Most studies investigating the relationship between various types of exercise and brain function are focused on its effect on Alzheimer disease risk, memory loss associated with aging or chronic impact on various cognitive functions. Rarely have investigations been concerned with changes related to an acute bout of exercise on cognitive function.

As we have seen, an endogenous substance that plays a central role in the health of neurons is brain-derived neurotrophic factor (BDNF). Acting via CREB (Cyclic AMP Response Element Binding Protein), BDNF can produce improvements in a finding called long term potentiation (LTP) which is a physiologic correlate of memory. Exercise training in animal studies is associated with elevation of BDNF. BDNF produces enhanced connectivity between nerve cells that improves brain function. Human studies have not examined biochemical compounds involved in acute exercise-induced improvements in cognitive function. A recent human trial investigated the effects of acute exercise on BDNF levels in blood and their relationship with associated cognitive functional improvements.

The exercise protocol involved riding an bicycle in an exercise physiology lab for about 30 minutes. Cognitive testing was done using the Stroop Test. It requires the subject to read 100 words as fast as possible. The words are "RED", "GREEN" or "BLUE". Each word is a different color, either red, green or blue but the color and the word can not be the same such as RED and the color red. Thus the word RED could be printed in green or blue ink, but not red ink. The test requires the subject to say the color of the word, not what the letters spell. Hence the word BLUE, printed in green, would require a response of "green". The greater the number of correct responses, the better the score.

BDNF levels were measured before the cycling and immediately thereafter.  BDNF levels were elevated 13% after the single exercise trial compared to baseline levels. The Stroop Test results also improved significantly after the cycling. This study demonstrates that strenuous physical activity induced a simultaneous increase in blood BDNF concentrations and function on the Stroop Test. It should be mentioned that in animal studies there is a close correlation between brain and blood BDNF changes after exercise implying that the changes of BDNF measured in blood are reflected in the brain..

Since BDNF has also been associated with enhanced learning in animal studies, in conjunction with the current findings cognitive activities following strenuous exercise might be expected to produce similar findings. This suggests possible mechanisms for orchestrating exercise and mentally challenging tasks for improved results. 

 

Physical activity has been associated with many healthy benefits including reductions in cardiovascular disease, colon and breast cancer, diabetes and obesity. Despite these robust effects, 75% of adults in the United States do not meet currently recommended guidelines for exercise. Estimates indicate that such inactivity was associated with health costs of $76 billion dollars in the United States in 2000. In addition to the physical and economic impact of a sedentary lifestyle, there is an emerging body of scientific research suggesting a connection between exercise and improved brain health and function. Although most of the investigations have evaluated aging humans, some recent studies have investigated the impact of physical activity on cognitive performance in children.

A meta-analysis of studies in school-age children found a positive relationship between level of activity and a number of measures of cognition (perceptual skills, IQ, achievement, verbal tests, math tests, memory, developmental level and academic readiness).

Recently, primarily due to the importance placed on standardized testing, many schools have reduced or done away with physical education (PE) requirements in an effort to ostensibly increase available time for scholastic pursuits. At odds with this mindset are recent studies indicating that performance on standardized tests of mathematics and reading were related to physical fitness scores. Fitness is linked to functioning of the fronto-parietal parts of the brain so it is not surprising that both math and reading elicit activation in this same neural network.

In adults, results from similar types of meta-analyses investigating exercise and cognitive processing reveal several key findings. First, physical activity has a beneficial impact on cognition. Second, chronic activity improves function in both normal adults and patients with early signs of Alzheimer disease. Third, exercise positively affects a broad range of cognitive variables. Fourth, the degree of improvement varies among mental modalities with some (such as executive control processes including scheduling, working memory, multi-tasking and dealing with ambiguity) showing disproportionately larger effects. This is exciting since these executive functions, and the brain regions that mediate them, tend to show age-related deterioration and these findings suggest that such changes may be amenable to intervention.

Consistent with these conclusions, MRI (Magnetic Resonance Imaging) studies have been used to asses the effects of fitness on brain anatomy. Typical findings reveal that higher levels of activity are associated with larger volumes of grey matter in the prefrontal and temporal brain regions as well as increased volume in the anterior white matter. These observations are important because such increases are predictive of better performance in older adults.

