Cognitive impairment affects 40-65% of people with MS. Why? In the past year, a number of studies have helped us build a better picture of the precise nature of cognitive problems that may affect multiple sclerosis sufferers:

  • poorer performance on executive function tasks is fully explained by slower processing speed (which is presumably a function of the degradation in white matter characteristic of MS)
  • slowing in processing speed is associated with weaker connections between the executive area and the brain regions involved in carrying out cognitive tasks
  • cognitive reserve helps counter the decline in memory and cognitive efficiency
  • brain reserve (greater brain volume, ie less shrinkage) helps counter the decline in cognitive efficiency
  • working memory capacity explains the link between cognitive reserve and long-term memory
  • subjective cognitive fatigue is linked to the time spent on the task, not on its difficulty
  • mnemonic training helps protect against cognitive decline, but appears to be less helpful in those with slow processing speed.

What all this implies is that a multi-pronged approach is called for, involving:

  • working memory training
  • training in effective memory strategies
  • practice in breaking down cognitive tasks into more manageable chunks of time
  • practice in framing tasks to accommodate slower processing speed
  • physical and mental activities that encourage neurogenesis (growing more neurons) and synaptogenesis (growing more connections).

Here's some more detail on those studies:

Slow processing speed accounts for executive deficits in MS

A study of 50 patients with MS and 28 healthy controls found no differences in performance on executive function tasks when differences in processing speed were controlled for. In other words, although MS patients performed more poorly than controls on these tasks, the difference was fully accounted for by the differences in processing speed. There were no differences in performance when there was no processing speed component to the task. Similarly, MS patients with a greater degree of brain atrophy performed more poorly than those with less atrophy, but again, this only occurred when there was a processing speed aspect to the task, and was fully accounted for by processing speed differences.

[3939] Leavitt, V. M., Wylie G., Krch D., Chiaravalloti N. D., DeLuca J., & Sumowski J. F.
(2014).  Does slowed processing speed account for executive deficits in multiple sclerosis? Evidence from neuropsychological performance and structural neuroimaging..
Rehabilitation Psychology. 59(4), 422 - 428.

Functional connectivity factor in cognitive decline in MS

A brain imaging study involving 29 participants with relapsing-remitting MS and 23 age- and sex- matched healthy controls found that, as expected, those with MS were much slower on a processing speed task, although they were as accurate as the controls. This slowing was associated with weaker functional connections between the dorsolateral prefrontal cortex (the executive area) and the regions responsible for carrying out the task. It's thought that this is probably due to decreased white matter (white matter degradation is symptomatic of MS).

[3938] Hubbard, N. A., Hutchison J. L., Turner M. P., Sundaram S., Oasay L., Robinson D., et al.
(2015).  Asynchrony in Executive Networks Predicts Cognitive Slowing in Multiple Sclerosis.

Brain and cognitive reserve protect against cognitive decline in MS

A study compared memory, cognitive efficiency, vocabulary, and brain volume in 40 patients with MS, at baseline and 4.5 years later. After controlling for disease progression, they found that those with better vocabulary (a proxy for cognitive reserve) experienced less decline in memory and cognitive efficiency, and those with less brain atrophy over the period showed less decline in cognitive efficiency.

Cognitive efficiency is a somewhat fuzzy concept, but essentially has to do with how much time and effort you need to acquire new knowledge; in this study, it was assessed using the Symbol Digit Modalities Test and Paced Auditory Serial Addition Task, two tests commonly used to detect cognitive impairment in MS patients.

[3943] Sumowski, J. F., Rocca M. A., Leavitt V. M., Dackovic J., Mesaros S., Drulovic J., et al.
(2014).  Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS.
Neurology. 82(20), 1776 - 1783.

Working memory capacity accounts for link between cognitive reserve & better memory

A study involving 70 patients with MS has found that working memory capacity explained the relationship between cognitive reserve and long-term memory, suggesting that interventions targeted at working memory may help protect against decline in long-term memory.

[3941] Sandry, J., & Sumowski J. F.
(2014).  Working Memory Mediates the Relationship between Intellectual Enrichment and Long-Term Memory in Multiple Sclerosis: An Exploratory Analysis of Cognitive Reserve.
Journal of the International Neuropsychological Society. 20(08), 868 - 872.

Cognitive fatigue linked to time on task, not difficulty

A study investigating cognitive fatigue in 32 individuals with MS and 24 controls has found that subjective and objective fatigue were independent of one another, and that subjective cognitive fatigue increased as time on task increased. This increase in cognitive fatigue was greater in the MS group. No relationship was found between cognitive fatigue and cognitive load. Fatigue was greater for the processing speed task than the working memory task.

In other words, the length of time spent is far more important than the difficulty of the task.

[3940] Sandry, J., Genova H. M., Dobryakova E., DeLuca J., & Wylie G.
(2014).  Subjective cognitive fatigue in multiple sclerosis depends on task length.
Frontiers in Neurology. 5, 214.

Story mnemonic training helps some

A series of small studies have found cognitive benefits for MS patients from a 10-session training program designed to build their memory skills using a modified story mnemonic. The MEMREHAB Trial involved 85 patients with MS, of whom 45 received the training. In the most recent analyses of the data, the benefits were found to be maintained six months later, but unfortunately, it appears that those with processing speed deficits gain less benefit from the training.

The training consists of four 45-minute sessions focused on building imagery skills, in which participants were given a story with highly visualizable scenes and given facilitated practice in using visualization to help them remember the story. In the next four sessions, they were given lists of words and instructed in how to build a memorable story from these words, that they could visualize. The sessions employed increasingly unrelated word lists. In the final two sessions, participants were taught how to apply the technique in real-world situations.

[3936] Chiaravalloti, N. D., & DeLuca J.
(2015).  The influence of cognitive dysfunction on benefit from learning and memory rehabilitation in MS: A sub-analysis of the MEMREHAB trial.
Multiple Sclerosis (Houndmills, Basingstoke, England).

[3937] Dobryakova, E., Wylie G. R., DeLuca J., & Chiaravalloti N. D.
(2014).  A pilot study examining functional brain activity 6 months after memory retraining in MS: the MEMREHAB trial.
Brain Imaging and Behavior. 8(3), 403 - 406.

While it’s well-established that chronic stress has all sorts of harmful effects, including on memory and cognition, the judgment on brief bouts of acute stress has been more equivocal. There is a certain amount of evidence that brief amounts of stress can be stimulating rather than harmful, and perhaps even necessary if we are to reach our full potential.

A recent rat study has found that brief stressful events caused stem cells in the hippocampus to proliferate into new neurons that, when mature two weeks later, improved the rats’ mental performance. But note that their performance took time to improve — there was no benefit only two days after.

Chronic stress also impacts the creation of new neurons, but in the opposite direction — it suppresses neurogenesis. The difference probably lies in how long the stress hormones remain elevated. Previous research modeling PTSD in rodents has found that severity and length are crucial variables.

This new study shows that higher levels of stress hormone initially increase the production of new neurons in response to the release of a protein, fibroblast growth factor 2 (FGF2), but these need time to develop. Interestingly, FGF2 deficiency has been linked to depression, and depression is also known to be associated with a reduction in neurogenesis.

[3379] Kirby, E. D., Muroy S. E., Sun W. G., Covarrubias D., Leong M. J., Barchas L. A., et al.
(2013).  Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2.
eLife. 2, e00362 - e00362.

Full text available at

A new study adds more support to the idea that the increasing difficulty in learning new information and skills that most of us experience as we age is not down to any difficulty in acquiring new information, but rests on the interference from all the old information.

Memory is about strengthening some connections and weakening others. A vital player in this process of synaptic plasticity is the NMDA receptor in the hippocampus. This glutamate receptor has two subunits (NR2A and NR2B), whose ratio changes as the brain develops. Children have higher ratios of NR2B, which lengthens the time neurons talk to each other, enabling them to make stronger connections, thus optimizing learning. After puberty, the ratio shifts, so there is more NR2A.

Of course, there are many other changes in the aging brain, so it’s been difficult to disentangle the effects of this changing ratio from other changes. This new study genetically modified mice to have more NR2A and less NR2B (reflecting the ratio typical of older humans), thus avoiding the other confounds.

To the researchers’ surprise, the mice were found to be still good at making strong connections (‘long-term potentiation’ - LTP), but instead had an impaired ability to weaken existing connections (‘long-term depression’ - LTD). This produces too much noise (bear in mind that each neuron averages 3,000 potential points of contact (i.e., synapses), and you will see the importance of turning down the noise!).

Interestingly, LTD responses were only abolished within a particular frequency range (3-5 Hz), and didn’t affect 1Hz-induced LTD (or 100Hz-induced LTP). Moreover, while the mice showed impaired long-term learning, their short-term memory was unaffected. The researchers suggest that these particular LTD responses are critical for ‘post-learning information sculpting’, which they suggest is a step (hitherto unknown) in the consolidation process. This step, they postulate, involves modifying the new information to fit in with existing networks of knowledge.

Previous work by these researchers has found that mice genetically modified to have an excess of NR2B became ‘super-learners’. Until now, the emphasis in learning and memory has always been on long-term potentiation, and the role (if any) of long-term depression has been much less clear. These results point to the importance of both these processes in sculpting learning and memory.

The findings also seem to fit in with the idea that a major cause of age-related cognitive decline is the failure to inhibit unwanted information, and confirm the importance of keeping your mind actively engaged and learning, because this ratio is also affected by experience.

A study using data from the Lothian Birth Cohort (people born in Scotland in 1936) has analyzed brain scans of 638 participants when they were 73 years old. Comparing this data with participants’ earlier reports of their exercise and leisure activities at age 70, it was found that those who reported higher levels of regular physical activity showed significantly less brain atrophy than those who did minimal exercise. Participation in social and mentally stimulating activities, on the other hand, wasn’t associated with differences in brain atrophy.

Regular physical exercise was also associated with fewer white matter lesions. While leisure activity was also associated with healthier white matter, this was not significant after factors such as age, social class, and health status were taken into account.

