Latest Research News
How exercise may protect against Alzheimer's
Previous research uncovered a hormone called irisin that is released into the circulation during physical activity, and appeared to play a role in energy metabolism. Mice studies have now found that irisin protected memory and synapses in the brain — disabling irisin in the hippocampus resulted in synapses and memory weakening; boosting brain levels of irisin improved synapses and memory.
Mice who swam nearly every day for five weeks didn’t develop memory impairment despite getting infusions of beta amyloid — however, blocking irisin completely eliminated the benefits of swimming.
Samples from brain banks have confirmed that irisin is present in the human hippocampus and that hippocampal levels of the hormone are reduced in those with Alzheimer's.
Short bouts of exercise prime the brain for learning
A mouse study found that short-term bursts of exercise (equivalent to a game of pickup basketball, or 4,000 steps) activated a gene (Mtss1L) that promotes an increase in synapses in the hippocampus — which primes the brain for learning.
Lourenco, M. V., Frozza, R. L., de Freitas, G. B., Zhang, H., Kincheski, G. C., Ribeiro, F. C., … De Felice, F. G. (2019). Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nature Medicine, 25(1), 165–175. https://doi.org/10.1038/s41591-018-0275-4
Chatzi, C., Zhang, Y., Hendricks, W. D., Chen, Y., Schnell, E., Goodman, R. H., & Westbrook, G. L. (2019). Exercise-induced enhancement of synaptic function triggered by the inverse BAR protein, Mtss1L. ELife, 8, e45920. https://doi.org/10.7554/eLife.45920
A study involving epilepsy patients who had electrodes implanted into their brain has revealed that memory consolidation during sleep doesn’t simply involve reactivation of the new memories.
Participants were given pictures to memorize, before taking an afternoon nap. Surprisingly, brainwave activity showed that both the pictures participants later remembered and those they later forgot, were reactivated during sleep. What was crucial was not the reactivation of the picture-specific gamma band activity, but its conjunction with “ripples” (extremely rapid fluctuations in activity) in the hippocampus. Only when the reactivation occurred at the same time as the ripples in the hippocampus did participants remember the picture.
What determined whether this happened? The evidence suggests that longer (and thus deeper) processing of the picture is needed, not simply a quick superficial look.
This phenomenon only occurred during nonREM sleep, not during wakefulness (the circumstances of sleep meant little time was spent in REM sleep).
The findings confirm earlier research with rodents.
Paper available at https://www.nature.com/articles/s41467-018-06553-y
(2018). Electrophysiological mechanisms of human memory consolidation.
Nature Communications. 9(1), 4103.
Do older adults forget as much as they think, or is it rather that they ‘misremember’?
A small study adds to evidence that gist memory plays an important role in false memories at any age, but older adults are more susceptible to misremembering because of their greater use of gist memory.
Gist memory is about remembering the broad story, not the details. We use schemas a lot. Schemas are concepts we build over time for events and experiences, in order to relieve the cognitive load. They allow us to respond and process faster. We build schemas for such things as going to the dentist, going to a restaurant, attending a lecture, and so on. Schemas are very useful, reminding us what to expect and what to do in situations we have experienced before. But they are also responsible for errors of perception and memory — we see and remember what we expect to see.
As we get older, we do of course build up more and firmer schemas, making it harder to really see with fresh eyes. Which means it’s harder for us to notice the details, and easier for us to misremember what we saw.
A small study involving 20 older adults (mean age 75) had participants look at 26 different pictures of common scenes (such as a farmyard, a bathroom) for about 10 seconds, and asked them to remember as much as they could about the scenes. Later, they were shown 300 pictures of objects that were either in the scene, related to the scene (but not actually in the scene), or not commonly associated to the scene, and were required to say whether or not the objects were in the picture. Brain activity was monitored during these tests. Performance was also compared with that produced in a previous identical study, involving 22 young adults (mean age 23).
As expected and as is typical, there was a higher hit rate for schematic items and a higher rate of false memories for schematically related lures (items that belong to the schema but didn’t appear in the picture). True memories activated the typical retrieval network (medial prefrontal cortex, hippocampus/parahippocampal gyrus, inferior parietal lobe, right middle temporal gyrus, and left fusiform gyrus).
Activity in some of these regions (frontal-parietal regions, left hippocampus, right MTG, and left fusiform) distinguished hits from false alarms, supporting the idea that it’s more demanding to retrieve true memories than illusory ones. This contrasts with younger adults who in this and previous research have displayed the opposite pattern. The finding is consistent, however, with the theory that older adults tend to engage frontal resources at an earlier level of difficulty.
Older adults also displayed greater activation in the medial prefrontal cortex for both schematic and non-schematic hits than young adults did.
While true memories activated the typical retrieval network, and there were different patterns of activity for schematic vs non-schematic hits, there was no distinctive pattern of activity for retrieving false memories. However, there was increased activity in the middle frontal gyrus, middle temporal gyrus, and hippocampus/parahippocampal gyrus as a function of the rate of false memories.
Imaging also revealed that, like younger adults, older adults also engage the ventromedial prefrontal cortex when retrieving schematic information, and that they do so to a greater extent. Activation patterns also support the role of the mediotemporal lobe (MTL), and the posterior hippocampus/parahippocampal gyrus in particular, in determining true memories from false. Note that schematic information is not part of this region’s concern, and there was no consistent difference in activation in this region for schematic vs non-schematic hits. But older adults showed this shift within the hippocampus, with much of the activity moving to a more posterior region.
Sensory details are also important for distinguishing between true and false memories, but, apart from activity in the left fusiform gyrus, older adults — unlike younger adults — did not show any differential activation in the occipital cortex. This finding is consistent with previous research, and supports the conclusion that older adults don’t experience the recapitulation of sensory details in the same way that younger adults do. This, of course, adds to the difficulty they have in distinguishing true and false memories.
Older adults also showed differential activation of the right MTG, involved in gist processing, for true memories. Again, this is not found in younger adults, and supports the idea that older adults depend more on schematic gist information to assess whether a memory is true.
However, in older adults, increased activation of both the MTL and the MTG is seen as rates of false alarms increase, indicating that both gist and episodic memory contribute to their false memories. This is also in line with previous research, suggesting that memories of specific events and details can (incorrectly) provide support for false memories that are consistent with such events.
Older adults, unlike young adults, failed to show differential activity in the retrieval network for targets and lures (items that fit in with the schema, but were not in fact present in the image).
What does all this mean? Here’s what’s important:
- older adults tend to use schema information more when trying to remember
- older adults find it harder to recall specific sensory details that would help confirm a memory’s veracity
- at all ages, gist processing appears to play a strong role in false memories
- memory of specific (true) details can be used to endorse related (but false) details.