Taken together, these data suggest that physical activity can have beneficial effects throughout the lifespan, even for individuals with neurodegenerative disease. Animal studies in this field have documented increased angiogenesis (number of blood vessels) and enhanced formation of synapses (the connections between nerve cells) and neurogenesis (formation of new nerve cells). Decreases in each of these measures have been documented in Alzheimer brains. Hence, researchers appear to be telling us that breaking a sweat on a regular basis is a tonic for our brain.

 

 

Acetylcholine is a neurotransmitter compound (brain chemical that allows nerve cells to speak with one another) associated with memory function. The link between acetylcholine levels in the brain and memory function is so tight that a group of medications mimicking the effect of acetylcholine are used as drugs for memory disorders, dementia and Alzheimer disease (AD). Hence, the findings of CDR Jack Tsao, USN, associate professor for the Uniformed Services University of the Health Sciences' (USU) Department of Neurology linking the use of anti-cholinergic (meaning drugs that block the action of acetylcholine and related compounds) drugs such as medications used in the treatment for stomach cramps, ulcers, motion sickness, overactive bladder and other conditions, to a more rapid decline in cognitive ability in older people comes as no surprise.

His study investigated the effects of consumption of medications with anti-cholinergic actions on the mental status of 870 Catholic nuns and clergy members who were about 75 years old.They underwent annual cognitive testing. In the study, 679 people took at least one medication with anti-cholinergic activity. The results revealed an association between the use of these medications and a decline in cognitive function that was 1.5 times as rapid as those who did not take the drugs.

"Our findings point to anti-cholinergic drugs having an adverse impact on cognitive performance in otherwise normal, older people," said Jack Tsao, M. D. "Doctors may need to take this into account before prescribing these commonly used drugs." Tsao noted that more research is required to define the exact mechanisms responsible for the rapid memory loss apparently associated with anti-cholinergic drugs and to identify which drugs were the primary offenders.

The study concept arose when one of the lead authors, Kenneth Heilman, M. D.,was evaluating a patient with memory complaints and hallucinations. Her cognitive testing was essentially normal with the exception of some memory issues. She didn't fit the criteria for Alzheimer-type dementia. However, she had just begun therapy with tolterodine (Detrol) a drug used to treat over-active bladder and urinary incontinence. After stopping the medication, her memory problems improved. When they reviewed the medical literature, they found that many medications that are not advertised as anti-cholinergic actually have anti-cholinergic properties when tested.

Anti-cholinergic medications range from the overactive-bladder drugs to anti-Parkinsonian agents, anti-spasmodic drugs for the bowel, ulcer medicines, antihistamines and other drugs with less well-known anti-cholinergic activity including lasix, coumadin and ranitidine (Zantac). Examples of some of these drugs are as follows:

Clidinium (Quarzan)

Dicyclomine (Bentyl)

Oxybutynin (Ditropan)

Amitriptyline (Elavil)

Imipramine (Tofranil)

Carbamazeine (Tegretol)

Cyclobenzaprine (Flexeril)

Orphenadrine (Norflex)

Trihexyphenidyl (Artane)

Benztropine (Cogentin)

Chlorpheniramine (Chlortrimeton)

Brompheniramine (Dimetane)

Cyproheptadine (Periactin)

Diphenhydramine (Benadryl)

Chlorpromazine (Thorazine)

Olanzapine (Zyprexa)

Transderm Scop (Scopolamine)

Solifenacin (Vesicare)

Check with your health care provider to see if there are alternatives to these drugs if any of these names are medications you are taking.

 

The cognitive abilities of older persons vary dramatically. There are tell tale signs in the brain that doctors use to make a definitive diagnosis of Alzheimer Disease (AD). These are referred to as "plaques" and "tangles." When they achieve a threshold degree and distribution, the neuropathologist doing the examination establishes that the brain findings are consistent with the diagnosis of AD. Interestingly, it has been established in many studies that approximately 40% of the subjects whose brains house this degree of pathology on post mortem exam have no evidence of mental impairment. This suggests that some brains are able to tolerate these potentially devastating findings much better than others. The "Million Dollar Question" is why. At present, the neurobiologic basis for this robust observation is not well understood.

