How physical exercise and fitness improves your brain function
Neurogenesis — the creation of new brain cells — occurs of course at a great rate in the very young. For a long time, it was not thought to occur in adult brains — once you were grown, it was thought, all you could do was watch your brain cells die!
Adult neurogenesis (the creation of new brain cells in adult brains) was first discovered in 1965, but only recently has it been accepted as a general phenomenon that occurs in many species, including humans (1998).
It's now widely accepted that adult neurogenesis occurs in the subgranular zone of the dentate gyrus within the hippocampus and the subventricular zone (SVZ) lining the walls of the lateral ventricles within the forebrain. It occurs, indeed, at a quite frantic rate — some 9000 new cells are born in the dentate gyrus every day in young adult rat brains — but under normal circumstances, at least half of those new cells will die within one or two months.
The neurons produced in the SVZ are sent to the olfactory bulb, while those produced in the dentate gyrus are intended for the hippocampus.
Adult neurogenesis might occur in other regions, but this is not yet well-established. However, recent research has found that small, non-pyramidal, inhibitory interneurons are being created in the cortex and striatum. These new interneurons appear to arise from a previously unknown class of local precursor cells. These interneurons make and secrete GABA (see below for why GABA is important), and are thought to play a role in regulating larger types of neurons that make long-distance connections between brain regions.
New neurons are spawned from the division of neural precursor cells — cells that have the potential to become neurons or support cells. How do they decide whether to remain a stem cell, turn into a neuron, or a support cell (an astrocyte or oligodendrocyte)?
Observation that neuroblasts traveled to the olfactory bulb from the SVZ through tubes formed by astrocytes has led to an interest in the role of those support cells. It's now been found that astrocytes encourage both precursor cell proliferation and their maturation into neurons — precursor cells grown on glia divide about twice as fast as they do when grown on fibroblasts, and are about six times more likely to become neurons.
Adult astrocytes are only about half as effective as embryonic astrocytes in promoting neurogenesis.
It’s been suggested that the role of astrocytes may help explain why neurogenesis only occurs in certain parts of the brain — it may be that there’s something missing from the glial cells in those regions.
The latest research suggests that the astrocytes influence the decision through a protein that it secretes called Wnt3. When Wnt3 proteins were blocked in the brains of adult mice, neurogenesis decreased dramatically; when additional Wnt3 was introduced, neurogenesis increased.
How are these new neurons then integrated into existing networks? Mouse experiments have found that the brain chemical called GABA is critical. Normally, GABA inhibits neuronal signals, but it turns out that with new neurons, GABA has a different effect: it excites them, and prepares them for integration into the adult brain. Thus a constant flood of GABA is needed initially; the flood then shifts to a more targeted pulse that gives the new neuron specific connections that communicate using GABA; finally, the neuron receives connections that communicate via another chemical, glutamate. The neuron is now ready to function as an adult neuron, and will respond to glutamate and GABA as it should.
The creation and development of new neurons in the adult brain is very much a "hot" topic right now — it's still very much a work-in-progress. However, it is clear that other brain chemicals are also involved. An important one is BDNF (brain-derived neurotrophic factor), which seems to be needed during the proliferation of hippocampal precursor cells to trigger their transformation into neurons.
Other growth factors have been found to stimulate proliferation of hippocampal progenitor cells: FGF-2 (fibroblast growth factor-2) and EGF (epidermal growth factor).
Recently it has been discovered that the normal form of the prion protein which, when malformed, causes mad cow disease, is also involved in neurogenesis. These proteins, in their normal form, are found throughout our bodies, and particularly in our brains. Now it seems that the more of these prion proteins that are available, the faster neural precursor cells turn into neurons.
The immune system's T cells (which recognize brain proteins) are also critically involved in enabling neurogenesis to occur. Among mice given environmental enrichment, only those with healthy T-cells had their production of new neurons boosted.
A number of factors have been found to affect the creation and survival of new neurons. For a start, damage to the brain (from a variety of causes) can provoke neurogenesis.
Moderate alcohol consumption over a relatively long period of time can also enhance the formation of new nerve cells in the adult brain (this may be related to alcohol's enhancement of GABA's function). Excess alcohol, however, has a detrimental effect on the formation of new neurons in the adult hippocampus. But although neurogenesis is inhibited during alcohol dependency, it does recover. A pronounced increase in new neuron formation in the hippocampus was found within four-to-five weeks of abstinence. This included a twofold burst in brain cell proliferation at day seven of abstinence.