What can you do about any of this? One approach would be to make an effort to recall specific sensory details of an event rather than relying on the easier generic event that comes to mind first. So, for example, if you’re asked to go to the store to pick up orange juice, tomatoes and muesli, you might end up with more familiar items — a sort of default position, as it were, because you can’t quite remember what you were asked. If you make an effort to remember the occasion of being told — where you were, how the other person looked, what time of day it was, other things you talked about, etc — you might be able to bring the actual items to mind. A lot of the time, we simply don’t make the effort, because we don’t think we can remember.
(Submitted). Differentiating True and False Schematic Memories in Older Adults.
The Journals of Gerontology: Series B.
Following previous research showing that having a smaller hippocampus is associated with increased risk of PTSD, a study involving 40 participants with PTSD and 36 trauma-exposed healthy controls has found that those PTSD patients who responded to the treatment had larger hippocampi compared to those who didn’t benefit from the therapy.
The participants were evaluated at baseline and after 10 weeks, during which time the PTSD group had prolonged exposure therapy.
The study found that both the resilient controls and the 23 patients with PTSD who responded to treatment had greater hippocampal volume at the beginning of the study than the 17 non-responders.
The findings add to growing evidence that the hippocampus is key to distinguishing between cues that signal safety and those that signal threat.
(2016). Greater hippocampal volume is associated with PTSD treatment response.
Psychiatry Research: Neuroimaging. 252, 36 - 39.
A new MRI technique has revealed that it is the structural integrity of the hippocampus more than its size that reflects fitness and correlates with cognitive performance.
Research has focused on hippocampal size because it is easier to measure, and in children and older adults there are strong correlations between hippocampal size and memory. But this is less true for healthy, young adults. This new, subtler, technique reveals that something else is going on — something that has probably been masked by the effects of size in older adults (whose hippocampi are shrinking) and younger children (whose brains are still growing).
The technique measures viscoelasticity. If the hippocampus is more elastic, memory is better. When it’s more viscous, memory is worse. Those with better aerobic fitness had better hippocampal elasticity.
(2017). Aerobic fitness, hippocampal viscoelasticity, and relational memory performance.
NeuroImage. 153, 179 - 188.
A post-mortem study of five Alzheimer's and five control brains has revealed the presence of iron-containing microglia in the subiculum of the Alzheimer's brains only. The subiculum lies within the hippocampus, a vital memory region affected early in Alzheimer's. None of the brains of those not diagnosed with Alzheimer's had the iron deposits or the microglia, in that brain region, while four of the five Alzheimer's brains contained the iron-containing microglia.
The microglia were mostly in an inflamed state. Growing evidence implicates brain inflammation in the development of Alzheimer's.
There was no consistent association between iron-laden microglia and amyloid plaques or tau in the same area.
Obviously, this is only a small study, and more research needs to be done to confirm the finding. However, this is consistent with previous findings of higher levels of iron in the hippocampi of Alzheimer's brain.
At the moment, we don't know how the iron gets into brain tissue, or why it accumulates in the subiculum. However, the researchers speculate that it may have something to do with micro-injury to small cerebral blood vessels.
This is an interesting finding that may lead to new treatment or prevention approaches if confirmed in further research.
(Submitted). Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease.
Neurobiology of Aging.
Glucose levels linked to cognitive decline in those with MCI
A study involving 264 older adults with mild cognitive impairment has found that those with normal glucose levels (167; 63%) had less cognitive decline over 2 years than those with impaired (high) glucose levels (97; 37%). They also showed less brain shrinkage and were less likely to develop Alzheimer’s. The fasting glucose levels were classified according to the American Diabetes criteria.
(2013). Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study.
The Lancet Neurology. 12(10), 957 - 965.
Rat study suggests cognitive decline in diabetics related to amyloid-beta buildup
A rat study supports the growing evidence of a link between type 2 diabetes and Alzheimer’s. In this study, 20 rats were fed a high-fat diet to give them type 2 diabetes. A subsequent test found that the diabetic rats had significantly poorer memories than the control group of rats on a healthy diet (the rats were taught to associate a dark cage with an electric shock; how long the rat continues to remember that the stimulus means a shock — as shown by their frozen reaction — is taken as a measure of how good their memory is; the diabetic rats froze for less than half the time of the controls).
The diabetic rats then had their brains (specifically, the hippocampus) injected with antibodies that disrupt amyloid-beta plaques. This produced no change in their behavior. However, when they were given antibodies that disrupt amyloid-beta oligomers (precursors of the plaques), the memory deficit was reversed, and they behaved the same as the healthy rats.
These findings suggest that the cognitive decline often seen in type 2 diabetes is not due to the disruption in insulin signaling, as thought, but rather the build-up of amyloid oligomers. Previous research has shown that the same enzymes break down both insulin and the oligomers, so when there’s a lot of insulin (which the enzymes prioritize), the enzymes don’t have as much opportunity to work on breaking down the oligomers. The oligomers collect, preventing the insulin from reaching their proper receptors in the hippocampus, which impairs cognitive function.
All this supports the idea that type 2 diabetes may be thought of as early-stage Alzheimer's. Obviously a lot more work needs to be done to confirm this picture, but certainly in the mean time, it can be taken as another reason to take type 2 diabetes very seriously.
McNay, E.C., Osborne, D., et al. 2014. Preliminary data presented at the Society for Neuroscience meeting in San Diego in November, 2013
High blood sugar makes Alzheimer’s plaque more toxic
A study of cell cultures taken from rodents’ cerebral blood vessels has found that, while cells exposed to either high glucose or amyloid-beta showed no changes in viability, exposure to both decreased cell viability by 40%. Moreover, cells from diabetic mice were more vulnerable to amyloid-beta, even at normal glucose levels.
The findings support evidence pointing to high glucose as a risk factor for vascular damage associated with Alzheimer’s, and adds weight to the view that controlling blood sugar levels is vital for those with diabetes.
(2014). Increased Susceptibility to Amyloid-β Toxicity in Rat Brain Microvascular Endothelial Cells under Hyperglycemic Conditions.
Journal of Alzheimer's Disease. 38(1), 75 - 83.
Mechanism by which diabetes increases Alzheimer's risk revealed
Although it's well-established now that diabetes is a major risk factor for dementia, the reason is still not well understood. To test the hypothesis that epigenetic changes in the brain, affecting synaptic function, may be part of the reason, the brains of diabetics and others were examined post-mortem. Diabetics' brains were found to have significantly higher expression of a class of molecules (histone deacetylases class IIa) and this was associated with impaired expression of synaptic proteins.
