Posts Tagged physical activity
- It is by now well established that exercise has positive effects on the brain, especially as we age.
- Less clear has been why physical activity affects the brain in the first place.
- Key events in the evolutionary history of humans may have forged the link between exercise and brain function.
- Cognitively challenging exercise may benefit the brain more than physical activity that makes fewer cognitive demands.
In the 1990s researchers announced a series of discoveries that would upend a bedrock tenet of neuroscience. For decades the mature brain was understood to be incapable of growing new neurons. Once an individual reached adulthood, the thinking went, the brain began losing neurons rather than gaining them. But evidence was building that the adult brain could, in fact, generate new neurons. In one particularly striking experiment with mice, scientists found that simply running on a wheel led to the birth of new neurons in the hippocampus, a brain structure that is associated with memory. Since then, other studies have established that exercise also has positive effects on the brains of humans, especially as we age, and that it may even help reduce the risk of Alzheimer’s disease and other neurodegenerative conditions. But the research raised a key question: Why does exercise affect the brain at all?
Physical activity improves the function of many organ systems in the body, but the effects are usually linked to better athletic performance. For example, when you walk or run, your muscles demand more oxygen, and over time your cardiovascular system responds by increasing the size of the heart and building new blood vessels. The cardiovascular changes are primarily a response to the physical challenges of exercise, which can enhance endurance. But what challenge elicits a response from the brain?
Answering this question requires that we rethink our views of exercise. People often consider walking and running to be activities that the body is able to perform on autopilot. But research carried out over the past decade by us and others would indicate that this folk wisdom is wrong. Instead exercise seems to be as much a cognitive activity as a physical one. In fact, this link between physical activity and brain health may trace back millions of years to the origin of hallmark traits of humankind. If we can better understand why and how exercise engages the brain, perhaps we can leverage the relevant physiological pathways to design novel exercise routines that will boost people’s cognition as they age—work that we have begun to undertake.
FLEXING THE BRAIN
To explore why exercise benefits the brain, we need to first consider which aspects of brain structure and cognition seem most responsive to it. When researchers at the Salk Institute for Biological Studies in La Jolla, Calif., led by Fred Gage and Henriette Van Praag, showed in the 1990s that running increased the birth of new hippocampal neurons in mice, they noted that this process appeared to be tied to the production of a protein called brain-derived neurotrophic factor (BDNF). BDNF is produced throughout the body and in the brain, and it promotes both the growth and the survival of nascent neurons. The Salk group and others went on to demonstrate that exercise-induced neurogenesis is associated with improved performance on memory-related tasks in rodents. The results of these studies were striking because atrophy of the hippocampus is widely linked to memory difficulties during healthy human aging and occurs to a greater extent in individuals with neurodegenerative diseases such as Alzheimer’s. The findings in rodents provided an initial glimpse of how exercise could counter this decline.
Following up on this work in animals, researchers carried out a series of investigations that determined that in humans, just like in rodents, aerobic exercise leads to the production of BDNF and augments the structure—that is, the size and connectivity—of key areas of the brain, including the hippocampus. In a randomized trial conducted at the University of Illinois at Urbana-Champaign by Kirk Erickson and Arthur Kramer, 12 months of aerobic exercise led to an increase in BDNF levels, an increase in the size of the hippocampus and improvements in memory in older adults.
Other investigators have found associations between exercise and the hippocampus in a variety of observational studies. In our own study of more than 7,000 middle-aged to older adults in the U.K., published in 2019 in Brain Imaging and Behavior, we demonstrated that people who spent more time engaged in moderate to vigorous physical activity had larger hippocampal volumes. Although it is not yet possible to say whether these effects in humans are related to neurogenesis or other forms of brain plasticity, such as increasing connections among existing neurons, together the results clearly indicate that exercise can benefit the brain’s hippocampus and its cognitive functions.
Researchers have also documented clear links between aerobic exercise and benefits to other parts of the brain, including expansion of the prefrontal cortex, which sits just behind the forehead. Such augmentation of this region has been tied to sharper executive cognitive functions, which involve aspects of planning, decision-making and multitasking—abilities that, like memory, tend to decline with healthy aging and are further degraded in the presence of Alzheimer’s. Scientists suspect that increased connections between existing neurons, rather than the birth of new neurons, are responsible for the beneficial effects of exercise on the prefrontal cortex and other brain regions outside the hippocampus.
