The inflamed brain

It is surprising to know how frequently inflammation is going on in brain tissue. The aging process itself is associated with dying off of cells, inflammation and mopping up of debris. However there are critical times when inflammation progresses rapidly, inducing both damage and repair (sometimes referred to as a ‘double-edged sword’) especially in stroke and multiple sclerosis. I have been thinking about ‘the inflamed brain’ and if there are strategies that someone could employ to reduce inflammation and enhance repair. I am reading a paper by Wolf-Dieter Heiss at Max Planck Institute for Neurological Research, Cologne, Germany in Annals of NY Academy of Science 2013 about inflammation after stroke. He explains that there are several phases of inflammation after stroke which I will summarize:

STAGE 1: Immediate effects (first few minutes)-when blood flow is reduced to an area, the brain cells, which are high users of oxygen and energy, are no longer able to carry-out their routine activities. The pumps within the cell that keep things in balance, fail. This results in an immediate loss of function of these cells-they do not ‘talk’ to other cells- so the person experiences a sudden loss of normal function (for example, sight, sensation, balance).

STAGE 2: Spreading of damage (first 6 hours or so) – The damaged cells in the core of the damage spill out their contents, including neurotransmitters, which produce waves of chemical/electrical activity in neighbouring cells. The tissue surrounding the core is called the penumbra and now becomes very vulnerable to injury since it is also has reduced blood flow at a time when activity is increasing. So the cells are being driven hard with very little gas in the tank. These cells reach a point when they can no longer function, the pumps fail and they also start to die off.

STAGE 3: Delayed injury (days and weeks)- There are three things happening during this phase, 1. Swelling, 2. More inflammation and 3. An automatic dying off of cells that are connected to the damaged region called ‘apoptosis’. Swelling happens because the chemicals released from dying cells attract inflammatory cells from the body triggering leakage from the small capillaries in the area. This swelling causes pressure because, of course, the brain (and spinal cord) is encased in bone. The inflammatory cells continue to leak in and cause other problems. Finally the cells that were previously connected to the damaged area are no longer receiving information so the body begins to shut them down.

What can be done to tilt the odds in favour of recovery during these phases? Here is what I think..
STAGE 1: This is really about prevention. What can you do so that if you do have a stroke, you have the best possible chance of recovery? Number 1 is to live a healthy lifestyle, reduce your intake of fat and salt, eat colourful foods that contain anti-oxidants which can help to reduce the effects of free radicals that are released when cells are under stress…and finally EXERCISE! Get in 30 minutes of moderate intensity exercise at least 3 times per week and everyday if you can. Walk, climb the stairs at work, cross-country ski, swim, do yoga, cut firewood.. do something that you feel a bit out of breath. Exercise increases blood supply to the brain (see my previous post about angiogenesis).

STAGE 2: if you suspect a stroke get help as soon as you can. There are two main ways to remove a blood clot (if you have one): one using drugs to dissolve the clot and another using a special surgery to insert a device into the blood vessel to grab the clot and either dissolve it or pull it out. Check out the warning signs of stroke here

http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483937/k.ED98/Stroke__Stroke_Warning_Signs.htm

STAGE 3: Key to enhancing recovery at this stage is excellent early hospital care by controlling body temperature, blood pressure, glucose and providing good nutrition (sometimes just saline in IV or using a feeding tube). The person with the brain injury should also be encouraged to move their limbs and get moving around if at all possible (for example rolling side to side and sitting at the bedside). Family members should be speaking to the person from their most affected side to encourage attention to that side. If the person with the stroke can’t move yet, gently move their limbs. Ask advice from the therapist, doctor or nurse. Be careful not to tug on the person’s affected arm as this can hurt the shoulder very easily. Make sure the affected arm does not droop over the side of the bed. Be aware that swallowing can be slowed so the person should be assessed before allowing them to drink liquids.

I encourage you to review the Canadian Best Practices for Stroke Care-an excellent resource for health professionals, patients and families based on research evidence.

http://www.strokebestpractices.ca/

Rehabilitation is for life

http://vimeo.com/86735159

This video is of Camp No Limits; an outdoor, physical challenge and rehabilitation camp for childhood amputees. It is run by a very close physiotherapy colleague of mine. When I watch it I think of two things:

1. Rehabilitation is for life: If you read back to my old post about ‘Recovery is a marathon not a sprint’, this story of Camp No Limits embodies the important concept that learning and recovery never ends. You have to challenge yourself to try the movements or tasks that seem to be beyond your capability right now-but one step at a time. Set goals for yourself. Find the right resources around you to give you the support you need. I know that before Camp No Limits, there were few opportunities for young amputees to get the coaching they needed to live life to the fullest.