Unfortunately, this study is reported in a journal to which I don’t have access. I would love to have more details about the leisure activities data and the brain scans. However, although the failure to find a positive effect of stimulating activities is disappointing, it’s worth noting another recent study, that produced two relevant findings. First, men with high levels of cognitive activity showed a significant reduction in white matter lesions, while women did not. Women with high levels of cognitive activity, on the other hand, showed less overall brain atrophy — but men did not.

Secondly, both genders showed less atrophy in a particular region of the prefrontal cortex, but there was no effect on the hippocampus — the natural place to look for effects (and the region where physical exercise is known to have positive effects).

In other words, the positive effects of cognitive activity on the brain might be quite different from the positive effects of physical exercise.

The findings do, of course, add to the now-compelling evidence for the benefits of regular physical activity in fighting cognitive decline.

It’s good news, then, that a small study has found that even frail seniors can derive significant benefits from exercise.

The study involved 83 older adults (61-89), some of whom were considered frail. Forty-three took part in group exercises (3 times a week for 12 weeks), while 40 were wait-listed controls. Participants were assessed for physical capacity, quality of life and cognitive health a week before the program began, and at the end.

Those who took part in the exercise program significantly improved their physical capacity, cognitive performance, and quality of life. These benefits were equivalent among frail and non-frail participants.

Frailty is associated with a higher risk of falls, hospitalizations, cognitive decline and psychological distress, and, of course, increases with age. In the U.S, it’s estimated that 7% of seniors aged 65 to 74, 18% of those aged 75 to 84, and 37% of seniors over the age of 85 are frail.

Green tea is thought to have wide-ranging health benefits, especially in the prevention of cardiovascular disease, inflammatory diseases, and diabetes. These are all implicated in the development of age-related cognitive impairment, so it’s no surprise that regular drinking of green tea has been suggested as one way to help protect against age-related cognitive decline and dementia. A new mouse study adds to that evidence by showing how a particular compound in green tea promotes neurogenesis.

The chemical EGCG, (epigallocatechin-3 gallate) is a known anti-oxidant, but this study shows that it also has a specific benefit in increasing the production of neural progenitor cells. Like stem cells, these progenitor cells can become different types of cell.

Mice treated with EGCG displayed better object recognition and spatial memory than control mice, and this improved performance was associated with the number of progenitor cells in the dentate gyrus and increased activity in the sonic hedgehog signaling pathway (confirming the importance of this pathway in adult neurogenesis in the hippocampus).

The findings add to evidence that green tea may help protect against cognitive impairment and dementia.

Like us, guinea pigs can’t make vitamin C, but must obtain it from their diet. This makes them a good model for examining the effects of vitamin C deficiency.

In a recent study looking specifically at the effects of prenatal vitamin C deficiency, 80 pregnant guinea pigs were fed a diet that was either high or low in vitamin C. Subsequently, 157 of the newborn pups were randomly allocated to either a low or high vitamin C diet (after weaning), creating four conditions: high/high (controls); high/low (postnatal depletion); low/high (postnatal repletion); low/low (pre/postnatal deficiency). Only males experienced the high/low condition (postnatal depletion).

Only the postnatal depletion group showed any effect on body weight; no group showed an effect on brain weight.

Nevertheless, although the brain as a whole grew normally, those who had experienced a prenatal vitamin C deficiency showed a significantly smaller hippocampus (about 10-15% smaller). This reduction was not reversed by later repletion.

This reduction appeared to be related to a significant reduction in the migration of new neurons into the dentate gyrus. There was no difference in the creation or survival of new neurons in the hippocampus.

This finding suggests that marginal deficiency in vitamin C during pregnancy (a not uncommon occurrence) may have long-term effects on offspring.

In my last report, I discussed a finding that intensive foreign language learning ‘grew’ the size of certain brain regions. This growth reflects gray matter increase. Another recent study looks at a different aspect: white matter.

In the study, monthly brain scans were taken of 27 college students, of whom 11 were taking an intensive nine-month Chinese language course. These brain scans were specifically aimed at tracking white matter changes in the students’ brains.

Significant changes were indeed observed in the brains of the language learners. To the researchers’ surprise, however, the biggest changes were observed in an area not previously considered part of the language network: the white matter tracts that cross the corpus callosum, the main bridge between the hemispheres. (I’m not quite sure why they were surprised, since a previous study had found that bilinguals showed higher white matter integrity in the corpus callosum.)

Significant changes were also observed within the left-hemisphere language network and in the right temporal lobe. The rate of increase in white matter was linear, showing a steady progression with each passing month.

The researchers suggest that plasticity in the adult brain may differ from that seen in children’s brains. While children’s brains change mainly through the pruning of unwanted connections and the death of unwanted cells, adult brains may rely mainly on neurogenesis and myelinogenesis.

The growth of new myelin is a process that is still largely mysterious, but it’s suggested that activity at the axons (the extensions of neurons that carry the electrical signals) might trigger increases in the size, density, or number of oligodendrocytes (the cells responsible for the myelin sheaths). This process is thought to be mediated by astrocytes, and in recent years we have begun to realize that astrocytes, long regarded as mere ‘support cells’, are in fact quite important for learning and memory. Just how important is something researchers are still working on.

The finding of changes between the frontal hemispheres and caudate nuclei is consistent with a previously-expressed idea that language learning requires the development of a network to control switching between languages.

Does the development of such a network enhance the task-switching facility in working memory? Previous research has found that bilinguals tend to have better executive control than monolinguals, and it has been suggested that the experience of managing two (or more) languages reorganizes certain brain networks, creating a more effective basis for executive control.

As in the previous study, the language studied was very different from the students’ native language, and they had no previous experience of it. The level of intensity was of course much less.

I do wonder if the fact that the language being studied was Mandarin Chinese limits the generality of these findings. Because of the pictorial nature of the written language, Chinese has been shown to involve a wider network of regions than European languages.

Nevertheless, the findings add to the evidence that adult brains retain the capacity to reorganize themselves, and add to growing evidence that we should be paying more attention to white matter changes.

[3143] Schlegel, A. A., Rudelson J. J., & Tse P. U.
(2012).  White Matter Structure Changes as Adults Learn a Second Language.
Journal of Cognitive Neuroscience. 24(8), 1664 - 1670.

Bialystok, E., Craik, F. I. M., & Luk, G. (2012). Bilingualism: consequences for mind and brain. Trends in Cognitive Sciences, 16(4), 240–250. doi:10.1016/j.tics.2012.03.001

Luk, G. et al. (2011) Lifelong bilingualism maintains white matter integrity in older adults. J. Neurosci. 31, 16808–16813

A small Swedish brain imaging study adds to the evidence for the cognitive benefits of learning a new language by investigating the brain changes in students undergoing a highly intensive language course.

The study involved an unusual group: conscripts in the Swedish Armed Forces Interpreter Academy. These young people, selected for their talent for languages, undergo an intensive course to allow them to learn a completely novel language (Egyptian Arabic, Russian or Dari) fluently within ten months. This requires them to acquire new vocabulary at a rate of 300-500 words every week.

Brain scans were taken of 14 right-handed volunteers from this group (6 women; 8 men), and 17 controls that were matched for age, years of education, intelligence, and emotional stability. The controls were medical and cognitive science students. The scans were taken before the start of the course/semester, and three months later.

The brain scans revealed that the language students showed significantly greater changes in several specific regions. These regions included three areas in the left hemisphere: the dorsal middle frontal gyrus, the inferior frontal gyrus, and the superior temporal gyrus. These regions all grew significantly. There was also some, more selective and smaller, growth in the middle frontal gyrus and inferior frontal gyrus in the right hemisphere. The hippocampus also grew significantly more for the interpreters compared to the controls, and this effect was greater in the right hippocampus.

Among the interpreters, language proficiency was related to increases in the right hippocampus and left superior temporal gyrus. Increases in the left middle frontal gyrus were related to teacher ratings of effort — those who put in the greatest effort (regardless of result) showed the greatest increase in this area.

In other words, both learning, and the effort put into learning, had different effects on brain development.

The main point, however, is that language learning in particular is having this effect. Bear in mind that the medical and cognitive science students are also presumably putting in similar levels of effort into their studies, and yet no such significant brain growth was observed.

Of course, there is no denying that the level of intensity with which the interpreters are acquiring a new language is extremely unusual, and it cannot be ruled out that it is this intensity, rather than the particular subject matter, that is crucial for this brain growth.

Neither can it be ruled out that the differences between the groups are rooted in the individuals selected for the interpreter group. The young people chosen for the intensive training at the interpreter academy were chosen on the basis of their talent for languages. Although brain scans showed no differences between the groups at baseline, we cannot rule out the possibility that such intensive training only benefited them because they possessed this potential for growth.

A final caveat is that the soldiers all underwent basic military training before beginning the course — three months of intense physical exercise. Physical exercise is, of course, usually very beneficial for the brain.

Nevertheless, we must give due weight to the fact that the brain scans of the two groups were comparable at baseline, and the changes discussed occurred specifically during this three-month learning period. Moreover, there is growing evidence that learning a new language is indeed ‘special’, if only because it involves such a complex network of processes and brain regions.

Given that people vary in their ‘talent’ for foreign language learning, and that learning a new language does tend to become harder as we get older, it is worth noting the link between growth of the hippocampus and superior temporal gyrus and language proficiency. The STG is involved in acoustic-phonetic processes, while the hippocampus is presumably vital for the encoding of new words into long-term memory.

Interestingly, previous research with children has suggested that the ability to learn new words is greatly affected by working memory span — specifically, by how much information they can hold in that part of working memory called phonological short-term memory. While this is less important for adults learning another language, it remains important for one particular category of new words: words that have no ready association to known words. Given the languages being studied by these Swedish interpreters, it seems likely that much if not all of their new vocabulary would fall into this category.

I wonder if the link with STG is more significant in this study, because the languages are so different from the students’ native language? I also wonder if, and to what extent, you might be able to improve your phonological short-term memory with this sort of intensive practice.

In this regard, it’s worth noting that a previous study found that language proficiency correlated with growth in the left inferior frontal gyrus in a group of English-speaking exchange students learning German in Switzerland. Is this difference because the training was less intensive? because the students had prior knowledge of German? because German and English are closely related in vocabulary? (I’m picking the last.)