This finding was confirmed in mice genetically engineered to develop an Alzheimer’s-type condition, who were induced to develop diabetes. The increase of HDAC IIa was associated with synaptic impairments in the hippocampus, through the work of amyloid oligomers.
Some 60% of Alzheimer's patients have at least one serious medical condition associated with diabetes.
(2014). Epigenetic Mechanisms Linking Diabetes and Synaptic Impairments.
Diabetes. 63(2), 645 - 654.
High Blood Sugar Linked to Dementia
A seven-year study involving 2,067 older adults (average age 76 at start) has found that those with a high blood glucose level, whether or not they had diabetes, were more likely to develop dementia. Moreover, this was a linear relationship — meaning that the risk steadily increased with higher glucose levels, and decreased the lower it was. Thus, even those with ‘normal’ glucose levels were subject to this relationship, with those whose blood sugar averaged 115 milligrams per deciliter, having an 18% higher risk of dementia than those at 100 mg/dL. Other risk factors, such as high blood pressure, smoking, exercise, and education, were taken into account in the analysis.
The findings add weight to the idea that the brain is a target organ for damage by high blood sugar.
Over the course of the study, a quarter (524) developed dementia of some kind, primarily Alzheimer’s disease or vascular dementia. At the beginning of the study, 232 (11%) had diabetes, and a further 111 developed it by the end of the study. Nearly a third (32%) of those with diabetes at the beginning of the study developed dementia, compared to just under a quarter of those without (24.5%).
The journal article is freely available at http://www.nejm.org/doi/full/10.1056/NEJMoa1215740#t=article
(2013). Glucose Levels and Risk of Dementia.
New England Journal of Medicine. 369(6), 540 - 548.
Undiagnosed pre-diabetes highly prevalent in early Alzheimer's disease
A study involving 128 patients with mild to moderate Alzheimer’s disease, which had specifically excluded those with known diabetes, found that 13% of them did in fact have diabetes, and a further 30% showed glucose intolerance, a pre-diabetic condition.
Turner presented his findings at the Alzheimer's Association International Congress in Boston on July 14.
Association between hypoglycemia, dementia in older adults with diabetes
A 12-year study involving 783 older adults with diabetes (average age 74) has found that 148 (19%) developed dementia. Those 61 patients (8%) who had a reported hypoglycemic event were twice as likely to develop dementia compared to those who didn’t suffer such an event (34% vs. 17%). Similarly, those with dementia were more likely to experience a severe hypoglycemic event.
The findings suggest some patients risk entering a downward spiral in which hypoglycemia and cognitive impairment fuel one another, leading to worse health
(2013). ASsociation between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus.
JAMA Internal Medicine. 173(14), 1300 - 1306.
Dementia risk greatest for older Native-Americans and African-Americans with diabetes
In the first study to look at racial and ethnic differences in dementia risk among older adults with type 2 diabetes, Native Americans were 64% more likely to develop dementia than Asian-Americans, and African-Americans were 44% more likely. Asian-Americans had the lowest risk, and non-Hispanic whites and Latinos were intermediate.
The study involved 22,171 older adults (60+), of whom 3,796 patients (17%) developed dementia over the 10 years of the study. Almost 20% of the African-Americans and Native Americans developed dementia.
The ethnic differences were not explained by diabetes-related complications, glycemic control or duration of diabetes, or neighborhood deprivation index, body mass index, or hypertension.
(2014). Racial/Ethnic Differences in Dementia Risk Among Older Type 2 Diabetic Patients: The Diabetes and Aging Study.
Diabetes Care. 37(4), 1009 - 1015.
A study involving 97 healthy older adults (65-89) has found that those with the “Alzheimer’s gene” (APOe4) who didn’t engage in much physical activity showed a decrease in hippocampal volume (3%) over 18 months. Those with the gene who did exercise showed no change in the size of their hippocampus, nor did those without the gene, regardless of exercise. Physical activity was classified as low if the participant reported two or fewer days per week of low intensity activity, such as no activity, slow walking or light chores. Physical activity was classified as high if the participant reported three or more days/week of moderate to vigorous activity
The finding suggests that those with the risky gene will benefit most from regular exercise — indeed, this is as yet the only known means to counteract hippocampal shrinkage.
(2014). Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease.
Frontiers in Aging Neuroscience. 6,
11 new genetic susceptibility factors for Alzheimer’s identified
The largest international study ever conducted on Alzheimer's disease (I-GAP) has identified 11 new genetic regions that increase the risk of late-onset Alzheimer’s, plus 13 other genes yet to be validated. Genetic data came from 74,076 patients and controls from 15 countries.
Eleven genes for Alzheimer's disease have previously been identified.
Some of the newly associated genes confirm biological pathways already known to be involved, including the amyloid (SORL1, CASS4 ) and tau (CASS4 , FERMT2 ) pathways. The role of the immune response and inflammation (HLA-DRB5/DRB1 , INPP5D , MEF2C ) already implied by previous work (CR1, TREM2) is reinforced, as are the importance of cell migration (PTK2B), lipid transport and endocytosis (SORL1 ). New hypotheses have also emerged related to hippocampal synaptic function (MEF2C , PTK2B), the cytoskeleton and axonal transport (CELF1 , NME8, CASS4) as well as myeloid and microglial cell functions (INPP5D).
All this reinforces the idea that there are several paths to Alzheimer's, and no single treatment approach is likely to be successful.
(2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.
Nature Genetics. 45(12), 1452 - 1458.
ADAM10 mutations increase risk of Alzheimer's
Mouse studies have found that two mutations in a gene called ADAM10 (which codes for an enzyme involved in processing the amyloid precursor protein) impaired the folding of the gene, resulting in an increase in toxic amyloid-beta, and reduced neurogenesis in the hippocampus. Previous research had found that either of these mutations was associated with an increased risk of Alzheimer’s in seven families with the late-onset form of the disease.
The finding suggests that increasing ADAM10 activity might be a potential therapeutic approach.
(2013). ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function.
Neuron. 80(2), 385 - 401.
TREM2 gene variant has dramatic effect on brain atrophy
Back in January 2013, a study (initially involving 2261 Icelanders, but then repeated on data from the U.S., Norway, the Netherlands, and Germany) reported on a rare genetic variant (TREM2) that nearly trebled Alzheimer’s risk. The variant was found in 0.46% of controls aged 85+. Carriers (aged 85-100) without Alzheimer’s also had poorer cognitive function than non-carriers.
TREM2 is thought to have an anti-inflammatory role, and so it’s thought that this rare mutation reduces its effectiveness.