The concept of "compensation" is commonly applied to many organ systems throughout the body and is an important determinant of health outcomes. When a relative donates a kidney, for example, the donor experiences no loss of renal function because of the large amount of reserve function in the remaining kidney. Hence, it easily compensated for the loss of its neighbor. The only change observed is that it may enlarge slightly over ensuing months due to enhanced physiologic demands. Is it possible that similar changes can occur in the brain.

Brain transplants have not been performed, at least yet. However, interesting findings noted on functional brain scans such as PET (Positron Emission Tomography) scans and fMRI (functional Magnetic Resonance Imaging) scans suggest there is an innate ability of one part of the brain to compensate for diminished function elsewhere. Thus, the brain, de facto, has a component of brain reserve. This is consistent with the notion that the functional organization of the brain is felt to be redundant. In addition, it has been postulated that there are differences between brains in their efficiency and ability to respond to certain environmental challenges.

Neuroimaging data of the type just mentioned support this view. When performing a cognitive task, aging is associated with lower activation of brain regions used by young subjects while performing the same task, and increased activation in other regions. This phenomenon has been interpreted as demonstrating compensation by alternate networks. Surprisingly, a similar pattern of brain activation has been observed in both young patients with mild AD and older subjects without AD. The implication is that the process of compensation (manifested by the engagement of additional brain resources) is a normal process during aging and in pathologic states such as AD (and presumable stroke, head injury and other disease states).

The concept of brain reserve was first referenced in a study of individuals with high levels of AD pathology post mortem who remained nondemented in life and had almost twice the number of neurons throughout their cerebral cortex in comparison to those who developed mental symptoms. It was felt that "those people might have started with a larger brain and more neurons and thus might be said to have a greater reserve."This neurocentric version of reserve relies on a genetically endowed advantage based on increased neuronal numbers.

Another perspective regarding brain reserve involves the concept of "neurocomputational flexibility" wherein certain individuals who have developed a range of cognitive strategies for solving complex problems are more likely to remain normal cognitively for longer despite progression of underlying disease. They may also have a greater number of potential neural pathways for execution of these cognitive processes, thus permitting maintenance of function despite neurological insult. In essence, this suggests that an individual who utilizes a specific brain network more efficiently, or is able to bring alternative brain networks on-line in response to increased demand may thus have greater brain reserve. Such a construct links brain reserve with performance of complex mental activities, increased neural and synaptic (a synapse is the point where one nerve cell contacts another) numbers and consequently enhanced brain function.

Numerous population-based cohort studies have examined the link between complex mental activity and risk of developing dementia. When analyzed together, they revealed an overall risk reduction of 46%. The separate effects of education, occupational complexity and cognitive lifestyle activities were similar in magnitude. The issue is whether such mental activity-related dementia risk remains modifiable in late life. Interestingly, participation in cognitive and social lifestyle activities in later life (independent of either education or occupational experiences) showed significant (50-66%) protection against risk of dementia.

What are the possible mechanisms behind this robust effect? Mental stimulation is a strong stimulator for the generation of a neurochemical called BDNF (Brain-Derived Neurotrophic Factor) and Nerve Growth Factor (NGF). They play critical roles in nerve cell survival, neuronal connectivity, resistance to disease and learning and memory. An enriched mental environment increases generation of new synapses by 150-200%. This effect is especially important for dementing illnesses because of the dramatic loss of synapses in these disorders. Even more intriguing is the suggestion that mental activity may diminish the production of AD neuropathology. These insights are potent incentives to engage in a mentally active lifestyle to ensure a vibrant future life.

During the billions of years of human (and pre-human) evolution, time has been divided into daily, seasonally, and yearly repeating cycles. Based on these imposed cycles, biological processes have developed that have enabled organisms to exploit temporal niches in their environment and to coordinate physiological responses to optimize metabolic efficiency and survival.