The researchers point out that hippocampal plasticity might also be a critical factor in determining an individual’s facility for learning a new language. Such plasticity does, of course, tend to erode with age — but this can be largely counteracted if you keep your hippocampus limber (as it were).

All these are interesting speculations, but the main point is clear: the findings add to the growing evidence that bilingualism and foreign language learning have particular benefits for the brain, and for protecting against cognitive decline.

Two years ago, I reported on a clinical trial of a nutrient cocktail called Souvenaid for those with early Alzheimer’s. The three-month trial, involving 225 patients, had some success in improving verbal recall, with those with the mildest level of impairment benefiting the most.

The ‘cocktail’, designed by a MIT professor of brain and cognitive science, includes choline, uridine and the omega-3 fatty acid DHA. Earlier research indicated that these nutrients — precursors to the lipid molecules that help make up neural membranes — need to be administered together to be effective. In animal studies, the cocktail increased the number of dendritic spines, which are reduced in Alzheimer’s disease.

A further trial of the supplement has now been reported on. This randomized, controlled double-blind study followed 259 patients with early Alzheimer’s for six months. The placebo group was given an iso-caloric control product. Compliance was high (around 97%), and no serious side effects occurred.

During the first three months, all patients improved their verbal memory performance, but after that those on placebo began to deteriorate, while those on Souvenaid continued to improve. Their performance at the end of the trial was significantly better than that of the placebo group. Moreover, brain scans showed that their brains began to show more normal activity patterns, consistent with the regaining of greater synaptic function.

Because the supplement only seems to be effective for those in the early stages (in this study, participants averaged around 25 on a scale of dementia that ranges from 1 to 30, with 30 being normal), a two-year trial is now underway with patients with MCI.

Scheltens, P. et al. 2012. Efficacy of Souvenaid in Mild Alzheimer’s Disease: Results from a Randomized, Controlled Trial. Journal of Alzheimer’s Disease, 31 (1), 225-36.

In the light of a general increase in caesarean sections, it’s somewhat alarming to read about a mouse study that found that vaginal birth triggers the expression of a protein in the brains of newborns that improves brain development, and this protein expression is impaired in the brains of those delivered by C-section.

The protein in question —mitochondrial uncoupling protein 2 (UCP2) — is important for the development of neurons and circuits in the hippocampus. Indeed, it has a wide role, being involved in regulation of fuel utilization, mitochondrial bioenergetics, cell proliferation, neuroprotection and synaptogenesis. UCP2 is induced by cellular stress.

Among the mice, natural birth triggered UCP2 expression in the hippocampus (presumably because of the stress of the birth), which was reduced in those who were born by C-section. Not only were levels of UCP2 lower in C-section newborns, they continued to be lower through to adulthood.

Cell cultures revealed that inhibiting UCP2 led to decreased number of neurons, neuron size, number of dendrites, and number of presynaptic clusters. Mice with (chemically or genetically) inhibited UCP2 also showed behavioral differences indicative of greater levels of anxiety. They explored less, and they showed poorer spatial memory.

The effects of reduced UCP2 on neural growth means that factors that encourage the growth of new synapses, such as physical exercise, are likely to be much less useful (if useful at all). Could this explain why exercise seems to have no cognitive benefits for a small minority? (I’m speculating here.)

Although the researchers don’t touch on this (naturally enough, since this was a laboratory study), I would also speculate that, if the crucial factor is stress during the birth, this finding applies only to planned C-sections, not to those which become necessary during the course of labor.

UCP2 is also a critical factor in fatty acid utilization, which has a flow-on effect for the creation of new synapses. One important characteristic of breast milk is its high content of long chain fatty acids. It’s suggested that the triggering of UCP2 by natural birth may help the transition to breastfeeding. This in turn has its own benefits for brain development.

I’ve reported before on how London taxi drivers increase the size of their posterior hippocampus by acquiring and practicing ‘the Knowledge’ (but perhaps at the expense of other functions). A new study in similar vein has looked at the effects of piano tuning expertise on the brain.

The study looked at the brains of 19 professional piano tuners (aged 25-78, average age 51.5 years; 3 female; 6 left-handed) and 19 age-matched controls. Piano tuning requires comparison of two notes that are close in pitch, meaning that the tuner has to accurately perceive the particular frequency difference. Exactly how that is achieved, in terms of brain function, has not been investigated until now.

The brain scans showed that piano tuners had increased grey matter in a number of brain regions. In some areas, the difference between tuners and controls was categorical — that is, tuners as a group showed increased gray matter in right hemisphere regions of the frontal operculum, the planum polare, superior frontal gyrus, and posterior cingulate gyrus, and reduced gray matter in the left hippocampus, parahippocampal gyrus, and superior temporal lobe. Differences in these areas didn’t vary systematically between individual tuners.

However, tuners also showed a marked increase in gray matter volume in several areas that was dose-dependent (that is, varied with years of tuning experience) — the anterior hippocampus, parahippocampal gyrus, right middle temporal and superior temporal gyrus, insula, precuneus, and inferior parietal lobe — as well as an increase in white matter in the posterior hippocampus.

These differences were not affected by actual chronological age, or, interestingly, level of musicality. However, they were affected by starting age, as well as years of tuning experience.

What these findings suggest is that achieving expertise in this area requires an initial development of active listening skills that is underpinned by categorical brain changes in the auditory cortex. These superior active listening skills then set the scene for the development of further skills that involve what the researchers call “expert navigation through a complex soundscape”. This process may, it seems, involve the encoding and consolidating of precise sound “templates” — hence the development of the hippocampal network, and hence the dependence on experience.

The hippocampus, apart from its general role in encoding and consolidating, has a special role in spatial navigation (as shown, for example, in the London cab driver studies, and the ‘parahippocampal place area’). The present findings extend that navigation in physical space to the more metaphoric one of relational organization in conceptual space.

The more general message from this study, of course, is confirmation for the role of expertise in developing specific brain regions, and a reminder that this comes at the expense of other regions. So choose your area of expertise wisely!

A study designed to compare the relative benefits of exercise and diet control on Alzheimer’s pathology and cognitive performance has revealed that while both are beneficial, exercise is of greater benefit in reducing Alzheimer’s pathology and cognitive impairment.

The study involved mice genetically engineered with a mutation in the APP gene (a familial risk factor for Alzheimer’s), who were given either a standard diet or a high-fat diet (60% fat, 20% carbohydrate, 20% protein vs 10% fat, 70% carbohydrate, 20% protein) for 20 weeks (from 2-3 to 7-8 months of age). Some of the mice on the high-fat diet spent the second half of that 20 weeks in an environmentally enriched cage (more than twice as large as the standard cage, and supplied with a running wheel and other objects). Others on the high-fat diet were put back on a standard diet in the second 10 weeks. Yet another group were put on a standard diet and given an enriched cage in the second 10 weeks.

Unsurprisingly, those on the high-fat diet gained significantly more weight than those on the standard diet, and exercise reduced that gain — but not as much as diet control (i.e., returning to a standard diet) did. Interestingly, this was not the result of changes in food intake, which either stayed the same or slightly increased.

More importantly, exercise and diet control were roughly equal in reversing glucose intolerance, but exercise was more effective than diet control in ameliorating cognitive impairment. Similarly, while amyloid-beta pathology was significantly reduced in both exercise and diet-control conditions, exercise produced the greater reduction in amyloid-beta deposits and level of amyloid-beta oligomers.

It seems that diet control improves metabolic disorders induced by a high-fat diet — conditions such as obesity, hyperinsulinemia and hypercholesterolemia — which affects the production of amyloid-beta. However exercise is more effective in tackling brain pathology directly implicated in dementia and cognitive decline, because it strengthens the activity of an enzyme that decreases the level of amyloid-beta.

Interestingly, and somewhat surprisingly, the combination of exercise and diet control did not have a significantly better effect than exercise alone.

The finding adds to the growing pile of evidence for the value of exercise in maintaining a healthy brain in later life, and helps explain why. Of course, as I’ve discussed on several occasions, we already know other mechanisms by which exercise improves cognition, such as boosting neurogenesis.

Genetic analysis of 9,232 older adults (average age 67; range 56-84) has implicated four genes in how fast your hippocampus shrinks with age (rs7294919 at 12q24, rs17178006 at 12q14, rs6741949 at 2q24, rs7852872 at 9p33). The first of these (implicated in cell death) showed a particularly strong link to a reduced hippocampus volume — with average consequence being a hippocampus of the same size as that of a person 4-5 years older.

Faster atrophy in this crucial brain region would increase people’s risk of Alzheimer’s and cognitive decline, by reducing their cognitive reserve. Reduced hippocampal volume is also associated with schizophrenia, major depression, and some forms of epilepsy.

In addition to cell death, the genes linked to this faster atrophy are involved in oxidative stress, ubiquitination, diabetes, embryonic development and neuronal migration.

A younger cohort, of 7,794 normal and cognitively compromised people with an average age of 40, showed that these suspect gene variants were also linked to smaller hippocampus volume in this age group. A third cohort, comprised of 1,563 primarily older people, showed a significant association between the ASTN2 variant (linked to neuronal migration) and faster memory loss.

In another analysis, researchers looked at intracranial volume and brain volume in 8,175 elderly. While they found no genetic associations for brain volume (although there was one suggestive association), they did discover that intracranial volume (the space occupied by the fully developed brain within the skull — this remains unchanged with age, reflecting brain size at full maturity) was significantly associated with two gene variants (at loci rs4273712, on chromosome 6q22, and rs9915547, on 17q21). These associations were replicated in a different sample of 1,752 older adults. One of these genes is already known to play a unique evolutionary role in human development.

A meta-analysis of seven genome-wide association studies, involving 10,768 infants (average age 14.5 months), found two loci robustly associated with head circumference in infancy (rs7980687 on chromosome 12q24 and rs1042725 on chromosome 12q15). These loci have previously been associated with adult height, but these effects on infant head circumference were largely independent of height. A third variant (rs11655470 on chromosome 17q21 — note that this is the same chromosome implicated in the study of older adults) showed suggestive evidence of association with head circumference; this chromosome has also been implicated in Parkinson's disease and other neurodegenerative diseases.