UPRIGHT AND ACTIVE
With mounting evidence that aerobic exercise can boost brain health, especially in older adults, the next step was to figure out exactly what cognitive challenges physical activity poses that trigger this adaptive response. We began to think that examining the evolutionary relation between the brain and the body might be a good place to start. Hominins (the group that includes modern humans and our close extinct relatives) split from the lineage leading to our closest living relatives, chimpanzees and bonobos, between six million and seven million years ago. In that time, hominins evolved a number of anatomical and behavioral adaptations that distinguish us from other primates. We think two of these evolutionary changes in particular bound exercise to brain function in ways that people can make use of today.
For more, visit —-> Why Your Brain Needs Exercise – Scientific American
Having suffered a car accident, I had some serious injuries. These included my spine, nerves and my brain. I had foot drop, where when you raise your leg, you can not raise your foot from your ankle, leaving it to hang limply. That means you cannot put any weight on it and it will not offer any support or flexibility. On top of this, due tExerciseo a damaged nerve in my neck, and had weakness down my left side. However after 10 days, the hospital team got me walking with crutches, and sent me home.
I knew that I needed to do some exercise to help rebuild some of my strength. But what I didn’t know was how good exercise is for your brain as well.
We all know that the more you practise at something, the better you will get at it. Well, the brain is just the same. Every time you perform an action, you are creating the building blocks for a new pathway in your brain. Let me give you an example. I used to love painting and drawing. But following my brain injury, I could barely write legibly. For me this was depressing, as my art was a part of who I was. My partner James, kept badgering me to keep trying although I felt he just didn’t understand. I couldn’t make my hand follow the instructions I gave it properly, leaving me frustrated.
Exercise doesn’t mean you have to hit the gym. Just practise a physical activity.
So many sheets of paper ended up in the bin. (I would like to apologise to the trees who were sacrificed for my cause.) But in time my writing improved, and I found my artistic flair returning to me. Just by reminding the muscles in my hand and arm how to behave, I had begun to regain my skill. But it wasn’t because the muscles needed to be rebuilt, it was because my brain needed to create new pathways to replace those that were damaged. This is the same process as when you learn a skill for the first time, and why your mother always said “practise makes perfect.” The more we do an action, the more the brain prioritises building pathways which make a shortcut to that action.
Now I know you are saying “but Michelle drawing and writing isn’t exercise.” And yes you are right, but I wanted to share this example with you to help you see that although there is the physical muscles movements, there is much more that needs to happen and I think we can all agree agree creativity is something very much in your brain.
Think about how in sports there is a tactical element, spacial awareness, problem solving… the list goes on.
I’m now 5 years on from my accident, and most people wouldn’t notice my slight limp. For someone who struggled to walk for so long, that’s not bad. I still have nerve damage, and I may do for the rest of my life, but I can deal with it. I’d be frightened to go skiing again, but it doesn’t affect my everyday life much at all. Yes I get pain and tire much easier, but I can cope with that.
My brain is still trying to repair my cognitive skills. Bearing in mind I couldn’t read or write to start with, I think it’s fair to say it’s doing a pretty good job. I even set up this website all by myself even though I had no experience of doing this sort of thing before. (If you are thinking of starting a blog but aren’t sure where to start head over to Starting a blog following a brain injury is difficult, but it is achievable to get some ideas on how to get going.)
No matter what your fitness level, or sporting ability never underestimate the importance of exercise.
You don’t need to run like you’re Mo Farah, just find something you enjoy which you can fit into your busy schedule. Dance, yoga and swimming are all great options. As evidence is growing to show regular exercise can stave off dementia, your brain will thank you for it. We all have days when just getting out of bed is an achievement, so don’t feel any shame in taking it easy. But just remember your efforts will encourage enhancements in much more than just becoming physically stronger. Your mental health and general well being will benefit too. Exercise can help your brain injury recovery process and you might even discover a talent for something new that you never knew you had.
Other articles you may like:
What exercises have you found most beneficial following your brain injury?
[Abstract] A physical activity program is no more effective than standard care at maintaining upper limb activity in community-dwelling people with stroke: secondary outcomes from a randomized trial
To evaluate whether an 18-month, physical activity coaching program is more effective than standard care in terms of upper-limb activity.