2. Neuroplasticity underlies new learning: Although these children do not have brain injury, they are capitalizing on neuroplasticity. As they practice and learn new skills like rock climbing, riding a bicycle and even riding a mechanical bull, neuroplasticity is at work to make new connections within the brain so that the new skill can be learned.

How to grow more blood vessels in the brain and why you should do it

Think about the blood vessels in your brain like streets in a growing and changing city. The blood vessels are critical to the movement of necessary nutrients to brain cells and the removal of undesirable toxins and waste products. In the city, the thoroughfares (arteries) move large volumes of traffic whereas the small side streets (capillaries) are able to penetrate deep into neighbourhoods.  Arteries and capillaries are the streets of the brain and make sure blood flows to the energy-consuming brain cells in every nook and cranny.

For the brain challenged by trauma, infection, stroke, dementia, Parkinson’s, multiple sclerosis and other disorders, density and quality of blood vessels is critical. Fortunately, the brain has the ability to modify its own blood vessel network just like the city can respond to growth of new suburbs by widening and building new streets. Angiogenesis is the sprouting of new capillaries from preexisting blood vessels while arteriogenesis is the increase in diameter of collateral (neighbouring) vessels in response to blockages in vessels that are the main suppliers of an area of tissue.

Most of what I am discussing here is reviewed exceptionally well by Ergul and group from University of Georgia in the journal Stroke (2012) and  Schmidt and colleagues from Charité University Medicine Berlin, Germany in the journal Cerebrovascular Diseases (2013). So for more detail read those. I will focus on angiogenesis since it is believed to be the primary method of growing new blood vessels in the brain.

So why is angiogenesis important? Angiogenesis increases blood flow to brain tissue which is especially important after a stroke or other injury to the brain. This has three beneficial effects 1. Improving the survival of vulnerable cells in the boundary zone around the damaged area,  2. Removing debris and unwanted chemicals and enzymes from the area and, 3. Creating an environment ripe for growth of new synapses and neurons (neuroplasticity). (Read my previous posts on Neuroplasticity for background)

 Exercise and Physical Therapy-induced Angiogenesis

What we know from animal studies is that exercise before a stroke, builds tolerance to brain ischemia (is-key-me-ya: lack of blood supply to a region of the brain). Animals engaging in regular moderate exercise before a stroke have less damage and better recovery than inactive animals. After a stroke or brain injury, exercise (and physical therapy) stimulates angiogenesis and improves physical and cognitive functioning.

So how much exercise is required to induce angiogenesis? My colleagues and I have just completed a review of studies examining the effects of exercise on angiogenesis after stroke. Of the 6 studies we examined, all were in animal models of stroke (no human studies) and they all used forced wheel or treadmill running. The studies showed that two weeks of daily, moderate to high intensity exercise (walking or running) beginning 1-3 days following stroke resulted in increased markers of angiogenesis. Although this is exciting, it is difficult to translate to the real world setting. First of all, the strokes in animals are very small, sometimes only a few mm. wide, not at all like stroke rehabilitation in humans. Furthermore, it is not practical to ask stroke patients to walk on a treadmill one or two days after stroke. Most are very ill and sometimes not able to sit up, let alone walk on a treadmill. Clearly the timeline in animals after stroke and in humans is very different, but how different we don’t know. A reasonable approach is to make sure aerobic training is included in the rehabilitation process. For the physiotherapist, begin building tolerance to exercise and get the heart rate above baseline gradually increasing intensity each day. Set goals and try to get family members involved. When the patient is able to walk with help, start using your gym equipment (arm ergometer, recumbent bike, etc) adapting them to support the hemiplegic side as necessary.  For the patient and family, try not to spend too much time in bed but if you are there, do your exercises (bridging, lifting your legs and so on). Find out from your therapist how intense you should be training and get help to set up a program. Ask for times you can go to the physio gym to do your aerobic workout.