Previous research has found an association between head size in infancy and later development of Alzheimer’s. It has been thought that this may have to do with cognitive reserve.

Interestingly, the analyses also revealed that a variant in a gene called HMGA2 (rs10784502 on 12q14.3) affected intelligence as well as brain size.

Why ‘Alzheimer’s gene’ increases Alzheimer’s risk

Investigation into the so-called ‘Alzheimer’s gene’ ApoE4 (those who carry two copies of this variant have roughly eight to 10 times the risk of getting Alzheimer’s disease) has found that ApoE4 causes an increase in cyclophilin A, which in turn causes a breakdown of the cells lining the blood vessels. Blood vessels become leaky, making it more likely that toxic substances will leak into the brain.

The study found that mice carrying the ApoE4 gene had five times as much cyclophilin A as normal, in cells crucial to maintaining the integrity of the blood-brain barrier. Blocking the action of cyclophilin A brought blood flow back to normal and reduced the leakage of toxic substances by 80%.

The finding is in keeping with the idea that vascular problems are at the heart of Alzheimer’s disease — although it should not be assumed from that, that other problems (such as amyloid-beta plaques and tau tangles) are not also important. However, one thing that does seem clear now is that there is not one single pathway to Alzheimer’s. This research suggests a possible treatment approach for those carrying this risky gene variant.

Note also that this gene variant is not only associated with Alzheimer’s risk, but also Down’s syndrome dementia, poor outcome following TBI, and age-related cognitive decline.

On which note, I’d like to point out recent findings from the long-running Nurses' Health Study, involving 16,514 older women (70-81), that suggest that effects of postmenopausal hormone therapy for cognition may depend on apolipoprotein E (APOE) status, with the fastest rate of decline being observed among HT users who carried the APOe4 variant (in general HT was associated with poorer cognitive performance).

It’s also interesting to note another recent finding: that intracranial volume modifies the effect of apoE4 and white matter lesions on dementia risk. The study, involving 104 demented and 135 nondemented 85-year-olds, found that smaller intracranial volume increased the risk of dementia, Alzheimer's disease, and vascular dementia in participants with white matter lesions. However, white matter lesions were not associated with increased dementia risk in those with the largest intracranial volume. But intracranial volume did not modify dementia risk in those with the apoE4 gene.

More genes involved in Alzheimer’s

More genome-wide association studies of Alzheimer's disease have now identified variants in BIN1, CLU, CR1 and PICALM genes that increase Alzheimer’s risk, although it is not yet known how these gene variants affect risk (the present study ruled out effects on the two biomarkers, amyloid-beta 42 and phosphorylated tau).

Same genes linked to early- and late-onset Alzheimer's

Traditionally, we’ve made a distinction between early-onset Alzheimer's disease, which is thought to be inherited, and the more common late-onset Alzheimer’s. New findings, however, suggest we should re-think that distinction. While the genetic case for early-onset might seem to be stronger, sporadic (non-familial) cases do occur, and familial cases occur with late-onset.

New DNA sequencing techniques applied to the APP (amyloid precursor protein) gene, and the PSEN1 and PSEN2 (presenilin) genes (the three genes linked to early-onset Alzheimer's) has found that rare variants in these genes are more common in families where four or more members were affected with late-onset Alzheimer’s, compared to normal individuals. Additionally, mutations in the MAPT (microtubule associated protein tau) gene and GRN (progranulin) gene (both linked to frontotemporal dementia) were also found in some Alzheimer's patients, suggesting they had been incorrectly diagnosed as having Alzheimer's disease when they instead had frontotemporal dementia.

Of the 439 patients in which at least four individuals per family had been diagnosed with Alzheimer's disease, rare variants in the 3 Alzheimer's-related genes were found in 60 (13.7%) of them. While not all of these variants are known to be pathogenic, the frequency of mutations in these genes is significantly higher than it is in the general population.

The researchers estimate that about 5% of those with late-onset Alzheimer's disease have changes in these genes. They suggest that, at least in some cases, the same causes may underlie both early- and late-onset disease. The difference being that those that develop it later have more protective factors.

Another gene identified in early-onset Alzheimer's

A study of the genes from 130 families suffering from early-onset Alzheimer's disease has found that 116 had mutations on genes already known to be involved (APP, PSEN1, PSEN2 — see below for some older reports on these genes), while five of the other 14 families all showed mutations on a new gene: SORL1.

I say ‘new gene’ because it hasn’t been implicated in early-onset Alzheimer’s before. However, it has been implicated in the more common late-onset Alzheimer’s, and last year a study reported that the gene was associated with differences in hippocampal volume in young, healthy adults.

The finding, then, provides more support for the idea that some cases of early-onset and late-onset Alzheimer’s have the same causes.

The SORL1 gene codes for a protein involved in the production of the beta-amyloid peptide, and the mutations seen in this study appear to cause an under-expression of SORL1, resulting in an increase in the production of the beta-amyloid peptide. Such mutations were not found in the 1500 ethnicity-matched controls.


Older news reports on these other early-onset genes (brought over from the old website):

New genetic cause of Alzheimer's disease

Amyloid protein originates when it is cut by enzymes from a larger precursor protein. In very rare cases, mutations appear in the amyloid precursor protein (APP), causing it to change shape and be cut differently. The amyloid protein that is formed now has different characteristics, causing it to begin to stick together and precipitate as amyloid plaques. A genetic study of Alzheimer's patients younger than 70 has found genetic variations in the promoter that increases the gene expression and thus the formation of the amyloid precursor protein. The higher the expression (up to 150% as in Down syndrome), the younger the patient (starting between 50 and 60 years of age). Thus, the amount of amyloid precursor protein is a genetic risk factor for Alzheimer's disease.

Theuns, J. et al. 2006. Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease. American Journal of Human Genetics, 78, 936-946.

Evidence that Alzheimer's protein switches on genes

Amyloid b-protein precursor (APP) is snipped apart by enzymes to produce three protein fragments. Two fragments remain outside the cell and one stays inside. When APP is produced in excessive quantities, one of the cleaved segments that remains outside the cell, called the amyloid b-peptides, clumps together to form amyloid plaques that kill brain cells and may lead to the development of Alzheimer’s disease. New research indicates that the short "tail" segment of APP that is trapped inside the cell might also contribute to Alzheimer’s disease, through a process called transcriptional activation - switching on genes within the cell. Researchers speculate that creation of amyloid plaque is a byproduct of a misregulation in normal APP processing.

[2866] Cao, X., & Südhof T. C.
(2001).  A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60.
Science. 293(5527), 115 - 120.

Inactivation of Alzheimer's genes in mice causes dementia and brain degeneration

Mutations in two related genes known as presenilins are the major cause of early onset, inherited forms of Alzheimer's disease, but how these mutations cause the disease has not been clear. Since presenilins are involved in the production of amyloid peptides (the major components of amyloid plaques), it was thought that such mutations might cause Alzheimer’s by increasing brain levels of amyloid peptides. Accordingly, much effort has gone into identifying compounds that could block presenilin function. Now, however, genetic engineering in mice has revealed that deletion of these genes causes memory loss and gradual death of nerve cells in the mouse brain, demonstrating that the protein products of these genes are essential for normal learning, memory and nerve cell survival.

Saura, C.A., Choi, S-Y., Beglopoulos, V., Malkani, S., Zhang, D., Shankaranarayana Rao, B.S., Chattarji, S., Kelleher, R.J.III, Kandel, E.R., Duff, K., Kirkwood, A. & Shen, J. 2004. Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration. Neuron, 42 (1), 23-36.

[2858] Consortium, E N I G M-A(ENIGMA)., & Cohorts Heart Aging Research Genomic Epidemiology(charge)
(2012).  Common variants at 12q14 and 12q24 are associated with hippocampal volume.
Nature Genetics. 44(5), 545 - 551.

[2909] Taal, R. H., Pourcain B S., Thiering E., Das S., Mook-Kanamori D. O., Warrington N. M., et al.
(2012).  Common variants at 12q15 and 12q24 are associated with infant head circumference.
Nature Genetics. 44(5), 532 - 538.

[2859] Cohorts Heart Aging Research Genomic Epidemiology,(charge), & Consortium E G G(EGG).
(2012).  Common variants at 6q22 and 17q21 are associated with intracranial volume.
Nature Genetics. 44(5), 539 - 544.

[2907] Stein, J. L., Medland S. E., Vasquez A A., Hibar D. P., Senstad R. E., Winkler A. M., et al.
(2012).  Identification of common variants associated with human hippocampal and intracranial volumes.
Nature Genetics. 44(5), 552 - 561.

[2925] Bell, R. D., Winkler E. A., Singh I., Sagare A. P., Deane R., Wu Z., et al.
(2012).  Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.

Kang, J. H., & Grodstein F. (2012).  Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiology of Aging. 33(7), 1129 - 1137.

Skoog, I., Olesen P. J., Blennow K., Palmertz B., Johnson S. C., & Bigler E. D. (2012).  Head size may modify the impact of white matter lesions on dementia. Neurobiology of Aging. 33(7), 1186 - 1193.

[2728] Cruchaga, C., Chakraverty S., Mayo K., Vallania F. L. M., Mitra R. D., Faber K., et al.
(2012).  Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families.
PLoS ONE. 7(2), e31039 - e31039.

Full text available at

[2897] Pottier, C., Hannequin D., Coutant S., Rovelet-Lecrux A., Wallon D., Rousseau S., et al.
(2012).  High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.
Molecular Psychiatry.

McCarthy, J. J., Saith S., Linnertz C., Burke J. R., Hulette C. M., Welsh-Bohmer K. A., et al. (2012).  The Alzheimer's associated 5′ region of the SORL1 gene cis regulates SORL1 transcripts expression. Neurobiology of Aging. 33(7), 1485.e1-1485.e8 - 1485.e1-1485.e8

The evidence that adult brains could grow new neurons was a game-changer, and has spawned all manner of products to try and stimulate such neurogenesis, to help fight back against age-related cognitive decline and even dementia. An important study in the evidence for the role of experience and training in growing new neurons was Maguire’s celebrated study of London taxi drivers, back in 2000.