The intervention group received follow-up visits and coaching on physical activity and exercise each month for 18 months after inclusion, by a physiotherapist. The control group received standard care.
The primary outcome, in this secondary analysis, was Motor Assessment Scale items 6, 7, and 8. Secondary outcomes were National Institute of Health Stroke Scale item 5, the Stroke Impact Scale domain 7, and the Modified Ashworth Scale in flexion/extension of the elbow.
In total, 380 persons with stroke were recruited, with mean (SD) age 72 (11) years, and baseline scores total National Institute of Health Stroke Scale was 1.4 (2.2)/1.6 (2.4) and Motor Assessment Scale items 6, 7 and 8 in the intervention/control group was 5.5 (1.2)/5.5 (1.2), 5.4 (1.4)/5.4 (1.3), and 3.6 (2)/3.5 (2), respectively. There was no significant difference between groups in terms of upper limb function in any of the Motor Assessment Scale items. In this population with minor stroke, upper-limb activity was good at three months post-stroke (74% of the maximum) and remained good 18 months later (77% of maximum).
via A physical activity program is no more effective than standard care at maintaining upper limb activity in community-dwelling people with stroke: secondary outcomes from a randomized trial – Birgitta Langhammer, Louise Ada, Mari Gunnes, Hege Ihle-Hansen, Bent Indredavik, Torunn Askim, 2019
[NEWS] New Virtual Reality Therapy game could offer relief for patients with chronic pain, mobility issues
A Virtual Reality Therapy game (iVRT) which could introduce relief for patients suffering from chronic pain and mobility issues has been developed by a team of UK researchers.
Dr Andrew Wilson and colleagues from Birmingham City University built the CRPS app in collaboration with clinical staff at Sandwell and West Birmingham Hospitals NHS Trust for a new way to tackle complex regional pain syndrome and to aid people living with musculoskeletal conditions.
Using a head mounted display and controllers, the team created an immersive and interactive game which mimics the processes used in traditional ‘mirror therapy’ treatment. Within the game, players are consciously and subconsciously encouraged to stretch, move and position the limbs that are affected by their conditions.
Mirror therapy is a medical exercise intervention where a mirror is used to create areflective illusion that encourages patient’s brain to move their limb more freely. This intervention is often used by occupational therapists and physiotherapists to treat CRPS patients who have experienced a stroke. This treatment has proven to be successful exercises are often deemed routine and mundane by patients, which contributes to decline in the completion of therapy.
Work around the CRPS project, which could have major implications for other patient rehabilitation programmes worldwide when fully realised, was presented at the 12th European Conference on Game Based Learning (ECGBL) in France late last year.
Dr Wilson, who leads Birmingham City University’s contribution to a European research study into how virtual reality games can encourage more physical activity, and how movement science in virtual worlds can be used for both rehabilitation and treatment adherence, explained, “The first part of the CRPS project was to examine the feasibility of being able to create a game which reflects the rehabilitation exercises that the clinical teams use on the ground to reduce pain and improve mobility in specific patients.”
“By making the game enjoyable and playable we hope family members will play too and in doing so encourage the patient to continue with their rehabilitation. Our early research has shown that in healthy volunteers both regular and casual gamers enjoyed the game which is promising in terms of our theory surrounding how we may support treatment adherence by exploiting involvement of family and friends in the therapy processes.”
The CRPS project was realized through collaborative working between City Hospital, Birmingham, and staff at the School of Computing and Digital Technology, and was developed following research around the provision of a 3D virtual reality ophthalmoscopy trainer.
Andrea Quadling, Senior Occupational Therapist at Sandwell Hospital, said “The concept of using virtual reality to treat complex pain conditions is exciting, appealing and shows a lot of potential. This software has the potential to be very helpful in offering additional treatment options for people who suffer with CRPS.”
[Abstract] Adherence to a Long-Term Physical Activity and Exercise Program After Stroke Applied in a Randomized Controlled Trial
[ARTICLE] Evaluation of a smartwatch-based intervention providing feedback of daily activity within a research-naive stroke ward: a pilot randomised controlled trial – Full Text
The majority of stroke patients are inactive outside formal therapy sessions. Tailored activity feedback via a smartwatch has the potential to increase inpatient activity. The aim of the study was to identify the challenges and support needed by ward staff and researchers and to examine the feasibility of conducting a randomised controlled trial (RCT) using smartwatch activity monitors in research-naive rehabilitation wards. Objectives (Phase 1 and 2) were to report any challenges and support needed and determine the recruitment and retention rate, completion of outcome measures, smartwatch adherence rate, (Phase 2 only) readiness to randomise, adherence to protocol (intervention fidelity) and potential for effect.
