Making new brain cells: how mice could help astronauts and DCM patients
Making new brain cells: how mice could help astronauts and DCM patients
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’.
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.
Figure 2: Diagram of the HU mouse model. From Barbosa et al 20118
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).
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!
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).
My Island
Yesterday, my husband dropped me off at the swimming baths. The large float around my waist and my cycling style of swimming does raise a smile or two. Some call me a ninja turtle, some the barnacle woman. Today my predicament was in the changing room. With my combination lock. I tried it, retried it, again and again to no avail. It wasn’t the wrong combination; it’s my date of birth but the lock is old and sometimes you have to press it together for it to open. I could see my issue was attracting the attention of others. So in my swimming costume, dripping, I went to reception. A female employee, with bolt cutters came to my rescue. She struggled a little until suddenly the lock exploded apart.I opened the locker. Opps. Someone else’s clothes. I used the ‘f’ word; it was called for.The leisure centre girl was laughing. The audience of women changing was lapping it up. I said this has probably happened to other people. No, she said. What an idiot.
My locker was only three doors away and I didn’t even think to try it. I was resolutely sure that the locker was mine. I felt so sorry for whoever’s locker it was. They came to the leisure centre to work out and relax. I had to lock their locker with my lock. I left an apologetic note on their door telling them the combination was at reception. Then I went for a cappuccino. With myelopathy you have to let these things wash over you.
I’ve been a little Norman Bates lately; stable one day, struggling with my myelopathy persona the next but I’m quite proud of myself. I’ve reached out to people to try to reconnect and everyone’s been so generous with their time and considerate of my condition. I’ve been going to events and sometimes only staying an hour; but enjoying that hour.I went to a lovely patisserie for coffee and cake this week but told Diane I could only stay an hour because I can’t stand independently, or straighten, if I sit over the hour. Also I’m learning how to be a bit precious. My husband calls me the princess and the pea because everything has to be just so. If a chair is too soft my back spasms, if my shoe laces are too tight I can’t put shoes on, if my teacup is too full I can’t lift it, if there is spice in my food I get IBS. I went from being totally laid back, able to eat street food cooked by greasy haired, uncompliant to hygiene standards, cooks to being very needy. I don’t beat myself up about it. I’m not elderly or frail or sick but titanium is holding my neck together and if I’m not careful my cervical spine might topple like Jenga bricks again. So, when I’m chatting I need my friend opposite me, not beside. I can get in a car, but I can’t get out without help. I need to be front of the loo queue because I can’t hold it. If we can’t be fussy now, when can we?
My youngest daughter was eighteen yesterday. When I think of Caitlan it’s like my heart bursts like a popping champagne bottle. She was ten when I was first admitted to hospital with what doctors thought was a stroke. We’re throwing her a party. If I thought too much about the organisation I’d feel overwhelmed. I’ve called it a casual gathering, that way expectations aren’t so high. I think if you have alcohol and food a party will run itself. My brother and his family are over from Kilkenny, Caitlan’s godparents from Dublin, I can’t wait. Having something to look forward to is paramount. I look forward to coffee with my husband, I love going to M&S Food Hall, I have book club, I love Grace coming home for the weekend. My four children are the painkiller that get my weak body out of bed. They are the smile on my face. They understand my condition better than neurologists, they live with my highs and lows and they pick me up.
I am happy. It’s a glorious feeling. Once I get going I feel my life is full of possibility even though by four I will be totally slayed with pain and tiredness, my limbs will be unresponsive, and I will sway around the house, everything falling from my grip…I’ll end up in bed for a few hours but at nine I will be enjoying Love Island with my family. If I think of 2018 so far I’ve been part of a training video to help doctors diagnose myelopathy earlier, I’ve been skyped (never skyped before) by Dr Nidhi who is gathering info to support early diagnosis. I’ve enjoyed two book club gatherings. Met Sharon for a pub lunch. Gone for innumerable coffees and cake and have the calories to prove it.