The small study, involving 16 male, right-handed taxi drivers with an average experience of 14.3 years (range 1.5 to 42 years), found that the taxi drivers had significantly more grey matter (neurons) in the posterior hippocampus than matched controls, while the controls showed relatively more grey matter in the anterior hippocampus. Overall, these balanced out, so that the volume of the hippocampus as a whole wasn’t different for the two groups. The volume in the right posterior hippocampus correlated with the amount of experience the driver had (the correlation remained after age was accounted for).

The posterior hippocampus is preferentially involved in spatial navigation. The fact that only the right posterior hippocampus showed an experience-linked increase suggests that the right and left posterior hippocampi are involved in spatial navigation in different ways. The decrease in anterior volume suggests that the need to store increasingly detailed spatial maps brings about a reorganization of the hippocampus.

But (although the experience-related correlation is certainly indicative) it could be that those who manage to become licensed taxi drivers in London are those who have some innate advantage, evidenced in a more developed posterior hippocampus. Only around half of those who go through the strenuous training program succeed in qualifying — London taxi drivers are unique in the world for being required to pass through a lengthy training period and pass stringent exams, demonstrating their knowledge of London’s 25,000 streets and their idiosyncratic layout, plus 20,000 landmarks.

In this new study, Maguire and her colleague made a more direct test of this question. 79 trainee taxi drivers and 31 controls took cognitive tests and had their brains scanned at two time points: at the beginning of training, and 3-4 years later. Of the 79 would-be taxi drivers, only 39 qualified, giving the researchers three groups to compare.

There were no differences in cognitive performance or brain scans between the three groups at time 1 (before training). At time 2 however, when the trainees had either passed the test or failed to acquire the Knowledge, those trainees that qualified had significantly more gray matter in the posterior hippocampus than they had had previously. There was no change in those who failed to qualify or in the controls.

Unsurprisingly, both qualified and non-qualified trainees were significantly better at judging the spatial relations between London landmarks than the control group. However, qualified trainees – but not the trainees who failed to qualify – were worse than the other groups at recalling a complex visual figure after 30 minutes (see here for an example of such a figure). Such a finding replicates previous findings of London taxi drivers. In other words, their improvement in spatial memory as it pertains to London seems to have come at a cost.

Interestingly, there was no detectable difference in the structure of the anterior hippocampus, suggesting that these changes develop later, in response to changes in the posterior hippocampus. However, the poorer performance on the complex figure test may be an early sign of changes in the anterior hippocampus that are not yet measurable in a MRI.

The ‘Knowledge’, as it is known, provides a lovely real-world example of expertise. Unlike most other examples of expertise development (e.g. music, chess), it is largely unaffected by childhood experience (there may be some London taxi drivers who began deliberately working on their knowledge of London streets in childhood, but it is surely not common!); it is developed through a training program over a limited time period common to all participants; and its participants are of average IQ and education (average school-leaving age was around 16.7 years for all groups; average verbal IQ was around or just below 100).

So what underlies this development of the posterior hippocampus? If the qualified and non-qualified trainees were comparable in education and IQ, what determined whether a trainee would ‘build up’ his hippocampus and pass the exams? The obvious answer is hard work / dedication, and this is borne out by the fact that, although the two groups were similar in the length of their training period, those who qualified spent significantly more time training every week (an average of 34.5 hours a week vs 16.7 hours). Those who qualified also attended far more tests (an average of 15.6 vs 2.6).

While neurogenesis is probably involved in this growth within the posterior hippocampus, it is also possible that growth reflects increases in the number of connections, or in the number of glia. Most probably (I think), all are involved.

There are two important points to take away from this study. One is its clear demonstration that training can produce measurable changes in a brain region. The other is the indication that this development may come at the expense of other regions (and functions).

In the first mouse study, when young and old mice were conjoined, allowing blood to flow between the two, the young mice showed a decrease in neurogenesis while the old mice showed an increase. When blood plasma was then taken from old mice and injected into young mice, there was a similar decrease in neurogenesis, and impairments in memory and learning.

Analysis of the concentrations of blood proteins in the conjoined animals revealed the chemokine (a type of cytokine) whose level in the blood showed the biggest change — CCL11, or eotaxin. When this was injected into young mice, they indeed showed a decrease in neurogenesis, and this was reversed once an antibody for the chemokine was injected. Blood levels of CCL11 were found to increase with age in both mice and humans.

The chemokine was a surprise, because to date the only known role of CCL11 is that of attracting immune cells involved in allergy and asthma. It is thought that most likely it doesn’t have a direct effect on neurogenesis, but has its effect through, perhaps, triggering immune cells to produce inflammation.

Exercise is known to at least partially reverse loss of neurogenesis. Exercise has also been shown to produce chemicals that prevent inflammation. Following research showing that exercise after brain injury can help the brain repair itself, another mouse study has found that mice who exercised regularly produced interleukin-6 (a cytokine involved in immune response) in the hippocampus. When the mice were then exposed to a chemical that destroys the hippocampus, the interleukin-6 dampened the harmful inflammatory response, and prevented the loss of function that is usually observed.

One of the actions of interleukin-6 that brings about a reduction in inflammation is to inhibit tumor necrosis factor. Interestingly, I previously reported on a finding that inhibiting tumor necrosis factor in mice decreased cognitive decline that often follows surgery.

This suggests not only that exercise helps protect the brain from the damage caused by inflammation, but also that it might help protect against other damage, such as that caused by environmental toxins, injury, or post-surgical cognitive decline. The curry spice cucurmin, and green tea, are also thought to inhibit tumor necrosis factor.

A three-year study following 1,262 healthy older Canadians (aged 67-84) has found that, among those who exercised little, those who had high-salt diets showed significantly greater cognitive decline. On the bright side, sedentary older adults who had low-salt consumption did not show cognitive decline over the three years. And those who had higher levels of physical activity did not show any association between salt and cognition.

Low sodium intake is associated with reduced blood pressure and risk of heart disease, adding even more weight to the mantra: what’s good for the heart is good for the brain.

The analysis controlled for age, sex, education, waist circumference, diabetes, and dietary intakes. Salt intake was based on a food frequency questionnaire. Low sodium intake was defined as not exceeding 2,263 mg/day; mid sodium intake 3,090 mg/day; and high sodium intake 3,091 and greater mg/day. A third of the participants fell into each group. Physical activity was also measured by a self-reported questionnaire (Physical Activity Scale for the Elderly). Cognitive function was measured by the Modified MMSE.

And adding to the evidence that exercise is good for you (not that we really need any more!), a rat study has found that aging rats that ran just over half a kilometer each week were protected against long-term memory loss that can happen suddenly following bacterial infection.

Previous research found that older rats experienced memory loss following E. coli infection, but young adult rats did not. In the older animals, microglia (the brain’s immune cells) were more sensitive to infection, releasing greater quantities of inflammatory molecules called cytokines in the hippocampus. This exaggerated response brought about impairments in synaptic plasticity (the neural changes that underlie learning) and reductions in BDNF.

In this study, the rats were given unlimited access to running wheels. Although the old rats only ran an average of 0.43 miles per week (50 times less distance than the young rats), they performed better on a memory test than rats who only had access to a locked exercise wheel. Moreover, the runners performed as well on the memory test as rats that were not exposed to E. coli.

The researchers are now planning to examine the role that stress hormones may play in sensitizing microglia, and whether physical exercise slows these hormones in older rats.

It wasn’t so long ago we believed that only young brains could make neurons, that once a brain was fully matured all it could do was increase its connections. Then we found out adult brains could make new neurons too (but only in a couple of regions, albeit critical ones). Now we know that neurogenesis in the hippocampus is vital for some operations, and that the production of new neurons declines with age (leading to the idea that the reduction in neurogenesis may be one reason for age-related cognitive decline).

What we didn’t know is why this happens. A new study, using mice genetically engineered so that different classes of brain cells light up in different colors, has now revealed the life cycle of stem cells in the brain.

Adult stem cells differentiate into progenitor cells that ultimately give rise to mature neurons. It had been thought that the stem cell population remained stable, but that these stem cells gradually lose their ability to produce neurons. However, the mouse study reveals that during the mouse's life span, the number of brain stem cells decreased 100-fold. Although the rate of this decrease actually slows with age, and the output per cell (the number of progenitor cells each stem cell produces) increases, nevertheless the pool of stem cells is dramatically reduced over time.

The reason this happens (and why it wasn’t what we expected) is explained in a computational model developed from the data. It seems that stem cells in the brain differ from other stem cells. Adult stem cells in the brain wait patiently for a long time until they are activated. They then undergo a series of rapid divisions that give rise to progeny that differentiate into neurons, before ‘retiring’ to become astrocytes. What this means is that, unlike blood or gut stem cells (that renew themselves many times), brain stem cells are only used once.

This raises a somewhat worrying question: if we encourage neurogenesis (e.g. by exercise or drugs), are we simply using up stem cells prematurely? The researchers suggest the answer depends on how the neurogenesis has been induced. Parkinson's disease and traumatic brain injury, for example, activate stem cells directly, and so may reduce the stem cell population. However, interventions such as exercise stimulate the progenitor cells, not the stem cells themselves.

Following several recent studies pointing to the negative effect of air pollution on children’s cognitive performance (see this April 2010 news report and this May 2011 report), a study of public schools in Michigan has found that 62.5% of the 3660 schools in the state are located in areas with high levels of industrial pollution, and those in areas with the highest industrial air pollution levels had the lowest attendance rates and the highest proportions of students who failed to meet state educational testing standards in English and math. Attendance rates are a potential indicator of health levels.

Minority students were especially hit by this — 81.5% of African American and 62.1% of Hispanic students attend schools in the top 10% of the most polluted areas, compared to 44.4% of white students.