In humans, because of evolutionary pressures, these rhythms have become entrained within our nervous systems. They are generated by the approximately 20,000 neurons located in the master clock in the suprachiasmatic nucleus (SCN) of the brain. It’s proximity to the optic nerves (the nerves connecting the eyes to the brain) is not surprising given the role the day-night (light-dark) cycle plays in this physiology. Its nexus with a part of the brain called the hypothalamus, the region that monitors and controls the body's internal milieu (fluid and electrolyte balance, temperature regulation, and hormonal status, etc.) has important implications as well.

The pacemakers for these rigidly regulated functional ebbs and flows are generated endogenously within the network of SCN nerve cells. More interestingly, each cell in this grouping has intrinsic clock-like abilities incorporated within its genetic makeup. Specific genes (referred to as clock genes) generate the rhythm. This is done using a biological trick called a negative feed back loop. It works as follows. The gene turns on and does what genes do. That is, it creates a protein that is released within the cell. Among other duties, this protein then interacts with the gene that created it and in so doing, turns it off. This process is repeated over and over again. The time it takes for one complete cycle is 24 hours. This nifty process constitutes the molecular basis for the biological clock that forms the basis for the circadian (within a day) cycles that coordinate many bodily processes. Circadian rhythmicity is abolished by damage to the SCN.

These clock genes, and their associated daily cycles, are genetically conserved over numerous species. They play vital roles in many biological phenomena including metabolism, hormonal regulation, fertility/reproduction, thermoregulation, bone formation, fat accumulation and sleep-wake cycles. As such, alterations in circadian periodicity might affect these processes. Mood disorders are even associated with rhythm disruption and clock gene variations. Under conditions of constant light or constant darkness, the synchronicity of the SCN neurons is lost. “Jet lag” seems to be a likely consequence of this environmentally induced perturbation. The advent of the “24 hour society” likely has had adverse impacts on the SCN and probably contributes to the prevalence of sleep disorders estimated to affect 20% of Americans.

In the regulation of hormonal function, timing is everything. This depends intimately on the internal clock mechanism that orchestrates the synthesis, secretion and control of hormones. It is well-known that differing exposure to light modulates hormonal regulation and melatonin levels. Other environmental stimuli such as social signals, poor nutrition, physical activity levels, sleep habits and stress produce effects that are integrated in to the functioning of this intricately balanced system. Common examples of adverse effects are altered menses, infertility, mood swings and difficulty concentrating and learning. Cortisol, the “stress” hormone can single-handedly reset the circadian clock.

It should be obvious that changes in many of the factors discussed above can induce functional alterations in our biological clock mechanism producing adverse health changes in many bodily systems.

 

 

There is increasing evidence for the presence of vitamin D, its receptor (VDR), and enzymes that activate vitamin D (change its chemical structure so it becomes biologically active in cells) in brain cells (neurons), brain supporting cells (glial cells, which outnumber neurons 10:1), spinal neurons and peripheral nerves in the arms and legs. These findings support roles for vitamin D in nervous system development and function. Such observations initiated a significant paradigm shift from vitamin D as the hormone that increased the absorption of calcium from the intestines to a hormone with systemic (throughout the entire body) actions.

On the microscopic scale, vitamin D is able to modulate and change the structure of neurons, their release and uptake of a diverse array of neurotransmitters (chemicals that enable neurons to communicate with each other), and how they carry out many daily functions. VDRs have been identified in the cerebral cortex, the cerebellum (balance center), and most interestingly of all, the limbic system (center of emotional processing). It has been recognized for many years that vitamin D deficiency is accompanied by irritability, anxiety and depression. Because it plays a central role in the regulation of seasonal rhythms, vitamin D deficiency has been linked to the incidence of SAD (Seasonal Affective Disorder). This is in keeping with its well known mood-elevating effects.

Mounting clinical evidence reveals a potentially important role for vitamin D in the aging brain.  As we age, dietary consumption of vitamin D and sun exposure are restricted and may lead to profound insufficiencies in serum vitamin D levels in the elderly. These have been associated with well-documented behavioral and cognitive declines. In line with such observations are animal data that reveal serotonin-elevating effects of a vitamin D rich diet. Serotonin is the feel good chemical that the group of anti-depressants including Zoloft, Prozac and Paxil elevate.