First admission, stroke patients (onset < 4 months) aged 40–75, able to walk 10 m prior to stroke and follow a two-stage command with sufficient cognition and vision (clinically judged) were recruited within the Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine. Phase 1: a non-randomised observation phase (to allow practice of protocol)—patients received no activity feedback. Phase 2: a parallel single-blind pilot RCT. Patients were randomised into one of two groups: to receive daily activity feedback over a 9-h period or to receive no activity feedback. EQ-5D-5L, WHODAS and RMI were conducted at baseline, discharge and 3 months post-discharge. Descriptive statistics were performed on recruitment, retention, completion and activity counts as well as adherence to protocol.
Out of 470 ward admissions, 11% were recruited across the two phases, over a 30-week period. Retention rate at 3 months post-discharge was 48%. Twenty-two percent of patients dropped out post-baseline assessment, 78% completed baseline and discharge admissions, from which 62% were assessed 3 months post-discharge. Smartwatch data were received from all patients. Patients were correctly randomised into each RCT group. RCT adherence rate to wearing the smartwatch was 80%. Baseline activity was exceeded for 65% of days in the feedback group compared to 55% of days in the no feedback group.
Delivery of a smartwatch RCT is feasible in a research-naive rehabilitation ward. However, frequent support and guidance of research-naive staff are required to ensure completeness of clinical assessment data and protocol adherence.
Exercise has an important role in the recovery of stroke, increasing cognition, arm function, balance and gait, in addition to reducing the risk of subsequent cardiovascular events [1, 2]. Despite the importance of general physical activity in recovery, the majority of stroke survivors receiving rehabilitation in hospital are inactive outside formal therapy sessions [3, 4]. In order to encourage long-term exercise adherence, it is recommended that physical activity goals are customised to the individual tolerance of the stroke patient .
Modern electronic activity monitors are able to provide a wide range of behavioural monitoring tools and are therefore emerging as a possible method to provide customised activity goals and feedback to promote exercise . Coinciding with the technological developments in activity monitoring, there is evidence to suggest that activity feedback of exercise may increase motivation to exercise. The provision of activity feedback has been found to be more effective in increasing physical activity levels than providing activity goals alone, in healthy controls [6–8] and in older adults undergoing rehabilitation . Interventions providing feedback and monitoring of activity have shown positive outcomes in relation to exercise adherence amongst older individuals . However, personalised activity feedback has also found to have no effect on actual or intended activity levels amongst controls . Despite studies suggesting a positive effect, more evidence is needed before such activity feedback interventions can be recommended to be used in treatment.
The literature has shown that remote monitoring of physical activity is feasible after stroke ; however, the impact of activity feedback on exercise levels within this population is less clear. A systematic review of studies investigating augmented feedback on motor activities after stroke concluded that findings were inconsistent due to the combination of multiple aspects and types of augmented feedback used . One study found that feedback of physical activity provided three times a week had no significant effect on the daily walking time of stroke inpatients . Little research to date has investigated the use of periodic feedback of daily activity amongst stroke patients undergoing rehabilitation. It is of interest to see whether increasing the frequency of activity feedback will elicit greater physical activity levels. The provision of daily activity feedback (via a smartwatch), relative to activity at fixed time points through-out the previous day, may have the potential to motivate stroke rehabilitation patients to be more active.
Conducting clinical trials within research-naive settings are commonly accompanied with ethical, cultural and organisational challenges . The present study will evaluate the feasibility of conducting the smartwatch intervention mentioned above within a research-naive stroke rehabilitation centre in Hefei, China (whereby no rehabilitation research has previously been conducted).
