Forget the stair master, brown fat is where the burn is at

There has been a flurry of articles recently about the rise in research on brown adipose tissue (BAT), endogenous body fat that contains higher levels of mitochondria and is used to help keep the body warm. Until only three years ago, this holy grail of body tissues ("good" fat that burns significantly more calories and can help rid the body of "bad" fat) was thought to exist only in rodents, where it was more commonly seen in the young and in thinner animals. However, BAT has also been seen in human infants, important in helping to keep newborns warm as they can not shiver to create their own body heat. BAT was thought to gradually disappear as individuals aged, but it is now believed that adults can retain small levels of their brown fat from childhood, with thinner individuals maintaining more, and that exercise can aid in this retention.

Mental and physical exercise: Alternatives to dopamine treatment in Parkinson's disease

A variety of studies have arisen recently touting unconventional methods for treating Parkinson's disease. Parkinson's is caused by damage to the neurons in the substantia nigra (SN), a region of the basal ganglia that is responsible for creating much of the brain's dopmaine. Dopamine is an essential neurotransmitter in a variety of behavioral and motivational mechanisms, often implicated in reward and addiction, however it is also a key component of the motor system. Feedback loops from the cortex to the basal ganglia circulate information about whether to initiate or inhibit a movement, and these cicuits are greased by dopamine, activating the excitatory loop and suppressing the inhibitory one. However, without adequate dopamine the system comes to a stalemate, making the initiation of movement much more difficult and causing the hesitation, trembling, and inertia characteristic of Parkinson's. Common treatments for Parkinson's include flooding the brain with dopamine agonists or the dopamine precursor L-DOPA. This helps to boost dopamine levels in the brain, causing the remaining healthy SN neurons to produce and fire greater amounts of the neurochemical, attempting to make up for the deficit from the impairment of the other cells. However, there are currently no treatments to prevent the progressive cell death in the SN, and in advanced stages it is difficult to compensate for the abundant cell loss. Excess "artificial" dopamine in the brain can also result in the downregulation of other dopamine producing and receiving cells, the brain adjusting to the new flood of dopamine by reducing its endogenous production and receptor sensitivity in an attempts to return to a dopaminergic homeostasis. Additionally, it is impossible to localize dopamine agonists to the motor regions of the brain, meaning that many Parkinson's patients treated with dopamine come to display symptoms similar to those seen in impulse control disorders, which are also commonly rooted in a widespread dysregulated dopamine system. These can include the development of compulsive gambling and shopping problems, sexually deviant behavior, and drug addiction.

Given the obvious shortcomings in the current treatment options, the need for alternative therapies for Parkinson's is widely acknowledged. Two labs taking on this problem have recently published results on alternative treatments that do not involve pharmacological challenge and instead target a patient's motor efficacy, one increasing the patient's control and the other withdrawing it.

The first, published in the Journal of Neuroscience, suggests that self-regulation of brain activity facilitated by real-time fMRI feedback can increase brain activation and decrease Parkinson's symptoms. Focusing on the supplementary motor region, an area of cortex that has direct connections with basal ganglia pathways and that is commonly shown to have diminished activity in Parkinson's, researchers at the University of Cardiff had patients mentally activate this region using motor imagery while in the fMRI scanner. Patients in the experiment group received direct feedback on their activation levels during the trials via a thermometer display, whereas those in the control group did not have any indication of their success at mentally activating the area. The patients who received the real-time feedback were able to activate the supplementary motor region to a greater extent than those who did not, successfully upregulating this area as well as other brain regions associated with the motor system. They also significantly improved their ability on a motor function test and a subjective assessment of Parkinson's symptoms, whereas control participants did not. Researchers speculate that this increase in activity and subsequent improvement in symptoms is due to a greater excitation of compensatory motor pathways, strengthening these connections and facilitating the activity of the under-utilized basal ganglia circuitry.