Most drugs of abuse such as nicotine, heroine, and cocaine suppress neurogenesis, but a new study suggests that cannabinoids also promote neurogenesis. The study involved a synthetic cannabinoid, which increased the proliferation of progenitor cells in the hippocampal dentate gyrus of mice, in a similar manner as some antidepressants have been shown to do. The cannabinoid also produced similar antidepressant effects. Further research is needed to confirm this early finding.
If antidepressants promote neurogenesis, it won't be surprising to find that chronic stress, anxiety and depression are associated with losing hippocampal neurons. A rat study has also found that stress in early life can permanently impair neurogenesis in the hippocampus.
Showing the other side of this picture, perhaps, an intriguing rat study found that status affected neurogenesis in the hippocampus, with high-status animals having around 30% more neurons in their hippocampus after being placed in a naturalistic setting with other rats.
Also, a study into the brains of songbirds found that birds living in large groups have more new neurons and probably a better memory than those living alone.
Both physical activity and environmental enrichment (“mental stimulation”) have been shown to affect both how many cells are born in the dentate gyrus of rats and how many survive. Learning that uses the hippocampus has also been shown to have a positive effect, although results here have been inconsistent.
Inconsistent results from studies looking at neurogenesis are, it is suggested, largely because of a confusion between proliferation and survival. Neurogenesis is measured in terms of these two factors, which researchers often fail to distinguish between: the generation of new brain cells, and their survival. But these are separate factors, that are independently affected by various factors.
The inconsistency found in the effects of learning may also be partly explained by the complex nature of the effects. For example, during the later phase of learning, when performance is starting to plateau, neurons created during the late phase were more likely to survive, but neurons created during the early phase of more rapid learning disappeared. It’s speculated that that this may be a “pruning” process by which cells that haven’t made synaptic connections are removed from the network.
And finally, rodent studies suggest a calorie-restricted diet may also be of benefit.
A few years ago, we were surprised by news that new neurons could be created in the adult brain. However, it’s remained a tenet that adult neurons don’t grow — this because researchers have found no sign that any structural remodelling takes place in an adult brain. Now a mouse study using new techniques has revealed that dramatic restructuring occurs in the less-known, less-accessible inhibitory interneurons. Dendrites (the branched projections of a nerve cell that conducts electrical stimulation to the cell body) show sometimes dramatic growth, and this growth is tied to use, supporting the idea that the more we use our minds, the better they will be.
For more, see the research reports
A study involving 581 breast cancer patients and 364 healthy age-matched people (mean age 53) has found that women with breast cancer reported significantly greater cognitive difficulties for up to six months after chemotherapy. Cognitive difficulties were evaluated using FACT-Cog, an assessment that examines a person's own perceived impairment as well as cognitive impairment perceived by others.
Compared to healthy controls, the FACT-Cog scores of women with breast cancer were 45% lower at outset. This difference increased substantially after chemotherapy (see graph). The first assessment after chemotherapy was at 4.8 months, with the second 6 months after that (i.e, nearly a year after chemotherapy). Patients were also much more likely to report significant cognitive decline from diagnosis to the first post-chemotherapy assessment (45.2% vs 10.4% of the controls), and from prechemotherapy to second post-chemotherapy assessment (36.5% v 13.6%).
Having more anxiety and depressive symptoms at the outset, and having lower cognitive reserve (assessed by a reading score), were significantly associated with lower scores.
Those who received hormone therapy and/or radiation treatment after chemotherapy had similar cognitive problems to women who received chemotherapy alone.
A rat study suggests one reason for chemo-brain is an effect of chemotherapy on the neurotransmitters dopamine and serotonin. Both of these are important for both mood and cognition.
After giving carboplatin (commonly used with breast, bladder, colon and other cancers) to rats over four weeks, researchers found that the release and uptake of both dopamine and serotonin in their brains became impaired, although overall levels didn’t change. The rats also showed impaired cognition.
A role for dopamine and serotonin in chemo-brain is consistent with findings that anxiety and depression are risk factors for chemo-brain. No surprise then, that a study has found that physical exercise helps improve cognition in breast cancer survivors.