Almost all (95%) of the industrial air pollution around schools comes from 12 chemicals (diisocyanates, manganese, sulfuric acid, nickel, chlorine, chromium, trimethylbenzene, hydrochloric acid, molybdenum trioxide, lead, cobalt and glycol ethers) that are all implicated in negative health effects, including increased risk of respiratory, cardiovascular, developmental and neurological disorders, as well as cancer.

There are potentially two issues here: the first is that air pollution causes health issues which lower school attendance and thus impacts academic performance; the other is that the pollution also directly effects the brain, thus affecting cognitive performance.

A new mouse study looking at the effects of air pollution on learning and memory has now found that male mice exposed to polluted air for six hours a day, five days a week for 10 months (nearly half their lifespan), performed significantly more poorly on learning and memory tasks than those male mice living in filtered air. They also showed more signs of anxiety- and depressive-like behaviors.

These changes in behavior and cognition were linked to clear differences in the hippocampus — those exposed to polluted air had fewer dendritic spines in parts of the hippocampus (CA1 and CA3 regions), shorter dendrites and overall reduced cell complexity. Previous mouse research has also found that such pollution causes widespread inflammation in the body, and can be linked to high blood pressure, diabetes and obesity. In the present study, the same low-grade inflammation was found in the hippocampus. The hippocampus is particularly sensitive to damage caused by inflammation.

The level of pollution the mice were exposed to was equivalent to what people may be exposed to in some polluted urban areas.

Twice a week for four weeks, female hamsters were subjected to six-hour time shifts equivalent to a New York-to-Paris airplane flight. Cognitive tests taken during the last two weeks of jet lag and a month after recovery from it revealed difficulty learning simple tasks that control hamsters achieved easily. Furthermore, the jet-lagged hamsters had only half the number of new neurons in the hippocampus that the control hamsters had.

The findings support earlier research indicating that chronic jet lag impairs memory and learning and reduces the size of the temporal lobe, and points to the loss of brain tissue as being due to reduced neurogenesis in the hippocampus. Although further research is needed to clarify this, indications are that the problem is not so much fewer neurons being created, but fewer new cells maturing into working cells, or perhaps new cells dying prematurely.

Hamsters are excellent subjects for circadian rhythm research because their rhythms are so precise.

Brain imaging of 49 children aged 9-10 has found that those who were physically fit had a hippocampus significantly bigger (around 12%) than those who were not fit. Animal studies and those with older adults have shown that aerobic exercise increases the growth of new brain cells in the hippocampus. Physical fitness was measured by how efficiently the children used oxygen while running on a treadmill. Fitter children also did better on tests of relational (but not item) memory, and this association was directly mediated by hippocampal volume.

Older news items (pre-2010) brought over from the old website

Neurogenesis improved in Alzheimer mice

Studies of adult neurogenesis in genetically engineered mice have revealed two main reasons why amyloid-beta peptides and apolipoprotein E4 impair neurogenesis, and identified drug treatments that can fix it. The findings point to a deficit in GABAergic neurotransmission or an imbalance between GABAergic and glutamatergic neurotransmission as an important contributor to impaired neurogenesis in Alzheimer’s. While stem cell therapy for Alzheimer’s is still a long way off, these findings are a big step toward that goal.

Gang Li et al. 2009. GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knockin Mice. Cell Stem Cell, 5 (6), 634-645.

Binggui Sun et al. 2009. Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer's Disease. Cell Stem Cell, 5 (6), 624-633.

Mouse study points to possible treatment for chemobrain

A mouse study has found that four commonly used chemotherapy drugs disrupt neurogenesis, and that the condition could be partially reversed with the growth hormone IGF-1. Surprising the researchers, both the drugs which cross the blood-brain barrier (cyclophosphamide and fluorouracil) and the two that don’t (paclitaxel and doxorubicin) reduced neurogenesis, with fluorouracil producing a 15.4% reduction, compared to 22.4% with doxorubicin, 30.5% with cyclophosphamide, 36% with paclitaxel. A second study of a single high dose of cyclophosphamide, a mainstay of breast cancer treatment, resulted in a 40.9% reduction. Administration of the experimental growth hormone IGF-1 helped in all cases, but was more effective with the high dose.

[1472] Janelsins, M. C., Roscoe J. A., Michel J. Berg, Thompson B. D., Gallagher M. J., Morrow G. R., et al.
(2009).  IGF-1 Partially Restores Chemotherapy-Induced Reductions in Neural Cell Proliferation in Adult C57BL/6 Mice.
Cancer Investigation.

Nerve-cell transplants help brain-damaged rats recover lost ability to learn

After destroying neurons in the subiculum of 48 adult rats, some were given hippocampal cells taken from newborn transgenic mice. On spatial memory tests two months later, the rats given cell transplants performed as well as rats which had not had their subiculums damaged; however, those without transplants had significantly impaired performance. The new cells were found to have mainly settled in the dentate gyrus, where they appeared to promote the secretion of two types of growth factors, namely BDNF and basic fibroblast growth factor (bFGF).

Rekha, J. et al. 2009. Transplantation of hippocampal cell lines restore spatial learning in rats with ventral subicular lesions. Behavioral Neuroscience, 123(6), 1197-1217.

Adult neurogenesis important for discriminating things that are close

A mouse study adds to our understanding of the role of adult neurogenesis — the birth of new brain cells in adults. Mice whose ability to grow new brain cells in the dentate gyrus was removed were able to learn a new location of a food reward in an eight-armed radial maze, but only when the new location was far enough from the original location. This inability to discriminate close locations was confirmed in a touch screen experiment. Computer modeling suggested that this benefit of new neurons might also apply to temporal information, helping us distinguish events occurring closely in time.

[501] Gage, F. H., Bussey T. J., Clelland C. D., Choi M., Romberg C., Clemenson G. D., et al.
(2009).  A Functional Role for Adult Hippocampal Neurogenesis in Spatial Pattern Separation.
Science. 325(5937), 210 - 213.

Baby neurons time-stamp new memories

Since its discovery ten years, adult neurogenesis has been a fruitful area of research, but although we know it’s important for learning and memory, we’re still a little vague on how. Now a new computational model suggests that immature cells are very excitable, easily provoked into firing, while older neurons are more discriminating. The dentate gyrus is designed to separate new memories into separate events (pattern separation), but the indiscriminate excitability of newborn neurons means they link events and memories that happen around the same time (pattern integration) instead. As the brain cells mature, they settle down and join established neural circuits, taking on their proper role, but clusters of neurons that "grew up" around the same time still retain the memories forged in their youth. Which is why independent events that have nothing in common but the fact that they occurred at the same time are connected in our minds: baby neurons have ‘time-stamped’ them.

[785] Aimone, J. B., Wiles J., & Gage F. H.
(2009).  Computational Influence of Adult Neurogenesis on Memory Encoding.
Neuron. 61(2), 187 - 202.

New brain cells are essential for learning

It was only a short time ago that it was accepted wisdom that new neurons were only created during childhood and that being an adult meant facing the gradual death, without replacement, of those neurons. Then, nearly a decade ago, it was discovered that adult brains could create new brain cells, albeit in a very limited way. However, it still hasn’t been clear how important adult neurogenesis is for learning and memory. Now a mouse study makes it clear that in one of the two regions in which neurogenesis takes place, it really is necessary. The study is the first to simultaneously study the two brain regions that produce new neurons, the subventricular zone and the dentate gyrus. Continual cell death was observed in the olfactory bulb, suggesting that newly born neurons (from the subventricular zone) are necessary to take their place. Neurons in the dentate gyrus, however, did not die regularly. However, when neurogenesis was knocked out in the olfactory bulb, no deficits occurred in smell memory, while the same action in the dentate gyrus did result in problems with spatial memory. The findings perhaps open up more questions than they answer — such as how odor memory is maintained when neurons in the olfactory bulb are being continuously replaced.

[1087] Kageyama, R., Imayoshi I., Sakamoto M., Ohtsuka T., Takao K., Miyakawa T., et al.
(2008).  Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain.
Nat Neurosci. 11(10), 1153 - 1161.

Injection of human umbilical cord blood helps aging brain

A rat study has found that a single intravenous injection of human umbilical cord blood mononuclear cells in aged rats significantly improved the microenvironment of the aged hippocampus and rejuvenated the aged neural stem/progenitor cells. The increase in neurogenesis seemed to be due to a decrease in inflammation. The results raise the possibility of cell therapy to rejuvenate the aged brain.

[686] Bachstetter, A., Pabon M., Cole M., Hudson C., Sanberg P., Willing A., et al.
(2008).  Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain.
BMC Neuroscience. 9(1), 22 - 22.

REM sleep deprivation reduces neurogenesis

And in another sleep study, rats deprived of REM sleep for four days showed reduced cell proliferation in the dentate gyrus of the hippocampus, where most adult neurogenesis takes place. The finding indicates that REM sleep is important for brain plasticity.

[507] Guzman-Marin, R., Suntsova N., Bashir T., Nienhuis R., Szymusiak R., & McGinty D.
(2008).  Rapid eye movement sleep deprivation contributes to reduction of neurogenesis in the hippocampal dentate gyrus of the adult rat.
Sleep. 31(2), 167 - 175.

Adult neurogenesis confirmed in primates

A study with marmosets has confirmed that the rate at which new neural cells form in the hippocampus (neurogenesis) begins to decline soon after reaching adulthood. This is the first study to confirm the finding from rodent studies in primates, and confirms that findings from rodent studies regarding ways of enhancing adult neurogenesis can be applied to primates.

[1373] Leuner, B., Kozorovitskiy Y., Gross C. G., & Gould E.
(2007).  Diminished adult neurogenesis in the marmoset brain precedes old age.
Proceedings of the National Academy of Sciences. 104(43), 17169 - 17173.

Research explains how lead exposure produces learning deficits

A rat study has shown how exposure to lead during brain development produces learning deficits — by reducing neurogenesis, and by altering the normal development of newly born neurons in the hippocampus. Dendrites (branches from neurons that make the connections with other neurons) were shorter and twisted in lead-exposed rats.

[738] Verina, T., Rohde C. A., & Guilarte T. R.
(2007).  Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats.
Neuroscience. 145(3), 1037 - 1047.