In a more recent study, brain scans of 478 older adults (average age 76), of whom 100 had Alzheimer's, 221 had MCI and 157 were healthy controls, found that those carrying the TREM2 mutation lost 1.4-3.3% more of their brain tissue than non-carriers, and twice as fast. The loss appeared to be concentrated in the temporal lobe and hippocampus. Those carrying the TREM2 mutation may develop the disease three years earlier than expected.
(2013). Variant of TREM2 Associated with the Risk of Alzheimer's Disease.
New England Journal of Medicine. 368(2), 107 - 116.
Rajagopalan, P., Hibar, D.P., & Thompson, P.M. (2013). TREM2 and neurodegenerative disease. The New England Journal of Medicine, 369(16), 1564-1567. Published online Oct. 16, 2013; doi:10.1056/NEJMc1306509
A new study involving 96 older adults initially free of dementia at the time of enrollment, of whom 12 subsequently developed mild Alzheimer’s, has clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads.
Specifically, it begins in the lateral entorhinal cortex (LEC), a gateway to the hippocampus. Over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular the parietal cortex. It’s thought that it spreads by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.
Mouse models comparing the effects of elevated levels of tau in the LEC with elevated levels of APP, and with elevated levels of both, found that LEC dysfunction occurred only in the mice with high levels of both tau and APP. The LEC normally accumulates tau, making it more vulnerable to the accumulation of APP.
(2014). Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease.
Nature Neuroscience. 17(2), 304 - 311.
The hippocampus is damaged early in Alzheimer’s, while the thalamus is generally unaffected until the late stages. Brain imaging of the hippocampus and the thalamus in 31 patients with Alzheimer's and 68 healthy controls has revealed increased levels of iron in the hippocampus of those with Alzheimer’s, but not in the thalamus. Moreover, this increased iron was associated with tissue damage in patients with Alzheimer's but not in the healthy older individuals.
The findings support the view that iron accumulation is a factor in the development of Alzheimer's disease. It’s theorized that the buildup of tau and amyloid-beta is a response to the destruction of myelin. Myelin, and the oligodendrocytes that produces it, have the highest levels of iron of any cells in the brain.
Raven, E.P. 2013. Increased Iron Levels and Decreased Tissue Integrity in Hippocampus of Alzheimer’s Disease Detected in vivo with Magnetic Resonance Imaging. Journal of Alzheimer’s Disease, 37 (1), 127-136
Brain scans have revealed that those who regularly practiced yoga had larger brain volume in the somatosensory cortex (maps the body), superior parietal cortex (involved in directing attention), visual cortex (perhaps because of visualization techniques), hippocampus, precuneus and the posterior cingulate cortex (the last two involved in our concept of self).
A new study adds to growing evidence of a link between sleep problems and Alzheimer’s. The interesting thing is that this association – between sleep apnea and Alzheimer’s biomarkers — wasn’t revealed until the data was separated out according to BMI.
Those with sleep apnea and a BMI under 25 showed several Alzheimer’s biomarkers (increased levels of tau in the cerebrospinal fluid, greater atrophy of the hippocampus, glucose hypometabolism in regions vulnerable to Alzheimer’s). This (with the exception of glucose hypometabolism in the mediotemporal lobe only) was not found in those with sleep apnea and a higher BMI.
The study involved 68 healthy older adults (average age 71), of whom 18 had normal breathing, 33 mild sleep apnea, and 17 moderate-severe apnea. Those in the latter group tended to have higher BMIs.
Some 10-20% of middle-aged adults in the U.S. have sleep apnea, and this jumps dramatically in those over 65 (30-60%), where the link to obesity is much smaller. The researchers suggest that early preclinical Alzheimer’s damage might be a reason, and plan follow-up research to assess what impact CPAP therapy for sleep apnea has on the Alzheimer’s biomarkers.
Those interested in the relationship between poor sleep and later development of Alzheimer’s might also like to read a Guardian article on the subject.
Osorio, R.S. et al. 2013. Sleep-Disordered Breathing, Aging And Risk For Alzheimer's Disease In Cognitively Normal Subjects. Abstract 38456. Presented at the ATS 2013 International Conference.
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.
(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 http://elife.elifesciences.org/content/2/e00362
Recent research has suggested that sleep problems might be a risk factor in developing Alzheimer’s, and in mild cognitive impairment. A new study adds to this gathering evidence by connecting reduced slow-wave sleep in older adults to brain atrophy and poorer learning.
The study involved 18 healthy young adults (mostly in their 20s) and 15 healthy older adults (mostly in their 70s). Participants learned 120 word- nonsense word pairs and were tested for recognition before going to bed. Their brain activity was recorded while they slept. Brain activity was also measured in the morning, when they were tested again on the word pairs.
As has been found previously, older adults showed markedly less slow-wave activity (both over the whole brain and specifically in the prefrontal cortex) than the younger adults. Again, as in previous studies, the biggest difference between young and older adults in terms of gray matter volume was found in the medial prefrontal cortex (mPFC). Moreover, significant differences were also found in the insula and posterior cingulate cortex. These regions, like the mPFC, have also been associated with the generation of slow waves.
When mPFC volume was taken into account, age no longer significantly predicted the extent of the decline in slow-wave activity — in other words, the decline in slow-wave activity appears to be due to the brain atrophy in the medial prefrontal cortex. Atrophy in other regions of the brain (precuneus, hippocampus, temporal lobe) was not associated with the decline in slow-wave activity when age was considered.
Older adults did significantly worse on the delayed recognition test than young adults. Performance on the immediate test did not predict performance on the delayed test. Moreover, the highest performers on the immediate test among the older adults performed at the same level as the lowest young adult performers — nevertheless, these older adults did worse the following day.
Slow-wave activity during sleep was significantly associated with performance on the next day’s test. Moreover, when slow-wave activity was taken into account, neither age nor mPFC atrophy significantly predicted test performance.
In other words, age relates to shrinkage of the prefrontal cortex, this shrinkage relates to a decline in slow-wave activity during sleep, and this decline in slow-wave sleep relates to poorer cognitive performance.
The findings confirm the importance of slow-wave brainwaves for memory consolidation.
All of this suggests that poorer sleep quality contributes significantly to age-related cognitive decline, and that efforts should be made to improve quality of sleep rather than just assuming lighter, more disturbed sleep is ‘natural’ in old age!
(2013). Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging.
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.
(2012). Neuroprotective lifestyles and the aging brain Activity, atrophy, and white matter integrity.
Neurology. 79(17), 1802 - 1808.
(2012). Benefits of Physical Exercise Training on Cognition and Quality of Life in Frail Older Adults.
The Journals of Gerontology Series B: Psychological Sciences and Social Sciences.
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.
(2012). Green tea epigallocatechin-3-gallate (EGCG) promotes neural progenitor cell proliferation and sonic hedgehog pathway activation during adult hippocampal neurogenesis.