The aim of this feasibility study was to identify the challenges and support needed by ward staff and researchers and to examine the feasibility of conducting an RCT using smartwatch activity monitors in research-naive rehabilitation wards. The objectives were to report any challenges and support needed and determine the recruitment and retention rate, completion of outcome measures, adherence to wearing the smartwatch, readiness to randomise, adherence to protocol (intervention fidelity) and potential for effect.[…]
What’s the most transformative thing that you can do for your brain today? Exercise! says neuroscientist Wendy Suzuki. Get inspired to go to the gym as Suzuki discusses the science of how working out boosts your mood and memory — and protects your brain against neurodegenerative diseases like Alzheimer’s.
This talk was presented at an official TED conference, and was featured by our editors on the home page.
What if I told you there was something that you can do right now that would have an immediate, positive benefit for your brain including your mood and your focus? And what if I told you that same thing could actually last a long time and protect your brain from different conditions like depression, Alzheimer’s disease or dementia. Would you do it? Yes!
I am talking about the powerful effects of physical activity. Simply moving your body,has immediate, long-lasting and protective benefits for your brain. And that can last for the rest of your life. So what I want to do today is tell you a story about how I used my deep understanding of neuroscience, as a professor of neuroscience, to essentially do an experiment on myself in which I discovered the science underlying why exercise is the most transformative thing that you can do for your brain today. Now, as a neuroscientist, I know that our brains, that is the thing in our head right now, that is the most complex structure known to humankind. But it’s one thing to talk about the brain,and it’s another to see it.
So here is a real preserved human brain. And it’s going to illustrate two key areas that we are going to talk about today. The first is the prefrontal cortex, right behind your forehead, critical for things like decision-making, focus, attention and your personality.The second key area is located in the temporal lobe, shown right here. You have two temporal lobes in your brain, the right and the left, and deep in the temporal lobe is a key structure critical for your ability to form and retain new long-term memories for facts and events. And that structure is called the hippocampus. So I’ve always been fascinated with the hippocampus. How could it be that an event that lasts just a moment, say, your first kiss, or the moment your first child was born, can form a memory that has changed your brain, that lasts an entire lifetime? That’s what I want to understand. I wanted to start and record the activity of individual brain cells in the hippocampus as subjects were forming new memories. And essentially try and decode how those brief bursts of electrical activity, which is how neurons communicate with each other, how those brief bursts either allowed us to form a new memory, or did not.
But a few years ago, I did something very unusual in science. As a full professor of neural science, I decided to completely switch my research program. Because I encountered something that was so amazing, with the potential to change so many lives that I had to study it. I discovered and I experienced the brain-changing effects of exercise. And I did it in a completely inadvertent way. I was actually at the height of all the memory work that I was doing — data was pouring in, I was becoming known in my field for all of this memory work. And it should have been going great. It was, scientifically. But when I stuck my head out of my lab door, I noticed something. I had no social life. I spent too much time listening to those brain cells in a dark room, by myself. (Laughter) I didn’t move my body at all. I had gained 25 pounds. And actually, it took me many years to realize it, I was actually miserable. And I shouldn’t be miserable. And I went on a river-rafting trip — by myself, because I had no social life.And I came back —
thinking, “Oh, my God, I was the weakest person on that trip.” And I came back with a mission. I said, “I’m never going to feel like the weakest person on a river-rafting trip again.” And that’s what made me go to the gym. And I focused my type-A personalityon going to all the exercise classes at the gym. I tried everything. I went to kickbox, dance, yoga, step class, and at first it was really hard. But what I noticed is that after every sweat-inducing workout that I tried, I had this great mood boost and this great energy boost. And that’s what kept me going back to the gym. Well, I started feeling stronger. I started feeling better, I even lost that 25 pounds.
And now, fast-forward a year and a half into this regular exercise program and I noticed something that really made me sit up and take notice. I was sitting at my desk, writing a research grant, and a thought went through my mind that had never gone through my mind before. And that thought was, “Gee, grant-writing is going well today.” And all the scientists —
yeah, all the scientists always laugh when I say that, because grant-writing never goes well. It is so hard; you’re always pulling your hair out, trying to come up with that million-dollar-winning idea. But I realized that the grant-writing was going well,because I was able to focus and maintain my attention for longer than I had before.And my long-term memory — what I was studying in my own lab — seemed to be better in me. And that’s when I put it together.