New research shows why too much memory may be a bad thing

People who are able to easily and accurately recall historical dates or long-ago events may have a harder time with word recall or remembering the day's current events. A mouse study reveals why. Neurogenesis has been thought of as a wholly good thing — having more neurons is surely a good thing — but now a mouse study has found that stopping neurogenesis in the hippocampus improved working memory. Working memory is highly sensitive to interference from information previously stored in memory, so it may be that having too much information may hinder performing everyday working memory tasks.

[635] Saxe, M. D., Malleret G., Vronskaya S., Mendez I., Garcia D. A., Sofroniew M. V., et al.
(2007).  Paradoxical influence of hippocampal neurogenesis on working memory.
Proceedings of the National Academy of Sciences. 104(11), 4642 - 4646.

Full text is available at

Sleep deprivation affects neurogenesis

A rat study has found that rats deprived of sleep for 72 hours had higher levels of the stress hormone corticosterone, and produced significantly fewer new brain cells in a particular region of the hippocampus. Preventing corticosterone levels from rising also prevented the reduction in neurogenesis.

[642] Mirescu, C., Peters J. D., Noiman L., & Gould E.
(2006).  Sleep deprivation inhibits adult neurogenesis in the hippocampus by elevating glucocorticoids.
Proceedings of the National Academy of Sciences. 103(50), 19170 - 19175.

Why neurogenesis is so much less in older brains

A rat study has revealed that the aging brain produces progressively fewer new nerve cells in the hippocampus (neurogenesis) not because there are fewer of the immature cells (neural stem cells) that can give rise to new neurons, but because they divide much less often. In young rats, around a quarter of the neural stem cells were actively dividing, but only 8% of cells in middle-aged rats and 4% in old rats were. This suggests a new approach to improving learning and memory function in the elderly.

[1077] Hattiangady, B., & Shetty A. K.
(2008).  Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus.
Neurobiology of Aging. 29(1), 129 - 147.

Neurogenesis not the sole cause of enriched environment effects

The creation of new neurons in the hippocampus (adult neurogenesis) and improved cognitive function have been repeatedly found in tandem with a more stimulating environment, and it’s been assumed that the improvement in cognitive function has resulted from the neurogenesis. However, a new study has produced the startling finding that if neurogenesis is prevented, an enriched environment still produces improved spatial memory skills and less anxiety in mice. This doesn't mean adult neurogenesis plays no role, but it does indicate that neurogenesis is not the whole story.

[601] Meshi, D., Drew M. R., Saxe M., Ansorge M. S., David D., Santarelli L., et al.
(2006).  Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment.
Nat Neurosci. 9(6), 729 - 731.

Losing sleep inhibits neurogenesis

A new sleep study using rats restricted rather than deprived them of sleep, to mimic more closely the normal human experience. The study found that the sleep-restricted rats had a harder time remembering a path through a maze compared to their rested counterparts. The sleep-restricted rats showed reduced survival rate of new hippocampus cells — learning spatial tasks increases the production of new cells in the hippocampus. This study shows that sleep plays a part in helping those new brain cells survive. However, the sleep-restricted rats that were forced to use visual and odor cues to remember their way through the maze did better on the task than their rested counterparts, implying that some types of learning don’t require sleep.

[994] Hairston, I. S., Little M. T. M., Scanlon M. D., Barakat M. T., Palmer T. D., Sapolsky R. M., et al.
(2005).  Sleep Restriction Suppresses Neurogenesis Induced by Hippocampus-Dependent Learning.
J Neurophysiol. 94(6), 4224 - 4233.

Fitness counteracts cognitive decline from hormone-replacement therapy

A study of 54 postmenopausal women (aged 58 to 80) suggests that being physically fit offsets cognitive declines attributed to long-term hormone-replacement therapy. It was found that gray matter in four regions (left and right prefrontal cortex, left parahippocampal gyrus and left subgenual cortex) was progressively reduced with longer hormone treatment, with the decline beginning after more than 10 years of treatment. Therapy shorter than 10 years was associated with increased tissue volume. Higher fitness scores were also associated with greater tissue volume. Those undergoing long-term hormone therapy had more modest declines in tissue loss if their fitness level was high. Higher fitness levels were also associated with greater prefrontal white matter regions and in the genu of the corpus callosum. The findings need to be replicated with a larger sample, but are in line with animal studies finding that estrogen and exercise have similar effects: both stimulate brain-derived neurotrophic factor.

[375] Erickson, K. I., Colcombe S. J., Elavsky S., McAuley E., Korol D. L., Scalf P. E., et al.
(2007).  Interactive effects of fitness and hormone treatment on brain health in postmenopausal women.
Neurobiology of Aging. 28(2), 179 - 185.

Immune function important for cognition

New research overturns previous beliefs that immune cells play no part in — and may indeed constitute a danger to — the brain. Following on from an earlier study that suggested that T cells — immune cells that recognize brain proteins — have the potential to fight off neurodegenerative conditions such as Alzheimer’s, researchers have found that neurogenesis in adult rats kept in stimulating environments requires these immune cells. A further study found that mice with these T cells performed better at some tasks than mice lacking the cells. The researchers suggest that age-related cognitive decline may be related to this, as aging is associated with a decrease in immune system function, suggesting that boosting the immune system may also benefit cognitive function in older adults.

[435] Ziv, Y., Ron N., Butovsky O., Landa G., Sudai E., Greenberg N., et al.
(2006).  Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood.
Nat Neurosci. 9(2), 268 - 275.

How new neurons are integrated in the adult brain

Now that we accept that new neurons can indeed be created in adult brains, the question becomes: how are these new neurons integrated into existing networks? Mouse experiments have now found that a 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. It’s hoped the discovery will help efforts to increase neuron regeneration in the brain or to make transplanted stem cells form connections more efficiently.

[237] Ge, S., Goh E. L. K., Sailor K. A., Kitabatake Y., Ming G-li., & Song H.
(2006).  GABA regulates synaptic integration of newly generated neurons in the adult brain.
Nature. 439(7076), 589 - 593.

Neuron growth in adult brain

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 remodeling 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. The finding also offers new hope that one day it may be possible to grow new cells to replace ones damaged by disease or spinal cord injury.

Lee, W.C.A., Huang, H., Feng, G., Sanes, J.R., Brown, E.N. et al. 2006. Dynamic remodeling of dendritic arbors in GABAergic interneurons of adult visual cortex. PLoS Biol 4(2): e29.

Full text available at

More light on adult neurogenesis; implications for dementia and brain injuries

New research has demonstrated that adult mice produce multi-purpose, or progenitor, cells in the hippocampus, and indicates that the stem cells ultimately responsible for adult hippocampal neurogenesis actually reside outside the hippocampus, producing progenitor cells that migrate into the neurogenic zones and proliferate to produce new neurons and glia. The finding may help in the development of repair mechanisms for people suffering from dementia and acquired brain injury.

[977] Bull, N. D., & Bartlett P. F.
(2005).  The Adult Mouse Hippocampal Progenitor Is Neurogenic But Not a Stem Cell.
J. Neurosci.. 25(47), 10815 - 10821.

Wnt signaling vital for adult neurogenesis

Neurogenesis (the birth of new neurons) only occurs in adult brains in two areas: the lateral ventricle, and the dentate gyrus (in the hippocampus). New neurons are spawned from the division of stem cells — but how do they decide whether to remain a stem cell, turn into a neuron, or a support cell (an astrocyte or oligodendrocyte)? A new study has pinpointed the protein that provides a vital chemical signal that helps this decision in the hippocampus. When Wnt3 proteins were blocked in the brains of adult mice, neurogenesis decreased dramatically; when additional Wnt3 was introduced, neurogenesis increased. Wnt3 molecules are secreted by astrocytes.

[537] Dearie, A. R., Gage F. H., Lie D-C., Colamarino S. A., Song H-J., Desire L., et al.
(2005).  Wnt signalling regulates adult hippocampal neurogenesis.
Nature. 437(7063), 1370 - 1375.

Why premature brains improve over time

A new study explains why premature babies often develop better than expected. A mouse study has found that infants born prematurely and with hypoxia (inadequate oxygen to the blood) are able to recover some cells, volume and weight in the brain after oxygen supply is restored, by a process of neurogenesis.

[1402] Fagel, D. M., Ganat Y., Silbereis J., Ebbitt T., Stewart W., Zhang H., et al.
(2006).  Cortical neurogenesis enhanced by chronic perinatal hypoxia.
Experimental Neurology. 199(1), 77 - 91.

One gene links neurogenesis with neurodegenerative diseases such as Alzheimer's

It used to be thought that the neurons we were born with (or created soon after birth) were all that we could ever have. Then it was discovered that certain neurons in specific brain regions, could be created in an adult brain (neurogenesis). A recent study has investigated the question of what’s different about these neurons, and to the researchers’ surprise, has discovered that replaceable neurons differed from unreplaceable neurons by having persistently low levels of a particular gene known as UCHL1. Intriguingly, UCHL1, expressed as a protein in high quantities throughout the brain, has also been identified as being deficient in degenerative diseases such as Alzheimer's and Parkinson's. Further research revealed that behavior that increases the chance of new neurons surviving is also associated with increases in the level of UCHL1 in replaceable neurons. The findings suggest that rising levels of UCHL1 may be associated with a reduced risk of neuronal death.

[336] Lombardino, A. J., Li X-C., Hertel M., & Nottebohm F.
(2005).  Replaceable neurons and neurodegenerative disease share depressed UCHL1 levels.
Proceedings of the National Academy of Sciences of the United States of America. 102(22), 8036 - 8041.

Social status influences brain structure

A rat study has found that dominant rats have more new nerve cells in the hippocampus than their subordinates, suggesting that social hierarchies can influence brain structure. Seven colonies of 6 rats (4 male and 2 female) established their pecking order within three days, and were tested two weeks later. The dominant males had some 30% more neurons in their dentate gyrus than both the subordinate rats and controls. The increase seems to be because the new cells constantly being born in this area of the brain (most of which usually die within a week) were surviving longer. Hippocampal neurons have already been shown to be responsive to negative factors such as stress, and positive factors such as exercise and environmental enrichment. The increase in neurons was maintained when the rats were removed from the social setting.