Molecular Nutrition & Food Research. 56(8), 1292 - 1303.
Full text available at http://onlinelibrary.wiley.com/doi/10.1002/mnfr.201200035/abstract
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.
(2012). Maternal Vitamin C Deficiency during Pregnancy Persistently Impairs Hippocampal Neurogenesis in Offspring of Guinea Pigs.
PLoS ONE. 7(10),
Full text is available at http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048488
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.
(2012). Growth of language-related brain areas after foreign language learning.
NeuroImage. 63(1), 240 - 244.
We know that stress has a complicated relationship with learning, but in general its effect is negative, and part of that is due to stress producing anxious thoughts that clog up working memory. A new study adds another perspective to that.
The brain scanning study involved 60 young adults, of whom half were put under stress by having a hand immersed in ice-cold water for three minutes under the supervision of a somewhat unfriendly examiner, while the other group immersed their hand in warm water without such supervision (cortisol and blood pressure tests confirmed the stress difference).
About 25 minutes after this (cortisol reaches peak levels around 25 minutes after stress), participants’ brains were scanned while participants alternated between a classification task and a visual-motor control task. The classification task required them to look at cards with different symbols and learn to predict which combinations of cards announced rain and which sunshine. Afterward, they were given a short questionnaire to determine their knowledge of the task. The control task was similar but there were no learning demands (they looked at cards on the screen and made a simple perceptual decision).
In order to determine the strategy individuals used to do the classification task, ‘ideal’ performance was modeled for four possible strategies, of which two were ‘simple’ (based on single cues) and two ‘complex’ (based on multiple cues).
Here’s the interesting thing: while both groups were successful in learning the task, the two groups learned to do it in different ways. Far more of the non-stressed group activated the hippocampus to pursue a simple and deliberate strategy, focusing on individual symbols rather than combinations of symbols. The stressed group, on the other hand, were far more likely to use the striatum only, in a more complex and subconscious processing of symbol combinations.
The stressed group also remembered significantly fewer details of the classification task.
There was no difference between the groups on the (simple, perceptual) control task.
In other words, it seems that stress interferes with conscious, purposeful learning, causing the brain to fall back on more ‘primitive’ mechanisms that involve procedural learning. Striatum-based procedural learning is less flexible than hippocampus-based declarative learning.
Why should this happen? Well, the non-conscious procedural learning going on in the striatum is much less demanding of cognitive resources, freeing up your working memory to do something important — like worrying about the source of the stress.
Unfortunately, such learning will not become part of your more flexible declarative knowledge base.
The finding may have implications for stress disorders such as depression, addiction, and PTSD. It may also have relevance for a memory phenomenon known as “forgotten baby syndrome”, in which parents forget their babies in the car. This may be related to the use of non-declarative memory, because of the stress they are experiencing.
(2012). Stress Modulates the Engagement of Multiple Memory Systems in Classification Learning.
The Journal of Neuroscience. 32(32), 11042 - 11049.
Memory problems in those with mild cognitive impairment may begin with problems in visual discrimination and vulnerability to interference — a hopeful discovery in that interventions to improve discriminability and reduce interference may have a flow-on effect to cognition.
The study compared the performance on a complex object discrimination task of 7 patients diagnosed with amnestic MCI, 10 older adults considered to be at risk for MCI (because of their scores on a cognitive test), and 19 age-matched controls. The task involved the side-by-side comparison of images of objects, with participants required to say, within 15 seconds, whether the two objects were the same or different.
In the high-interference condition, the objects were blob-like and presented as black and white line-drawings, with some comparison pairs identical, while others only varied slightly in either shape or fill pattern. Objects were rotated to discourage a simple feature-matching strategy. In the low-interference condition, these line-drawings were interspersed with color photos of everyday objects, for which discriminability was dramatically easier. The two conditions were interspersed by a short break, with the low interference condition run in two blocks, before and after the high interference condition.
A control task, in which the participants compared two squares that could vary in size, was run at the end.
The study found that those with MCI, as well as those at risk of MCI, performed significantly worse than the control group in the high-interference condition. There was no difference in performance between those with MCI and those at risk of MCI. Neither group was impaired in the first low-interference condition, although the at-risk group did show significant impairment in the second low-interference condition. It may be that they had trouble recovering from the high-interference experience. However, the degree of impairment was much less than it was in the high-interference condition. It’s also worth noting that the performance on this second low-interference task was, for all groups, notably higher than it was on the first low-interference task.
There was no difference between any of the groups on the control task, indicating that fatigue wasn’t a factor.
The interference task was specifically chosen as one that involved the perirhinal cortex, but not the hippocampus. The task requires the conjunction of features — that is, you need to be able to see the object as a whole (‘feature binding’), not simply match individual features. The control task, which required only the discrimination of a single feature, shows that MCI doesn’t interfere with this ability.
I do note that the amount of individual variability on the interference tasks was noticeably greater in the MCI group than the others. The MCI group was of course smaller than the other groups, but variability wasn’t any greater for this group in the control task. Presumably this variability reflects progression of the impairment, but it would be interesting to test this with a larger sample, and map performance on this task against other cognitive tasks.
Recent research has suggested that the perirhinal cortex may provide protection from visual interference by inhibiting lower-level features. The perirhinal cortex is strongly connected to the hippocampus and entorhinal cortex, two brain regions known to be affected very early in MCI and Alzheimer’s.
The findings are also consistent with other evidence that damage to the medial temporal lobe may impair memory by increasing vulnerability to interference. For example, one study has found that story recall was greatly improved in patients with MCI if they rested quietly in a dark room after hearing the story, rather than being occupied in other tasks.
There may be a working memory component to all this as well. Comparison of two objects does require shifting attention back and forth. This, however, is separate to what the researchers see as primary: a perceptual deficit.
All of this suggests that reducing “visual clutter” could help MCI patients with everyday tasks. For example, buttons on a telephone tend to be the same size and color, with the only difference lying in the numbers themselves. Perhaps those with MCI or early Alzheimer’s would be assisted by a phone with varying sized buttons and different colors.
The finding also raises the question: to what extent is the difficulty Alzheimer’s patients often have in recognizing a loved one’s face a discrimination problem rather than a memory problem?
Finally, the performance of the at-risk group — people who had no subjective concerns about their memory, but who scored below 26 on the MoCA (Montreal Cognitive Assessment — a brief screening tool for MCI) — suggests that vulnerability to visual interference is an early marker of cognitive impairment that may be useful in diagnosis. It’s worth noting that, across all groups, MoCA scores predicted performance on the high-interference task, but not on any of the other tasks.