The second method, published in Exercise and Sport Sciences Reviews, takes an alternative approach, deliberately taking the control out of the hands (or legs) of the participants. Researchers at the Cleveland Clinic in Ohio are investigating the idea that forced exercise, with exertion levels out of the patient's control, can be more effective in treating Parkinson's symptoms than voluntary physical activity. Led by Dr. Jay Alberts, researchers had patients ride on the back of tandem bicycles where the energy output was set at 50% higher than the patients' comfortable self-selected effort levels. After eight weeks at the greater energy expenditure, patients had a significant decrease in tremors and other motor symptoms, which lasted for approximately one month after treatment was stopped. Additionally, the benefits seen were not just a result of localized increased muscle tone or coordination as has been the case in previous studies investigating the effects of exercise in Parkinson's. Instead, participants showed improvements in movement throughout the body, as well as increased neural activity during MRI scans of the basal ganglia and cortex. Researchers are as yet unsure of the basis for these improvements, though the emotional and cognitive benefits of exercise are widely known. In an interview with the New York Times, Dr. Alberts speculated that the effects could stem from the release of stress hormones during exercise, which can trigger the neurochemical systems and are more active during forced or very high intensity activities than comfortable voluntary levels of exertion.

While these studies are still only addressing the symptoms rather than the root of the problem, they do provide new evidence for treatment options beyond the standard fair. Importantly, neither of these methods comes with any of the adverse side effects of dopaminergic treatments, which can severely undermine the efficacy and quality of life improvements for patients with Parkinson's disease. Further research is of course always needed, and certainly these methods would need to be used in tandem with current drug therapies, but these studies present an interesting alternative to complete reliance on pharmacological medication to treat the symptoms of neurological disorders.

A neural workout

Last week I wrote about some of the emotional benefits of regular moderate exercise. This week, several timely new articles have come out touting the cognitive advantages of even minimal daily activity. Numerous studies have shown evidence of the neurological benefits of exercise, which can foster cell growth and new cell generation (known as neurogenesis). One region that seems to be particularly impacted is the hippocampus, an area known to be involved in memory consolidation. Prior studies in mice have shown that exercise can trigger neurogenesis in the hippocampus, and in humans exercise has been linked to better performance on memory assessments and spatial learning, as well as a decreased risk for dementia. While some of these benefits are believed to be due to the new proliferation of cells in the hippocampus and other associated regions of the brain, several studies published recently suggest that exercise may serve more as a protective factor against neurological decay than boosting existing memory performance.

study presented last week at the Alzheimer's Association International Conference by doctors at the University of California, San Francisco used mathematical modeling to estimate risk factors for the development of Alzheimer's disease, and came up with seven critical variables: diabetes, hypertension, obesity, smoking, depression, cognitive inactivity, low education, and physical inactivity. Researchers predicted that these seven variables were to blame in nearly 50% of the current cases of Alzheimer's present today, and lack of exercise alone was attributed to over 20% of cases. In addition, researchers predicted that reducing these risk factors could potentially stave off over one million future cases. However, these numbers are theoretical and first author Dr. Deborah Barnes, as well as other lead researchers in the field, are careful to caution against using these numbers as hard goals and guidelines. Barnes notes that while these seven factors do increase the risk for Alzheimer's, a causal relationship has not yet definitively been established, and therefore simply changing one's behavior in regards to one or all of the variables may not be enough to prevent onset of the disease.

While the association between Alzheimer's and exercise is still tentative, there is certainly little doubt about the mental and physical benefits of daily activity. However, previous studies have largely focused on moderate to high levels of exercise in humans and animals, such as the widely recommended guidelines of 30 minutes of exertion 5 days a week. But what about those who cannot get out that much or that often? Fortunately there is new evidence that the cognitive benefits of daily activity can come from even minimal movement, akin to the normal amounts of daily exertion put forth via walking, household chores, and even fidgeting. In a longitudinal study investigating elderly adults aged 70 and up, those with the least amount of daily average energy expenditure had the greatest amounts of cognitive decline over a period of three years, whereas those who were most active had significantly less cognitive impairment both over the three year study period, as well as after a five-year follow-up. It seems that even small efforts such as walking around the block or even moving around the house, which often go unreported in other studies of physical activity, can help stave off the neural deterioration that commonly occurs as we progress into old age.