Caitlan recently returned from a geography trip to Iceland. Putting on her crampons, about to step foot on a glacier she thought of me. My mum will never do this, she’ll never see this powerful landscape with winds that take your breath away. It’s true. But it’s ok. I’ve come a long way since my dramatic arrival at A&E. I’m walking. I’m sleeping. I’m managing my pain. I’m with my family. I think of my life like Bear Grylls’ The Island. Myelopathy is my island. I’m not a giver upper and I’ve learnt to enjoy simple things.
Right now I’m sitting by the window, the sun is shining, a squirrel has just run the gauntlet across my garden fence while my two dogs are going bonkers. Spanish rap is playing. I’m glad to be alive; the alternative is an eternity I’d like to avoid. I’ve come to not expect too much of myself. Myelopathy is the long game.
You can check out Alison’s blog My Hell opathy here
Neck Muscles and CSM/DCM
Reviewed by B.Davies
Neck Muscles and CSM– An Update Part 1 of 2
This will be the first of a 2 part mini-series on the properties of muscles in the neck and how they impacts outcomes of surgery. We previously looked at this following an early piece of research from North America. This series will serve as an update on this research.
Why was this study conducted?
As outlined previously, the amount of fat found within muscles has been linked to the type of symptoms experienced by patients; including the amount of neck pain and walking ability. This new study was done on a separate cohort of patients than the previous study and included measures of neck strength and other quality of life scales not assessed previously which addresses some weaknesses of the previous study.
How was the study conducted?
This study used MRI imaging to measure the size and the amount of fat in muscles in the neck. Neck strength was measured by clinicians using a hand held force sensor. Several questionnaires were performed to assess function, pain, and quality of life. Importantly, this study used what is called a “cross-sectional’ design meaning it only looks at 1 time point.
What was discovered?
Larger muscles and larger amounts of lean muscle (i.e. muscle without fat) in the neck were associated with increased strength. (We already knew this in general, but it is good to ensure there isn’t something different about patients with cervical myelopathy). More fat in muscles of the neck was associated with more disability measured by the mJOA. Importantly, neither strength, muscle size, or muscle fat were associated with pain, duration of symptoms, neck disability index, or quality of life in this study.
Why is this important?
Between the previous study linked above and this study, it appears that muscle fat may be a biomarker of disability and function in patients with myelopathy. Currently there are no biomarkers for myelopathy, which makes it difficult to assess how severe it is or give an idea of how things will develop. More research will be needed to investigate the usefulness of muscle fat as a biomarker, but given that it can be quantified based on existing widely avaliable imaging techniques, it could enter routine clinical practice quickly.
Why could muscle fat relate to the severity of myelopathy?
One reason this is being investigated is that fat infiltrates muscle as a response to nerve injury and disuse. For example, if a nerve is injured the nerve doesn’t tell the muscle to contract as much and it allows more fat to become deposited within the muscle itself.
References
- Fortin M et al. Relationship Between Cervical Muscle Morphology Evaluated By MRI, Cervical Muscle Strength And Functional Outcomes In Patients With
Degenerative Cervical Myelopathy. Musculoskeletal Science and Practice. 38; epub 2018: 1-7
- Fortin M, et al. Association Between Paraspinal Muscle Morphology, Clinical Symptoms and Functional Status in Patients With Degenerative Cervical Myelopathy. Spine (PhilaPa 1976). 2016 May 23
More to Myelopathy than meets the eye
Edited by B.Davies
We don’t really know what symptoms a “typical” patient with myelopathy has.
In fact, the huge number of often quite subtle and non-specific symptoms is probably one of the main reasons why early diagnosis is so challenging (Davies et al., 2018).
When medical students prepare for exams they tend to learn stereotypical descriptions of conditions. For myelopathy, this might be a patient with walking problems and clumsy hands.
However, increasingly symptoms that one might never consider could be linked with myelopathy are emerging from the shadows.
Depressed or anxious mood is one such symptom (Stoffman et al., 2005).