The study used self-reported data from 1,477 breast cancer survivors, as well as from accelerometers worn by 362 of the women. It found that breast cancer survivors who did more moderate or vigorous physical activity (including brisk walking, biking, jogging, or an exercise class) had fewer subjective memory problems.
Higher levels of physical activity were associated with lower levels of fatigue and distress, and higher levels of physical confidence. The researchers suggest that exercise reduces subjective memory problems via these factors.
A cognitive-behavioral therapy called "Memory and Attention Adaptation Training" (MAAT), which helps cancer survivors to increase their awareness of situations where memory problems can arise and to develop skills to either prevent memory failure or to compensate for memory dysfunction, has been trialed in a small randomized study involving 47 Caucasian breast cancer survivors. The patients were an average of four years post-chemotherapy.
The participants were either assigned to eight visits of MAAT (30 to 45 minutes each visit) or supportive talk therapy for the same length of time. Both treatments were delivered over a videoconference network between health centers.
MAAT participants reported significantly fewer memory problems as well as improved processing speed two months after treatment. They also reported much less anxiety about cognitive problems.
 Janelsins MC, Heckler CE, Peppone LJ, Kamen C, Mustian KM, Mohile SG, Magnuson A, Kleckner IR, Guido JJ, Young KL, et al. Cognitive Complaints in Survivors of Breast Cancer After Chemotherapy Compared With Age-Matched Controls: An Analysis From a Nationwide, Multicenter, Prospective Longitudinal Study. Journal of Clinical Oncology [Internet]. 2016 ;35(5):506 - 514. Available from: http://dx.doi.org/10.1200/JCO.2016.68.5826
 Kaplan SV, Limbocker RA, Gehringer RC, Divis JL, Osterhaus GL, Newby MD, Sofis MJ, Jarmolowicz DP, Newman BD, Mathews TA, et al. Impaired Brain Dopamine and Serotonin Release and Uptake in Wistar Rats Following Treatment with Carboplatin. ACS Chemical Neuroscience [Internet]. 2016 ;7(6):689 - 699. Available from: http://dx.doi.org/10.1021/acschemneuro.5b00029
 Phillips SM, Lloyd GR, Awick EA, McAuley E. Relationship between self-reported and objectively measured physical activity and subjective memory impairment in breast cancer survivors: role of self-efficacy, fatigue and distress. Psycho-Oncology [Internet]. 2016 :n/a - n/a. Available from: http://onlinelibrary.wiley.com/doi/10.1002/pon.4156/abstract
 Ferguson RJ, Sigmon ST, Pritchard AJ, LaBrie SL, Goetze RE, Fink CM, A. Garrett M. A randomized trial of videoconference-delivered cognitive behavioral therapy for survivors of breast cancer with self-reported cognitive dysfunction. Cancer [Internet]. 2016 ;122(11):1782 - 1791. Available from: http://onlinelibrary.wiley.com/doi/10.1002/cncr.29891/abstract
Data from 876 patients (average age 78) in the 30-year Cardiovascular Health Study show that virtually any type of aerobic physical activity can improve brain volume and reduce Alzheimer's risk.
A higher level of physical activity was associated with larger brain volumes in the frontal, temporal, and parietal lobes including the hippocampus, thalamus and basal ganglia. Among those with MCI or Alzheimer's (25% of the participants), higher levels of physical activity were also associated with less brain atrophy. An increase in physical activity was also associated with larger grey matter volumes in the left inferior orbitofrontal cortex and the left precuneus.
Further analysis of 326 of the participants found that those with the highest energy expenditure were half as likely to have developed Alzheimer's disease five years later.
Physical activity was assessed using the Minnesota Leisure-Time Activities questionnaire, which calculates kilocalories/week using frequency and duration of time spent in 15 different leisure-time activities: swimming, hiking, aerobics, jogging, tennis, racquetball, walking, gardening, mowing, raking, golfing, bicycling, dancing, calisthenics, and riding an exercise cycle.
The study does not look at whether some types of physical activity are better than others, unfortunately, but its message that overall physical activity, regardless of type, helps in the fight against cognitive impairment is encouraging.
 Raji CA, Merrill DA, Eyre H, Mallam S, Torosyan N, Erickson KI, Lopez OL, Becker JT, Carmichael OT, H. Gach M, et al. Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study. Journal of Alzheimer's disease: JAD. 2016 .
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