 

See inside the brain with CLARITY

Last year in 2012, Dr. Karl Desseiroth and colleagues from Stanford University published their technology, called CLARITY, in Nature, the most prestigious scientific journal in the world. CLARITY marks the start of a new chapter in brain imaging. Imagine being able to see through the brain in such a way that you can actually see neurons connect to each other. The YouTube video I have posted below describes their work which is truly exciting. Think about what this means for brain recovery and neuroplasticity research!!

Real-world Challenges of Translating Research Evidence into Clinical Rehabilitation Practice (and vice versa!)

A wise person recently said to me “Sometimes I think the translational issue is one where therapists don’t want to listen, and researchers don’t want to communicate.”
I find myself in an interesting position as both ‘therapist’ and ‘researcher’ and even more convoluted; both ‘basic scientist in neuroscience’ and ‘clinical researcher’. I appreciate the challenges to knowledge translation that he mentions. Research and the application of research to the clinical situation is a complicated issue that sometimes depends on the ‘hat’ you are wearing. When I wear my ‘scientist hat’ I think that clinicians should really seek out evidence-based practice however when I wear my ‘clinician hat’ I understand that in my hectic day I don’t have time to read the hundreds of articles published in my field every 6 months or so.
Researchers don’t seem to want to spend time synthesizing this research for me. Furthermore, in many cases, the studies are performed on specific patients in an ‘ideal’ environment that may or may not be applicable to my patients. The classic example of that is constraint-induced therapy which has been mostly studied in patients with very good hand recovery and no cognitive or memory impairments at all and no other health problems. These patients represent the minority of people I see. The clinician will argue that health researchers should really reach out and study what is really important on the frontlines. So I try not to get offended when wearing my hats. It is true that clinicians, basic scientists, clinical researchers, policy makers are all operating in their own silos and it takes quite a bit of momentum to get cross-talk. I know that the Heart and Stroke Foundation Partnership for Stroke Recovery and other organizations are working on this. I believe lack of communication has got to do with the comfort level that you have when finding yourself in an unfamiliar silo; sometimes you just have to admit that you really don’t understand the methods and applicability of someone else’s area. You just have to be open to learning and collaboration.
In terms of evidence-based practice, only a small fraction of what I do as a clinician has been tested and found effective in people with stroke. It is not that there is evidence to say that my technique does not work; there is just no evidence yet. I must rely on my clinical judgement as well as the advice from experienced and trusted colleagues and the outcomes I see right in front of me among the patients I work with. Researchers tend to study a discrete intervention, like muscle stimulation or treadmill training. Because patients are so different (I have never met two people with stroke who have the exact same recovery profile) I often have to take an eclectic approach derived from research in coaching/training and exercise, research in other conditions and my own creativity and ability to problem solve.True progress will happen when scientists, clinicians and patients collaborate to undertake studies that are grounded in real-world practices and challenges. You don’t have to be an expert in someone else’s area, you just have to be open to communication and sharing.

Sleep your brain healthy; Just press ‘SAVE’

Sleep is like the ‘SAVE’ icon on your computer. When you sleep, memories become more solidly formed and stored inside your brain. Studies in both humans and animals show that when you lose sleep, even for just a few hours per night, you develop memory problems. (Imagine not pressing the ‘SAVE’ button and losing precious information). You can imagine then, how important sleep becomes for a brain trying to relearn and rewire after brain injury (Please see my post from Jan 2012 on ‘Sleep and Brain Recovery’ for more discussion).

So what aspects of sleep are most important; total hours of sleep, naps, how long it takes to go to sleep, waking up at night, or daytime sleepiness? A recent study published in Sleep Medicine (May 2012) followed 2012 people over the age of 65 for 10 years. The study, a partnership between researchers at University of Cambridge, UK and University of South Australia (Keage 2012), found that older people who take a nap during the day are two thirds less likely to develop cognitive impairment 10 years later. The authors describe napping as ‘protective’ against cognitive decline.

Furthermore, sleeping less than 6 hours each night doubled the risk of cognitive impairment over 10 years. People who reported daytime sleepiness had 2.5 times the risk of developing cognitive impairment 10 years later. The results of this study suggest that to preserve brain health over the long term you should sleep between 6 and 9 hours per night and have about a 60 minute daytime nap.

