” you may ask and “What has this got to do with living with a chronic condition?” Could the words we think and use every day help us deal with our condition? Remember that the actual words you say matter, not just the thoughts you convey. Try to use more positive words on a daily basis even if you are unable to replace negative words with positive ones, try replacing them with more accurate neutral ones. Instead of, “This chair is horrible”, try“This chair is not for me.”
Try not to use absolutes, especially in relation to your goals, where falling short of your expectations can be particularly depressing. These words and phrases include: “always”, “never”, “nothing” - the list goes on. Replace them with nuance. Instead of, “I can walk that far”, try “Sometimes I can’t walk that far”.
So the key is to think and speak in a more positive manner. Positive thinking often starts with self-talk. Self-talk is the endless stream of unspoken thoughts that run through your head. These automatic thoughts can be positive or negative. Some of your self-talk comes from logic and reason. Other self-talk may arise from misconceptions that you create because of lack of information.
Positive thinking doesn't mean that you keep your head in the sand and ignore life's less pleasant situations. Positive thinking just means that you approach unpleasantness in a more positive and productive way. You think the best is going to happen, not the worst.
The Health Benefits of Positive Thinking
Researchers continue to explore the effects of positive thinking and optimism on health. Health benefits that positive thinking may provide include:
You can learn to turn negative thinking into positive thinking. The process is simple, but it does take time and practice - you're creating a new habit, after all.
If you are looking for another way to relieve discomfort that doesn't involve drugs, some age-old techniques - including meditation and yoga as well as newer variations, may help reduce your need for pain medication.
Research suggests that because pain involves both the mind and the body, mind-body therapies may have the capacity to alleviate pain by changing the way you perceive it. How you feel pain is influenced by your genetic makeup, emotions, personality, and lifestyle. It's also influenced by past experience. If you've been in pain for a while, your brain may have rewired itself to perceive pain signals even after the signals aren't being sent any more. Stress and pain are tightly connected and can have a strong influence on each other. Therefore, if positive thinking is able to counter some of the effects of chronic stress, it could also help lower pain levels.
Practising Positive Thinking Every Day
If you tend to have a negative outlook, don't expect to become an optimist overnight. But with practice, eventually your self-talk will contain less self-criticism and more self-acceptance. You may also become less critical of the world around you.
When your state of mind is generally optimistic, you're better able to handle everyday stress in a more constructive way. That ability may contribute to the widely observed health benefits of positive thinking.
Being careful with our self talk is essential for our own. wellbeing. And we can also take care to avoid ill-considered words that could damage the wellbeing of others.
Our minds too often seem to be programmed to keep recalling and dwelling on negative comments which drown out or dismiss any positive feedback we have received.
The tongue is the strongest muscle in the human body so be careful on how you use it may it be online by txt or word of mouth because "words can only be forgiven not forgotten”.
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