The region of the brain called the hippocampus is the center of memory function. As it ages, so do our memories. Recent reports support the role for vitamin D as a potent anti-inflammatory agent in rat hippocampi. Another study demonstrated that vitamin D supplementation in animals slowed the development of biomarkers of aging in the hippocampus. Given the important role of the hippocampus in cognitive information processing, it is not surprising that vitamin D status influences the development of age-related mental functioning.

Global vitamin D deficiency is on the rise, not only in the elderly, but in the young and middle-aged as well. Experts in vitamin D metabolism and preventative medicine have published studies demonstrating the safety of daily amounts of vitamin D in the 4000 to 5000 IU range. The current recommended daily amount is in the 400 IU range. It is clear that this level is woefully inadequate. Because vitamin D is inexpensive and easily produced, there is no reason to permit such deficiencies, and their associated diseases, to exist!

Multiple Sclerosis (MS) is a slowly progressive, often disabling disease of the nervous system. It consists of regions of nerve injury characterized by demyelination or loss of the protective fatty coating of the nerves. When this fatty myelin coating is damaged, it is akin to removal of the plastic coating of the wires in your home. If the wire connecting a light to a wall outlet loses its insulation, the light will go out because the electricity stops being conducted. When nerves lose their myelin, or insulation, the same thing happens. Conduction from one nerve to the next is interrupted. If this develops in a group of nerves responsible for sensation on the hand, for example, numbness will be the result. The disease produces multiple and varied neurological symptoms. There are activations and remissions during the course of the disorder. The exact cause of MS is unknown. Inheriting genetic risk factors for MS is not sufficient to cause this disease. Exposure to environmental risk factors is also required. MS may thus be preventable if these unidentified factors can be avoided.

An interesting observation regarding the incidence of MS is that it increases with decreasing exposure to solar radiation. Incidence of MS is lowest in the tropics.This suggests that sunlight may be protective for MS. Since the vitamin D system is exquisitely responsive to sunlight and MS is highest where environmental supplies of vitamin D are lowest, it has been suggested that vitamin D may protect genetically susceptible individuals. Studies on MS and vitamin D have found that periods of low vitamin D precede the occurrence of high MS activity, while periods of high vitamin D precede low MS activity.

To study the relationship between vitamin D and the risk of developing MS, Dr. Walter Willett and his associates at Harvard and the University of California at Irvine used data from two large prospective human cohorts to determine whether or not vitamin D intake is associated with risk for developing MS.

Over 180,000 women were followed for 10 years. Diet and total vitamin D intake (including that from vitamin supplements) were assessed at baseline and every 4 years thereafter. During the follow up period, 173 cases of MS were confirmed. The study results identified a 40% reduction in the risk of developing MS in those subjects who used daily supplemental vitamin D in amounts greater than or equal to 400 IU, versus those who took no supplemental vitamin D. The authors interpreted the results as supporting a protective effect of vitamin D intake on the risk of developing MS.

In the 1950s, it was noted that the average annual sunshine exposure and the winter daily solar radiation at a person's birthplace correlated strongly and inversely with the life time incidence of MS. This was subsequently confirmed in other studies. It was later observed that the season of birth in those who later developed MS differed significantly from the general population. The consensus of these studies appears to suggest a higher risk if the first or second trimester of pregnancy were during the fall or winter, the seasons of low or absent synthesis of vitamin D by the skin in mothers living at moderate to high latitudes.

There are numerous examples where simple dietary supplementation has been quite effective in preventing specific diseases. This is best exemplified by the connection between folate supplementation during pregnancy and prevention of neural tube defects (spina bifida and anencephaly). It seems this preventive effect works not by correcting a simple, nutritional deficiency, but by influencing specific pathways in early brain development. A related influence may be true for vitamin D due to its beneficial impact on oligodendrocytes (the cells responsible for making the fatty coating of nerves (myelin)). For this reason, if these arguments have validity, the potential health and economic benefits of vitamin D supplementation in areas of high MS prevalence are large. Routine vitamin D provision in pregnancy and childhood is a simple and cost-effective strategy to try and reduce the burden of a potentially devastating disease that destroys many lives.