So how much cognitive impairment rests on problems with interference?
Newsome, R. N., Duarte, A., & Barense, M. D. (2012). Reducing Perceptual Interference Improves Visual Discrimination in Mild Cognitive Impairment : Implications for a Model of Perirhinal Cortex Function, Hippocampus, 22, 1990–1999. doi:10.1002/hipo.22071
Della Sala S, Cowan N, Beschin N, Perini M. 2005. Just lying there, remembering: Improving recall of prose in amnesic patients with mild cognitive impairment by minimising interference. Memory, 13, 435–440.
My recent reports on brain training for older adults (see, e.g., Review of working memory training programs finds no broader benefit; Cognitive training shown to help healthy older adults; Video game training benefits cognition in some older adults) converge on the idea that cognitive training can indeed be beneficial for older adults’ cognition, but there’s little wider transfer beyond the skills being practiced. That in itself can be valuable, but it does reinforce the idea that the best cognitive training covers a number of different domains or skill-sets. A new study adds little to this evidence, but does perhaps emphasize the importance of persistence and regularity in training.
The study involved 59 older adults (average age 84), of whom 33 used a brain fitness program 5 days a week for 30 minutes a day for at least 8 weeks, while the other group of 26 were put on a waiting list for the program. After two months, both groups were given access to the program, and both were encouraged to use it as much or as little as they wanted. Cognitive testing occurred before the program started, at two months, and at six months.
The first group to use the program used the program on average for 80 sessions, compared to an average 44 sessions for the wait-list group.
The higher use group showed significantly higher cognitive scores (delayed memory test; Boston Naming test) at both two and six months, while the lower (and later) use group showed improvement at the end of the six month period, but not as much as the higher use group.
I’m afraid I don’t have any more details (some details of the training program would be nice) because it was a conference presentation, so I only have access to the press release and the abstract. Because we don’t know exactly what the training entailed, we don’t know the extent to which it practiced the same skills that were tested. But we may at least add it to the evidence that you can improve cognitive skills by regular training, and that the length/amount of training (and perhaps regularity, since the average number of sessions for the wait-list group implies an average engagement of some three times a week, while the high-use group seem to have maintained their five-times-a-week habit) matters.
Another interesting presentation at the conference was an investigation into mental stimulating activities and brain activity in older adults.
In this study, 151 older adults (average age 82) from the Rush Memory and Aging Project answered questions about present and past cognitive activities, before undergoing brain scans. The questions concerned how frequently they engaged in mentally stimulating activities (such as reading books, writing letters, visiting a library, playing games) and the availability of cognitive resources (such as books, dictionaries, encyclopedias) in their home, during their lifetime (specifically, at ages 6, 12, 18, 40, and now).
Higher levels of cognitive activity and cognitive resources were also associated with better cognitive performance. Moreover, after controlling for education and total brain size, it was found that frequent cognitive activity in late life was associated with greater functional connectivity between the posterior cingulate cortex and several other regions (right orbital and middle frontal gyrus, left inferior frontal gyrus, hippocampus, right cerebellum, left inferior parietal cortex). More cognitive resources throughout life was associated with greater functional connectivity between the posterior cingulate cortex and several other regions (left superior occipital gyrus, left precuneus, left cuneus, right anterior cingulate, right middle frontal gyrus, and left inferior frontal gyrus).
Previous research has implicated a decline in connectivity with the posterior cingulate cortex in mild cognitive impairment and Alzheimer’s disease.
Cognitive activity earlier in life was not associated with differences in connectivity.
The findings provide further support for the idea “Use it or lose it!”, and suggests that mental activity protects against cognitive decline by maintaining functional connectivity in important neural networks.
Miller, K.J. et al. 2012. Memory Improves With Extended Use of Computerized Brain Fitness Program Among Older Adults. Presented August 3 at the 2012 convention of the American Psychological Association.
Han, S.D. et al. 2012. Cognitive Activity and Resources Are Associated With PCC Functional Connectivity in Older Adults. Presented August 3 at the 2012 convention of the American Psychological Association.
http://www.sciencedaily.com/releases/2012/08/120803193555.htm (first study only)
Genetic comparisons have pinpointed a specific protein as crucial for brain size, both between and within species. Another shows how genetic regulation in the frontal lobes distinguishes the human brain from that of closely related species, and points to two genes in particular as critical.
The protein determining brain size
Comparison of genome sequences from humans and other animals has revealed what may be a crucial protein in the development of the human brain. The analysis found that humans have more than 270 copies of a protein called DUF1220 — more than any other animal studied — and that the number of copies in a species seems to match how close they are to us. Chimpanzees, for example, have 125, and gorillas 99, while marmosets have only 30, and mice just one.
Moreover, comparison of humans with microcephaly and macrocephaly reveals that those with microcephaly (“small brain”) have lower numbers of this protein than normal for humans, and those with macrocephaly (“large brain”) have higher numbers. Copy numbers of the protein were also correlated with gray matter volume in humans without these brain disorders.
In other words, evidence from three lines of inquiry converge on DUF1220 copy number being associated with brain size.
Differences in gene expression and connectivity
But the development of the human brain is not only about size. The human brain is more complex, more connected, than the brains of most other animals. Another genetic analysis has been comparing gene activity in humans, chimpanzees and rhesus macaques, using post-mortem brain tissue of three regions in particular – the frontal cortex, hippocampus and striatum.
Gene expression in the frontal lobe of humans showed a striking increase in molecular complexity, with much more elaborate regulation and connection. The biggest differences occurred in the expression of human genes involved in plasticity.
One gene in particular stood out as behaving differently in the human brain. This gene — called CLOCK, for obvious reasons — is thought to be the master regulator of our body’s clocks. The finding suggests it has influence beyond this role. Interestingly, this gene is often disrupted in mood disorders such as depression and bipolar syndrome.
A second important distinction was how many more connections there were in human brains among networks that included the language genes FOXP1 and FOXP2.
In comparison to all this, gene expression in the caudate nucleus was very similar across all three species.
The findings point to the role of learning (the genes involved in plasticity) and language in driving human brain evolution. They also highlight the need to find out more about the CLOCK gene.
(2012). DUF1220-Domain Copy Number Implicated in Human Brain-Size Pathology and Evolution.
The American Journal of Human Genetics. 91(3), 444 - 454.
(2012). Human-Specific Transcriptional Networks in the Brain.
Neuron. 75(4), 601 - 617.
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.
(2012). Ucp2 Induced by Natural Birth Regulates Neuronal Differentiation of the Hippocampus and Related Adult Behavior.
PLoS ONE. 7(8), e42911 - e42911.
Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0042911
Our life-experiences contain a wealth of new and old information. The relative proportions of these change, of course, as we age. But how do we know whether we should be encoding new information or retrieving old information? It’s easy if the information is readily accessible, but what if it’s not? Bear in mind that (especially as we get older) most information / experiences we meet share some similarity to information we already have.
This question is made even more meaningful when you consider that it is the same brain region — the hippocampus — that’s involved in both encoding and retrieval, and these two processes depend (it is thought) on two quite opposite processes. While encoding is thought to rely on pattern separation (looking for differences), retrieval is thought to depend on pattern completion.
A recent study looked at what happens in the brain when people rapidly switch between encoding new objects and retrieving recently presented ones. Participants were shown 676 pictures of objects and asked to identify each one as being shown for the first time (‘new’), being repeated (‘old’), or as a modified version of something shown earlier (‘similar’). Recognizing the similar items as similar was the question of interest, as these items contain both old and new information and so the brain’s choice between encoding and retrieval is more difficult.
What they found was that participants were more likely to recognize similar items as similar (rather than old) if they had viewed a new item on the preceding trial. In other words, the experience of a new item primed them to notice novelty. Or to put it in another way: context biases the hippocampus toward either pattern completion or pattern separation.
This was supported by a further experiment, in which participants were shown both the object pictures, and also learned associations between faces and scenes. Critically, each scene was associated with two different faces. In the next learning phase, participants were taught a new scene association for one face from each pair. Each face-scene learning trial was preceded by an object recognition trial (new and old objects were shown and participants had to identify them as old or new) — critically, either a new or old object was consistently placed before a specific face-scene association. In the final test phase, participants were tested on the new face-scene associations they had just learned, as well as the indirect associations they had not been taught (that is, between the face of each pair that had not been presented during the preceding phase, and the scene associated with its partnered face).
What this found was that participants were more likely to pair indirectly related faces if those faces had been consistently preceded by old objects, rather than new ones. Moreover, they did so more quickly when the faces had been preceded by old objects rather than new ones.
This was interpreted as indicating that the preceding experience affects how well related information is integrated during encoding.
What all this suggests is that the memory activities you’ve just engaged in bias your brain toward the same sort of activities — so whether or not you notice changes to a café or instead nostalgically recall a previous meal, may depend on whether you noticed anyone you knew as you walked down the street!
An interesting speculation by the researchers is that such a memory bias (which only lasts a very brief time) might be an adaptive mechanism, reflecting the usefulness of being more sensitive to changes in new environments and less sensitive to irregularities in familiar environments.
(2012). Memory’s Penumbra: Episodic Memory Decisions Induce Lingering Mnemonic Biases.
Science. 337(6093), 485 - 487.
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!
(2012). Navigating the Auditory Scene: An Expert Role for the Hippocampus.
The Journal of Neuroscience. 32(35), 12251 - 12257.
Full text available at http://www.jneurosci.org/content/32/35/12251.abstract?sid=2d788914-e53c-...
I have reported previously on research suggesting that rapamycin, a bacterial product first isolated from soil on Easter Island and used to help transplant patients prevent organ rejection, might improve learning and memory. Following on from this research, a new mouse study has extended these findings by adding rapamycin to the diet of healthy mice throughout their life span. Excitingly, it found that cognition was improved in young mice, and abolished normal cognitive decline in older mice.
Anxiety and depressive-like behavior was also reduced, and the mice’s behavior demonstrated that rapamycin was acting like an antidepressant. This effect was found across all ages.
Three "feel-good" neurotransmitters — serotonin, dopamine and norepinephrine — all showed significantly higher levels in the midbrain (but not in the hippocampus). As these neurotransmitters are involved in learning and memory as well as mood, it is suggested that this might be a factor in the improved cognition.
Other recent studies have suggested that rapamycin inhibits a pathway in the brain that interferes with memory formation and facilitates aging.
(2010). Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease.
PLoS ONE. 5(4), e9979 - e9979.
(2011). Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage.
Proceedings of the National Academy of Sciences. 108(9), 3791 - 3796.
A study involving those with a strong genetic risk of developing Alzheimer’s has found that the first signs of the disease can be detected 25 years before symptoms are evident. Whether this is also true of those who develop the disease without having such a strong genetic predisposition is not yet known.
The study involved 128 individuals with a 50% chance of inheriting one of three mutations that are certain to cause Alzheimer’s, often at an unusually young age. On the basis of participants’ parents’ medical history, an estimate of age of onset was calculated.
The first observable brain marker was a drop in cerebrospinal fluid levels of amyloid-beta proteins, and this could be detected 25 years before the anticipated age of onset. Amyloid plaques in the precuneus became visible on brain scans 15-20 years before memory problems become apparent; elevated cerebrospinal fluid levels of the tau protein 10-15 years, and brain atrophy in the hippocampus 15 years. Ten years before symptoms, the precuneus showed reduced use of glucose, and slight impairments in episodic memory (as measured in the delayed-recall part of the Wechsler’s Logical Memory subtest) were detectable. Global cognitive impairment (measured by the MMSE and the Clinical Dementia Rating scale) was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.
Family members without the risky genes showed none of these changes.
The risky genes are PSEN1 (present in 70 participants), PSEN2 (11), and APP (7) — note that together these account for 30-50% of early-onset familial Alzheimer’s, although only 0.5% of Alzheimer’s in general. The ‘Alzheimer’s gene’ APOe4 (which is a risk factor for sporadic, not familial, Alzheimer’s), was no more likely to be present in these carriers (25%) than noncarriers (22%), and there were no gender differences. The average parental age of symptom onset was 46 (note that this pushes back the first biomarker to 21! Can we speculate a connection to noncarriers having significantly more education than carriers — 15 years vs 13.9?).
The results paint a clear picture of how Alzheimer’s progresses, at least in this particular pathway. First come increases in the amyloid-beta protein, followed by amyloid pathology, tau pathology, brain atrophy, and decreased glucose metabolism. Following this biological cascade, cognitive impairment ensues.
The degree to which these findings apply to the far more common sporadic Alzheimer’s is not known, but evidence from other research is consistent with this progression.
It must be noted, however, that the findings are based on cross-sectional data — that is, pieced together from individuals at different ages and stages. A longitudinal study is needed to confirm.
The findings do suggest the importance of targeting the first step in the cascade — the over-production of amyloid-beta — at a very early stage.
Researchers encourage people with a family history of multiple generations of Alzheimer’s diagnosed before age 55 to register at http://www.DIANXR.org/, if they would like to be considered for inclusion in any research.
(2012). Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease.
New England Journal of Medicine. 120723122607004 - 120723122607004.