In recent years we have realised that myelopathy patients suffer from high levels of depressed or anxious mood and that this often improves after spinal surgery. But we have had little understanding of why this is the case.
A recent study from Japan has provided a little more insight (Sawada et al., 2018). The Japanese team studied the activity levels of various sites in the brain in myelopathy patients before and after surgery. They also studied individuals without myelopathy as a control group for comparison.
To do this, the team asked participants to do a simple finger-tapping exercise whilst they observed activity levels in the brain using functional magnetic resonance imaging.
The team found that before surgery individuals in the myelopathy group had a significantly higher activation in an area of the brain called the supplementary motor area compared to individuals in the group without myelopathy.
Next the team found that activation of brain areas, including the anterior cingulate cortex, the supplementary motor area and the thalamus significantly correlated with depression. This meant that the greater a patient’s depression, the greater the activation they had in these brain areas.
Finally, the team found that both depression and activity in the anterior cingulate cortex and supplementary motor area decreased following surgery for myelopathy.
Interesting!
The team argue that up to now surgeons have focussed on the “typical” symptoms such as the clumsy hands and walking problems when deciding whether to operate. They believe that their work may lead to future surgical decisions taking more account of the psychological symptoms too!
Davies, B.M., Mowforth, O.D., Smith, E.K., and Kotter, M.R. (2018). Degenerative cervical myelopathy. BMJ 360, k186.
Sawada, M., Nakae, T., Munemitsu, T., and Hojo, M. (2018). Cortical Reorganizations for Recovery from Depressive State After Spinal Decompression Surgery. World Neurosurg. 112, e632–e639.
Stoffman, M.R., Roberts, M.S., and King, J.T. (2005). Cervical spondylotic myelopathy, depression, and anxiety: a cohort analysis of 89 patients. Neurosurgery 57, 307–313; discussion 307-313.
Community Champion Frank Dutton shares his top fundraising tips
Community Champion Frank Dutton
I created a ‘lucky numbers’ board featuring 1-100. I then made a list of those numbers with spaces next to them for people to write down their names and telephone numbers. It cost £1 per number and I decided on a winning pay-out of £25 which, if all the numbers had been taken, would deliver a tidy profit of £75 for Myelopathy.org.
I set my table up in the club room. I took along some laminated photos of people’s CT scans, including my own, as visual aids. I also made copies of one of the charity’s media releases about the condition and the need for early diagnosis, and the basic facts about myelopathy. These are part of the Myelopathy.org fundraising pack.
It was very interesting to see how people reacted to the photographs and then responded to the information in the leaflets and that I was able to supply about myelopathy.
The fundraising experience was a positive one and the fact that I was able to raise £71.10 (no idea where the 10p came from) was a bonus. I am now really looking forward to taking part in the next fundraising event. So, if you have any ideas or want to hold a fundraiser yourself, please let me or one of the Myelopathy.org team know.
My top five tips for fundraising.
1) Plan where you want to hold your fundraiser and contact relevant authority/fête organiser/owner etc for permission
2) Share, share, share. Use social media, such as Facebook, WhatsApp, Instagram etc, to gain maximum promotion and coverage for your fundraising activity.
3) Make it personal. Tell your own story so that people can understand more about your experiences and your reasons for fundraising. Sometimes that personal touch/story can elicit donations.
4) Remember your inspiration. There’s a reason why you are supporting this cause. Hold on to your inspiration and bring all that enthusiasm to your fundraising activities.
5) Have fun. If you are not enjoying yourself, you will give off all the wrong vibes. So, smile and perhaps rope in a friend or two to help so that you can jolly each other along.
Neck Muscles and CSM– An Update Part 2 of 2
Reviewed by B.Davies
Neck Muscles and CSM– An Update Part 2 of 2
This second of a 2-part mini-series on the properties of muscles in the neck and how they impact outcomes of surgery. We previously looked at this following an early piece of research from North America. This series will serve as an update on this research.