[372] Kozorovitskiy, Y., & Gould E.
(2004).  Dominance Hierarchy Influences Adult Neurogenesis in the Dentate Gyrus.
J. Neurosci.. 24(30), 6755 - 6759.

Learning involves the death of neurons too

When we think about learning at the neural level, it is always the birth of new neurons and new synaptic connections that is thought of. Now it appears that death is involved too. A recent rat study has found that while new cells are being generated in the hippocampus, other cells are dying off. The study distinguished two phases of learning during a water maze task: the first phase, when the rat learns to navigate the maze; and the second phase, when the learned behavior is refined. During the second phase, it appears, new cells are born in the dentate gyrus, while some of the cells that were born during the first phase, disappear. If true, this could be "a trimming mechanism that suppresses neurons that have not established learning-related synaptic connections."

[724] Dobrossy, M. D., Drapeau E., Aurousseau C., Le Moal M., Piazza P. V., & Abrous D. N.
(0).  Differential effects of learning on neurogenesis: learning increases or decreases the number of newly born cells depending on their birth date.
Mol Psychiatry. 8(12), 974 - 982.

FGF-2 implicated in adult neurogenesis

The whole question of neurogenesis (the making of new neurons) in the adult brain has been much debated – does neurogenesis happen? how does it happen? how much does it happen? Well, recent research has appeared to answer the first question – yes, neurogenesis does happen in the adult brain – and now a new study provides some clarification about the mechanism. Experiments with a special strain of laboratory-bred mice indicate that fibroblast growth factor-2 (FGF-2) is at least partly responsible for regulating the replacement of neurons, and suggest that supplementation with FGF-2 might be a beneficial strategy for those suffering traumatic brain injury, by both enhancing neurogenesis and reducing neurodegeneration.

[887] Moskowitz, M. A., Yoshimura S., Teramoto T., Whalen M. J., Irizarry M. C., Takagi Y., et al.
(2003).  FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice.
Journal of Clinical Investigation. 112(8), 1202 - 1210.

Too much exercise may be bad for the brain

Mice bred for 30 generations to display increased voluntary wheel running behavior – an "exercise addiction" – showed much higher amounts of BDNF (brain-derived neurotrophic factor – a chemical involved in protecting and producing neurons in the hippocampus) than normal, sedentary mice. In a related study, it was found that the mice also grow more neurons there as well. However, while BDNF and neurogenesis are good for learning and memory, this doesn’t necessarily mean an exercise addict learns at a faster rate. The “running addict” mice in fact performed much worse than normal mice when attempting to navigate around a maze. It could be that too much BDNF and neuron production may be a bad thing, or it may be that the hyperactive wheel running exercise actually kills or damages neurons in the hippocampus, and the high BDNF production is simply trying to minimize this damage. At the moment, all we can say with surety is that exercise greatly activates the hippocampus.

[747] Johnson, R. A., Rhodes J. S., Jeffrey S. L., Garland T., & Mitchell G. S.
(2003).  Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running.
Neuroscience. 121(1), 1 - 7.

[504] Rhodes, J. S., van Praag H., Jeffrey S., Girard I., Mitchell G. S., Garland, Theodore J., et al.
(2003).  Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running..
Behavioral Neuroscience. 117(5), 1006 - 1016.

Rat studies provide more evidence on why aging can impair memory

Among aging rats, those that have difficulty navigating water mazes have no more signs of neuron damage or cell death in the hippocampus, a brain region important in memory, than do rats that navigate with little difficulty. Nor does the extent of neurogenesis (birth of new cells in an adult brain) seem to predict poorer performance. Although the researchers have found no differences in a variety of markers for postsynaptic signals between elderly rats with cognitive impairment and those without, decreases in a presynaptic signal are correlated with worse cognitive impairment. That suggests that neurons in the impaired rat brains may not be sending signals correctly.

Gallagher, M. 2002. Markers for memory decline. Paper presented at the Society for Neuroscience annual meeting in Orlando, Florida, 5 November

New neurons in adult brains are functional

Following studies indicating that new neurons are generated in the adult mammalian hippocampus, this study demonstrates that these newly generated cells do mature into functional neurons.

[590] van Praag, H., Schinder A. F., Christie B. R., Toni N., Palmer T. D., & Gage F. H.
(2002).  Functional neurogenesis in the adult hippocampus.
Nature. 415(6875), 1030 - 1034.

Living in large groups could give you a better memory

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. Does this have relevance for humans? We don't know yet, but it has been observed that social animals such as elephants tend to have better memories than loners.

[774] Lipkind, D., Nottebohm F., Rado R., & Barnea A.
(2002).  Social change affects the survival of new neurons in the forebrain of adult songbirds.
Behavioural Brain Research. 133(1), 31 - 43.

New study contradicts earlier finding of new brain cell growth in the adult primate neocortex

A very exciting finding a couple of years ago, was that adult monkeys were found to be able to create new neurons in the neocortex, the most recently evolved part of the brain. However a new study, using the most sophisticated cell analysis techniques available to analyze thousands of cells in the neocortex, has found that those neurons that appear to be new are in fact two separate cells, usually one “old” neuron and one newly created cell of a different type, such as a glial cell — although new neurons were indeed found in the hippocampus and the olfactory bulb (both older parts of the brain).

[208] Kornack, D. R., & Rakic P.
(2001).  Cell Proliferation Without Neurogenesis in Adult Primate Neocortex.
Science. 294(5549), 2127 - 2130.


BDNF is involved in protecting and producing neurons in the hippocampus. higher levels of BDNF are associated with higher levels of neurogenesis. Neurotrophins are molecules that function in the survival, growth and migration of neurons

Nerve-cell transplants help brain-damaged rats recover lost ability to learn

After destroying neurons in the subiculum of 48 adult rats, some were given hippocampal cells taken from newborn transgenic mice. On spatial memory tests two months later, the rats given cell transplants performed as well as rats which had not had their subiculums damaged; however, those without transplants had significantly impaired performance. The new cells were found to have mainly settled in the dentate gyrus, where they appeared to promote the secretion of two types of growth factors, namely BDNF and basic fibroblast growth factor (bFGF).

Rekha, J. et al. 2009. Transplantation of hippocampal cell lines restore spatial learning in rats with ventral subicular lesions. Behavioral Neuroscience, 123(6), 1197-1217.

Exercise may counteract bad effect of high-fat diet on memory

An animal study has investigated the interaction of diet and exercise on synaptic plasticity (an important factor in learning performance). A diet high in fat reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, and impaired performance on spatial learning tasks, but both of these consequences were prevented in those animals with access to voluntary wheel-running. Exercise appeared to interact with the same molecular systems disrupted by the high-fat diet.

[883] Molteni, R., Wu A., Vaynman S., Ying Z., Barnard R. J., & Gómez-Pinilla F.
(2004).  Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor.
Neuroscience. 123(2), 429 - 440.

Too much exercise may be bad for the brain

Mice bred for 30 generations to display increased voluntary wheel running behavior – an "exercise addiction" – showed much higher amounts of BDNF (brain-derived neurotrophic factor – a chemical involved in protecting and producing neurons in the hippocampus) than normal, sedentary mice. In a related study, it was found that the mice also grow more neurons there as well. However, while BDNF and neurogenesis are good for learning and memory, this doesn’t necessarily mean an exercise addict learns at a faster rate. The “running addict” mice in fact performed much worse than normal mice when attempting to navigate around a maze. It could be that too much BDNF and neuron production may be a bad thing, or it may be that the hyperactive wheel running exercise actually kills or damages neurons in the hippocampus, and the high BDNF production is simply trying to minimize this damage. At the moment, all we can say with surety is that exercise greatly activates the hippocampus.

Johnson, R.A., Rhodes, J.S., Jeffrey, S.L., Garland, T. Jr., & Mitchell, G.S. 2003. Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running. Neuroscience, 121 (1), 1-7.

Rhodes, J.S., van Praag, H., Jeffrey, S., Girard, I., Mitchell, G.S., Garland, T. Jr., & Gage, F.H. 2003. Exercise Increases Hippocampal Neurogenesis to High Levels but Does Not Improve Spatial Learning in Mice Bredfor Increased Voluntary Wheel Running. Behavioral Neuroscience, 117 (5), 1006–1016.

Meal skipping protects the nerve cells of mice

Further to the study reported in January, a new mouse study suggests fasting every other day may protect brain neurons as well as or better than either vigorous exercise or caloric restriction. The mice were allowed to eat as much as they wanted on non-fasting days, and did not, overall, eat fewer calories than the control group. Their nerve cells however, proved to be more resistant to neurotoxin injury or death than nerve cells of both the calorie-restricted mice or the control group. Previous research has found that meal-skipping diets can stimulate brain cells in mice to produce a protein called brain-derived neurotrophic factor (BDNF) that promotes the survival and growth of nerve cells. The researchers are now investigating the effects of meal-skipping on the cardiovascular system in laboratory rats.

[1429] Anson, M. R., Guo Z., de Cabo R., Iyun T., Rios M., Hagepanos A., et al.
(2003).  Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake.
Proceedings of the National Academy of Sciences of the United States of America. 100(10), 6216 - 6220.

Gene linked to poor episodic memory

Brain derived neurotrophic factor (BDNF) plays a key role in neuron growth and survival and, it now appears, memory. We inherit two copies of the BDNF gene - one from each parent - in either of two versions. Slightly more than a third inherit at least one copy of a version nicknamed "met," which the researchers have now linked to poorer memory. Those who inherit the “met” gene appear significantly worse at remembering events that have happened to them, probably as a result of the gene’s effect on hippocampal function. Most notably, those who had two copies of the “met” gene scored only 40% on a test of episodic (event) memory, while those who had two copies of the other version scored 70%. Other types of memory did not appear to be affected. It is speculated that having the “met” gene might also increase the risk of disorders such as Alzheimer’s and Parkinsons.

[1039] Dean, M., Egan M. F., Kojima M., Callicott J. H., Goldberg T. E., Kolachana B. S., et al.
(2003).  The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function.
Cell. 112(2), 257 - 269.