 

We last spoke about the daily intake of vitamin D being suboptimal for most persons. Production of vitamin D by the skin is rapid and prolific. When light-skinned individuals sunbathe in the summer for about 20 minutes they are able to generate at least 10,000 IUs of vitamin D within 24 hours. A pregnant mother would have to drink 100 glasses of milk or consume 50 prenatal vitamins to equal this amount of vitamin D. Because of medical advice over the past 20 years to limit sun exposure and use sun-blocking agents, along with recommendations of the American Medical Association's Council on Scientific Affairs to "keep infants out of the sun as much as possible," generation of vitamin D by the skin has fallen dramatically. The consumption of vitamin D in food and supplemental form has not offset this deficit. This dramatically limits the exposure of the brain to optimal vitamin D during pregnancy and thereafter. Such limited exposure of the brain to vitamin D during key developmental stages is novel in the history of mankind and is chronologically associated with rising rates of autism.

Animal data from studies in vitamin D deficient maternal rats have documented abnormal nerve cell growth and proliferation. Reduced expression of a number of genes involved in determination of neuronal structure were observed as were alterations in memory and learning. Another group showed that vitamin D deficiency disrupts 36 proteins involved in mammalian brain development. This is consistent with anatomical studies in rats that revealed increased brain size and enlarged ventricles (the fluid spaces in the brain) similar to children with autism.

A human clinical study in 20 autistic children found that even low daily doses (150 IU) of vitamin D improved sleep and gastrointestinal problems. In other human studies investigating childhood cognition in 'normal' kids, improvements from 1% to 6% have been documented. In one fifth of the children, improvements of about 15% were detected. This may have been the most vitamin D deficient cohort. Recently, low maternal seafood consumption (a rich source of vitamin D) was linked to infants with low verbal IQs and poor outcomes in fine motor skills, communication, and social development. These are all seen to some degree in the autistic spectrum. Consistent with this observation is the association of increased fish intake during pregnancy with improved infant cognition.

When formula fed babies (formula contains significant amounts of vitamin D) are weaned to various juices, such as apple and grape juice, one might expect to see more cases of autism develop. A prospective study of 87 infants, some at high risk for development of autism, and others not, found no difference in cognition at age 6 months (prior to weaning to juice type diets). However, around the age of weaning initial signs developed in those who developed autism with rapid progression between 1 and 2 years of age. This timeline correlates with the age many children with autism deteriorate.

If vitamin D is somehow linked with autism, the prevalence should be lower in sunny climates or near the equator. Recent CDC (Center for Disease Control) data from 14 states showed the state with the highest prevalence was New Jersey (the second most northern state); Alabama, with the lowest prevalence, was the most southern state.

If there is an association between vitamin D deficiency and autism, drugs which lower vitamin D should be more likely to be related to the development of autism. There is little known about drugs that interfere with vitamin D metabolism, but sodium valproate is in this category. It is one of the few gestational drugs that are linked with autism.

Melanin is the skin pigment that makes skin dark and is also an efficient sunscreen. If this is the case, children born to dark skinned mothers might be expected to have more neurodevelopmental disorders. Four recent US studies found a higher incidence of autism in black children. Similar findings exist for dark-skinned immigrants in Europe. Low vitamin D levels are 150% more likely in pregnant black females than in white females. Furthermore, 45% of pregnant black females are severely deficient compared to only 2% of pregnant white women. The most startling observation is that prenatal vitamins containing 400 IUs of vitamin D offered little protection for mother or infant in either population.

The hormones estrogen and testosterone have dramatically different effects on vitamin D levels. Estrogen seems to be associated with higher vitamin D while testosterone is not. If estrogen increases neuronal vitamin D during pregnancy, while testosterone does not, this suggests male brains may not be as protected from vitamin D deficiencies.

These observations are consistent with the genetic basis of autism, the male and dark-skinned predominance, the timeline for development, and the timing of recommendations for sun avoidance.

If vitamin D deficiency contributes to the cause of autism, it has medical, social, and financial consequences. Simple preventative measures are at hand that are both widely available and inexpensive.