However, if you still can't be bothered to get up and start moving, you can always resort to surgical implants and get one of these to improve your memory.

Exercise, endocannabinoids and natural highs

The benefits of exercise on the mind and the body are widely pronounced, with even moderate amounts decreasing the risk for heart disease, stroke, diabetes, dementia, depression, aggression and Alzheimer's, to name a few. Those of us who exercise regularly may also know first hand of the almost immediate mood enhancing benefits of exercise, often touted as "runner's high". However, the exact mechanisms for this emotional boost are still unknown. Once believed to be the result of endorphins, natural opioid peptides released in the body that resemble synthetic opiates, working as analgesics and creating feelings of euphoria, this idea has recently come under scrutiny. The molecules creating these opioid peptides are too large to pass through the blood-brain barrier, meaning that endorphins released in the blood stream during exercise would be unable to make their way into the brain. However, a different endogenous drug system has begun to garner attention, and some researchers are instead now focusing on endocannabinoids, the organic derivative of cannabis, or marijuana, found in the body. Endocannabinoids are made up of lipids, which are small enough to pass through the blood-brain barrier when released in the blood stream, and have similar effects of reducing pain and anxiety and fostering feelings of well-being. A number of studies published in recent years (and succinctly summarized here by the New York Times), have looked at the endocannabinoid system and exercise in mice and have found strong links between the two. Neuroscientists in Rome using single cell recordings in the striatum (the region touted as the pleasure center of the brain) discovered that both running and sucrose consumption increased the sensitivity of cannabinoid receptors in the striatum, indicating a greater activation of the pleasure system. This upregulation in cannabinoid transmission also helped to serve as a protective factor for the mice when stressors were introduced into the environment, providing neurological support for the claims that exercise can have strong emotional benefits, preventing stress, anxiety and depression.

Another study investigating the pleasurable effects of running researched mice specifically bred without cannabinoid receptors in the brain. Researchers in France discovered that mice deficient in cannabinoid receptors ran 30-40% less over the course of a week than normal mice. Taken with the other mood-enhancing benefits of running, this further suggests that endocannabinoids are involved in the pleasure derived from exercise.

A seemingly paradoxical alternative effect of endocannabinoids is their role in eating as well as exercise. Endocannabinoids are responsible for some of the pleasure derived from food, and in addition to the analgesic and anxiolytic effects, medicinal marijuana is also used to stimulate patients’ appetite, which can be affected by terminal illnesses or treatment. Recently, a team of scientists at the University of California, Irvine discovered that endocannabinoids not only provoke hunger and provide pleasure when we eat, but also increase desire and urges for fatty foods in particular. In a study published this month in PNAS, researchers fed rats a sham liquid diet high in fat content (sham diets work by draining the contents of the stomach before the meal is digested, meaning that only the taste and act of consumption are registered, not the actual nutritional value or satiety signals). The diet high in fat, but not ones of primarily sugar or protein, selectively increased levels of endocannabinoids in the intestines. However, when the vagus nerve (responsible for taste) was cut, this increase of endocannabinoids in the stomach did not occur. This suggests that it is the taste sensation of the fat and communication from the brain to the GI tract that elicits this release. This elevation of endocannabinoids also affected metabolic processes in the stomach, creating a feedback loop where signals were sent back to the brain creating a greater demand for more high fat foods. Conversely, when endocannabinoid antagonists (drugs that decrease the amount of endocannabinoids in the body) were given to the rats, they selectively consumed less high fat solution, but did not alter intake of their normal food chow. This study provides strong evidence for the fat-specific effect endocannabinoids have on appetite and craving, potentially creating a perpetuating cycle of demand and consumption of high fat foods.

The paradoxical effects of endocannabinoids on the brain suggest that they have much to do with pleasure, and while they may encourage a binge on potato chips, at least they will also help you enjoy burning them off afterwards.