Maybe all that exercise that I had included and added to my life was changing my brain. Maybe I did an experiment on myself without even knowing it. So as a curious neuroscientist, I went to the literature to see what I could find about what we knewabout the effects of exercise on the brain. And what I found was an exciting and a growing literature that was essentially showing everything that I noticed in myself.Better mood, better energy, better memory, better attention. And the more I learned,the more I realized how powerful exercise was. Which eventually led me to the big decision to completely shift my research focus. And so now, after several years of really focusing on this question, I’ve come to the following conclusion: that exercise is the most transformative thing that you can do for your brain today for the following three reasons.
Number one: it has immediate effects on your brain. A single workout that you do will immediately increase levels of neurotransmitters like dopamine, serotonin and noradrenaline. That is going to increase your mood right after that workout, exactly what I was feeling. My lab showed that a single workout can improve your ability to shift and focus attention, and that focus improvement will last for at least two hours.And finally, studies have shown that a single workout will improve your reaction timeswhich basically means that you are going to be faster at catching that cup of Starbucks that falls off the counter, which is very, very important.
But these immediate effects are transient, they help you right after. What you have to do is do what I did, that is change your exercise regime, increase your cardiorespiratory function, to get the long-lasting effects. And these effects are long-lasting because exercise actually changes the brain’s anatomy, physiology and function. Let’s start with my favorite brain area, the hippocampus. The hippocampus —or exercise actually produces brand new brain cells, new brain cells in the hippocampus, that actually increase its volume, as well as improve your long-term memory, OK? And that including in you and me.
Number two: the most common finding in neuroscience studies, looking at effects of long-term exercise, is improved attention function dependent on your prefrontal cortex. You not only get better focus and attention, but the volume of the hippocampus increases as well. And finally, you not only get immediate effects of mood with exercise but those last for a long time. So you get long-lasting increases in those good mood neurotransmitters.
But really, the most transformative thing that exercise will do is its protective effects on your brain. Here you can think about the brain like a muscle. The more you’re working out, the bigger and stronger your hippocampus and prefrontal cortex gets. Why is that important? Because the prefrontal cortex and the hippocampus are the two areas that are most susceptible to neurodegenerative diseases and normal cognitive decline in aging. So with increased exercise over your lifetime, you’re not going to cure dementia or Alzheimer’s disease, but what you’re going to do is you’re going to create the strongest, biggest hippocampus and prefrontal cortex so it takes longer for these diseases to actually have an effect. You can think of exercise, therefore, as a supercharged 401K for your brain, OK? And it’s even better, because it’s free.
And so I’m going to tell you the answer to that question. First, good news: you don’t have to become a triathlete to get these effects. The rule of thumb is you want to get three to four times a week exercise minimum 30 minutes an exercise session, and you want to get aerobic exercise in. That is, get your heart rate up. And the good news is, you don’t have to go to the gym to get a very expensive gym membership.Add an extra walk around the block in your power walk. You see stairs — take stairs.And power-vacuuming can be as good as the aerobics class that you were going to take at the gym.
So I’ve gone from memory pioneer to exercise explorer. From going into the innermost workings of the brain, to trying to understand how exercise can improve our brain function, and my goal in my lab right now is to go beyond that rule of thumb that I just gave you — three to four times a week, 30 minutes. I want to understand the optimum exercise prescription for you, at your age, at your fitness level, for your genetic background, to maximize the effects of exercise today and also to improve your brain and protect your brain the best for the rest of your life.
People with epilepsy (PWE) are less physically active compared with the general population. Explanations include prejudice, overprotection, unawareness, stigma, fear of seizure induction and lack of knowledge of health professionals. At present, there is no consensus on the role of exercise in epilepsy. This paper reviews the current evidence surrounding the risks and benefits associated with physical activity (PA) in this group of patients. In the last decade, several publications indicate significant benefits in physiological and psychological health parameters, including mood and cognition, physical conditioning, social interaction, quality of life, as well as potential prevention of seizure presentation. Moreover, experimental studies suggest that PA provides mechanisms of neuronal protection, related to biochemical and structural changes including release of β-endorphins and steroids, which may exert an inhibitory effect on the occurrence of abnormal electrical activity. Epileptic discharges can decrease or disappear during exercise, which may translate into reduced seizure recurrence. In some patients, exercise may precipitate seizures. Available evidence suggests that PA should be encouraged in PWE in order to promote wellbeing and quality of life. There is a need for prospective randomized controlled studies that provide stronger clinical evidence before definitive recommendations can be made.