Why is sleep so important? Well, studies show that people who experience sleep deprivation for 24 hours have higher levels of stress hormones in the blood (See my post “Chronic stress and depression is bad for your brain” November 2012). They also make more errors on thinking tests (Joo and group, Journal Clinical Neurology 2012). People with chronic insomnia have significantly lower scores on tests of attention and concentration. They have impaired memory and thinking compared to people who sleep normally (Noh and group, Journal Clinical Neurology 2012) and what is most alarming is that people with insomnia have shrinkage of a very important cashew-sized section of the brain critical for forming memories called the hippocampus. During medical sleep studies, insomniacs who have experienced insomnia longer and who are more restless at night, have more brain shrinkage and more cognitive impairment. These are clearly NOT GOOD THINGS!! So pay attention to sleep. It is very likely that a good night’s sleep (or a daytime nap) can, not help maximize your recovery from a brain injury, but also promote a healthy brain in the long term.

There are plenty of resources on the internet but to sleep your brain healthy, the Canadian Sleep Society (www.canadiansleepsociety.ca) recommends some basic habits to improve your sleep. Try these simple solutions first.
1. Go to bed only when sleepy and use a relaxing bedtime routine (bath, reading etc)
2. Remove noise, light and other distractions
3. Avoid caffeine, nicotine, and other stimulants
4. Avoid strenuous exercise, large meals or long naps close to bedtime

Exercise counteracts the harmful effects of chronic stress and depression on the brain

The concept that exercise is an effective treatment for depression is not new. The Cochrane Collaboration, an enormous network of scientific experts around the world recently published (Rimer et al July 2012) a review of 28 articles studying the effects of exercise on depression symptoms with a total of 1101 participants. They showed that exercise significantly improved symptoms of depression, although modestly, but the benefits were long lasting.

http://summaries.cochrane.org/CD004366/exercise-for-depression

Since we know that depression is a ‘condition of the brain’, what may be more interesting is studying the effects of exercise on the depressed (or stressed) brain. How does exercise affect the depressed brain? Is there is a level of exercise that is optimal in treating the harmful effects of stress and depression. What type of exercise (running, walking, strength training etc) is best?

In my previous post ‘Chronic stress and depression is bad for your brain’, I talked about how chronic stress activates the body’s hypothalamic-pituitary-adrenal (HPA) axis. Stress disrupts the delicate balance of neurotransmitters and other molecules in the brain, signaling the hypothalamus to release hormones which in turn signal the pituitary to activate the adrenal glands in the abdomen, just above the kidneys, to produce cortisol. Cortisol is not the bad guy- but prolonged high levels of cortisol disrupt the body’s homeostasis, weaken the immune system and impair memory (http://en.wikipedia.org/wiki/Cortisol). However, it is important to appreciate that the relationship between chronic stress and depression, cortisol and the neuroimmune response has not been completely mapped out. I will try to explain now how exercise fits in.

The key battleground between chronic stress on one side and exercise on the other is the neuroimmune system.  The neuroimmune system acts as the gatekeeper between the nervous system and the immune system. The nervous system especially the brain and spinal cord have a very privileged position in that they are separated and protected from infection and inflammatory cells circulating in the body (within the blood vessels). In animal studies, chronic stress and depression disrupts this balance and increases inflammation and production of free radicals within the brain as well as blunts the production of beneficial neurotrophins. Exercise on the other hand seems to work in the opposite direction: reducing inflammation, increasing anti-oxidant activity and enhancing production of neurotrophins (Refer to my post “Neurotrophins are brain fertilizers’).

One of the first studies examining how exercise could protect the brain from the harmful effects of stress was published in Neuroscience in 2004 (Adlard & Cotman). Rats were randomized to 3 weeks of running wheel exercise or to regular housing and then underwent a stressful event (enclosed in a small tube for 2 hours). They found that exercise protected the brain against the stress-induced decrease in the neurotrophin, BDNF.

Nakajima et al (2010 Behav. Brain Res.) showed that in rats receiving chronic severe immobilization stress (12 hours/day, 6 days/week for 5 weeks), there was accumulation of brain cell damage (lipid peroxidation), loss of the natural neurogenesis (growth of new neurons in the brain) and impaired cognitive function. Exposure to exercise between the exposures to immobilization stress reduced the severity of the harmful effects of stress.

Most of the research in the field is consistent with the concept that exercise is a potential treatment to reverse or limit the neuroimmune mechanisms related to stress-associated depression. The jury is out regarding the intensity, duration and type of exercise required but the general trend is a moderate (fast walking), regular (almost every day) approach.

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