Why was this study conducted?
For a short recap of the previous 2 blogs related to this: how much fat there is within muscles has been related to symptoms of myelopathy. Additionally, cervical lordosis, or, the curve of the neck, is believed to be related to outcomes following laminoplasty.1
How was the study conducted?
This study performed a pre-operative MRI at which they performed measurements of the neck muscles. They then tracked the participants for 12 months post cervical laminoplasty to assess the curvature of the neck with x-ray.
What was discovered?
The main finding was that muscle size at multiple vertebral levels in the neck is related to loss of curve following surgery. The smaller the neck muscle size, the greater loss of neck curve.
Why is this important?
This is further evidence suggesting the muscles in your neck are important in myelopathy. It should be noted that this study only looked at patients who underwent a laminoplasty, one of many different types of surgical procedure for myelopathy (i.e. it is unclear whether this finding would be applicable to other types of surgery such as ACDF).
Whilst this link is again being drawn, it remains to be seen whether or not treatments to help neck musculature could make a difference to patients. The authors in this study suggest it could better advise on the type of surgery that is to be performed. Drilling down to these questions will be an important next step for this line of research.
Have you had any therapy to strengthen your neck pre- or post- surgery? Did it help?
Reference
Lee BJ et al. Importance of the Preoperative Cross-Sectional Area of the Semispinalis Cervicis as a Risk Factor for Loss of Lordosis after Laminoplasty in Patients with Cervical Spondylotic Myelopathy. Euro Spine J. epub 2018: 1-10
Heart Break for Myelopathy
Risk of acute coronary syndrome in patients with cervical spondylosis
J.Hamilton
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What were the aims of the study?Various studies in the past have described cervical spondylosis (CS), the degenerative changes in the cervical bones and ligaments contributing to degenerative cervical myelopathy, as associated with increased sympathetic nervous tone[1][2].
The sympathetic nervous system plays a role in controlling blood pressure, heart rate and various other aspects of our cardiovascular health. But part of its control structure also lies in close proximity to the cervical spine. |
The authors noted that no research had been done to link the above statements, if CS does cause increased sympathetic activity, does this logically follow that CS causes an increased incidence of cardiovascular events?
With this in mind, the aim of the study was to determine if cervical spondylosis increased the risk of cardiovascular health issues, specifically acute coronary syndrome (ACS), which in common terms is a heart attack.
How was the study performed?
All the patients were followed up until they had a diagnosis of ACS, died, or the end of the research period occurred at the end of 2011. After this, the number of ACS events in each group were measured as a rate over the number of “person years”. This being the number of times a diagnosis of ACS was made for every year a patient lived.
In this paper, the incidence of ACS was measured as number of ACS/1000-person years. These were then compared between various groups to obtain a ratio, to determine the relative risk of ACS occurring in a person with CS compared to someone without ACS in a similar state of health.
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What were the main findings?
Looking in more detail at the patients with CS, for those with myelopathy the risk was slightly higher, increasing by 20% but i
nterestingly, it seems treatment of CS has an effect in reducing ACS risk:– Patients receiving spinal decompression surgery were less likely to have an ACS (27% reduction)
– Patients receiving rehabilitative therapy were less likely to have an ACS (33% reduction)
The statistical difference between the form of treatment for CS and reducing ACS risk was not significant.
How could cervical spondylosis cause acute coronary syndrome?
What can we take from this study?
There are a number of limitations to this study, and the actually increases in risk are relatively small. But it adds to the research of CSM and Cardiovascular disease, and once again shows the far reaching impacts of CSM.
References
[2]M. Singh, I. Khurana, Z.S. Kundu, A. Aggarwal, Galvanic skin response in pa- tients with cervical spondylosis, IJHSR 6 (2016) 148e152.
[3] N. Marina, A.G. Teschemacher, S. Kasparov, A.V. Gourine, Glia, sympathetic activity and cardiovascular disease, Exp. Physiol. 101 (2016) 565e576,
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