Interpreting brain activity is a very tricky business. Even the most basic difference can be interpreted in two ways — i.e., what does it mean if a region is more active in one group of people compared to another? A new study not only indicates a new therapeutic approach to amnestic mild cognitive impairment, but also demonstrates the folly of assuming that greater activity is good.
Higher activity in the dentate gyrus/CA3 region of the hippocampus is often seen in disorders associated with an increased Alzheimer's risk, such as aMCI. It’s been thought, reasonably enough, that this might reflect compensatory activity, as the brain recruits extra resources in the face of memory loss. But rodent studies have suggested an alternative interpretation: that the increased activity might itself be part of the problem.
Following on from animal studies, this new study has investigated the effects of a drug that reduces hippocampal hyperactivity. The drug, levetiracetam, is used to treat epilepsy. The 17 patients with aMCI (average age 73) were given a placebo in the first two-week treatment phase and a low dose of the epilepsy drug during the second treatment phase, while 17 controls (average age 69) were given a placebo in both treatment phases. The treatments were separated by four weeks, and brain scans were given at the end of each phase. Participants carried out a cognitive task designed to assess memory errors attributable to a dysfunction in the dentate gyrus/CA3 region (note that these neighboring areas are not clearly demarcated from each other, and so are best analyzed as one).
As predicted, those with aMCI showed greater activity in this region, and treatment with the drug significantly reduced that activity. The drug treatment also significantly improved their performance on the three-choice recognition task, with a significant decrease in memory errors. It did not have a significant effect on general cognition or memory (as measured by delayed recall on the Verbal Paired Associates subtest of the Wechsler Memory Scale, the Benton Visual Retention Test, and the Buschke Selective Reminding Test).
These findings make it clear that the excess activity in the hippocampus is not compensatory, and also point to the therapeutic value of targeting this hyperactivity for those with aMCI. It also raises the possibility that other conditions might benefit from this approach. For example, those who carry the Alzheimer’s gene, APOE4, also show increased hippocampal activity.
(2012). Reduction of Hippocampal Hyperactivity Improves Cognition in Amnestic Mild Cognitive Impairment.
Neuron. 74(3), 467 - 474.
Now that we’ve pretty much established that sleep is crucial for consolidating memory, the next question is how much sleep we need.
A new study compared motor sequence learning in 16 people with mild obstructive sleep apnea to a matched control group (also attending the sleep clinic). There were no significant differences between the groups in total sleep time, sleep efficiency and sleep architecture (time spent in the various sleep stages), subjective measures of sleepiness, or performance on a psychomotor vigilance task (a task highly sensitive to sleep deprivation).
Nor were there any differences in learning performance during the training phase on the motor task.
But the interesting thing about consolidation is that skills usually improve overnight — your performance the next day will usually be better than it was at the end of your training. And here there was a significant difference between the groups, with the controls showing much greater overnight improvement on the motor sequence task. For sequences learned in the morning and tested 12 hours later on the same day, however, there were no differences between the groups.
So given all the factors relating to sleep that were the same between the two groups, what was the factor behind the group consolidation difference? It turns out it was (principally) the arousal index (arousals were scored on the basis of abrupt shifts in EEG frequency that last at least 3 seconds with 10 seconds of stable sleep preceding), and to a lesser extent the apnea-hypopnea index.
It seems likely, then, that arousals from sleep may (depending, presumably, on timing) interrupt the transfer of labile memories from the hippocampus to the neocortex for long-term storage. Thus, the more arousals you have, the more likely it is that this process will be interrupted.
(2012). Increased Sleep Fragmentation Leads to Impaired Off-Line Consolidation of Motor Memories in Humans.
PLoS ONE. 7(3), e34106 - e34106.
Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0034106
Data from the very large and long-running Cognitive Function and Ageing Study, a U.K. study involving 13,004 older adults (65+), from which 329 brains are now available for analysis, has found that cognitive lifestyle score (CLS) had no effect on Alzheimer’s pathology. Characteristics typical of Alzheimer’s, such as plaques, neurofibrillary tangles, and hippocampal atrophy, were similar in all CLS groups.
However, while cognitive lifestyle may have no effect on the development of Alzheimer's pathology, that is not to say it has no effect on the brain. In men, an active cognitive lifestyle was associated with less microvascular disease. In particular, the high CLS group showed an 80% relative reduction in deep white matter lesions. These associations remained after taking into account cardiovascular risk factors and APOE status.
This association was not found in women. However, women in the high CLS group tended to have greater brain weight.
In both genders, high CLS was associated with greater neuronal density and cortical thickness in Brodmann area 9 in the prefrontal lobe (but not, interestingly, in the hippocampus).
Cognitive lifestyle score is produced from years of education, occupational complexity coded according to social class and socioeconomic grouping, and social engagement based on frequency of contact with relatives, neighbors, and social events.
The findings provide more support for the ‘cognitive reserve’ theory, and shed some light on the mechanism, which appears to be rather different than we imagined. It may be that the changes in the prefrontal lobe (that we expected to see in the hippocampus) are a sign that greater cognitive activity helps you develop compensatory networks, rather than building up established ones. This would be consistent with research suggesting that older adults who maintain their cognitive fitness do so by developing new strategies that involve different regions, compensating for failing regions.
(2012). Multiple Biological Pathways Link Cognitive Lifestyle to Protection from Dementia.
Biological Psychiatry. 71(9), 783 - 791.
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.
(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.
(2012). Common variants at 12q14 and 12q24 are associated with hippocampal volume.
Nature Genetics. 44(5), 545 - 551.
(2012). Common variants at 12q15 and 12q24 are associated with infant head circumference.
Nature Genetics. 44(5), 532 - 538.
(2012). Common variants at 6q22 and 17q21 are associated with intracranial volume.
Nature Genetics. 44(5), 539 - 544.
(2012). Identification of common variants associated with human hippocampal and intracranial volumes.
Nature Genetics. 44(5), 552 - 561.
(2012). Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.
Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiology of Aging. 33(7), 1129 - 1137.(2012).
Head size may modify the impact of white matter lesions on dementia. Neurobiology of Aging. 33(7), 1186 - 1193.(2012).
(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 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031039
(2012). High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.
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(2012).
Why ‘Alzheimer’s gene’ increases Alzheimer’s risk: http://www.futurity.org/health-medicine/alzheimers-gene-opens-floodgate-in-brain/
More genes involved in Alzheimer’s: Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015918
Same genes linked to early- and late-onset Alzheimer's: http://www.eurekalert.org/pub_releases/2012-02/wuso-sgl020112.php
Another gene identified in early-onset Alzheimer's: http://www.eurekalert.org/pub_releases/2012-04/ind-ang040412.php
A new study explains how marijuana impairs working memory. The component THC removes AMPA receptors for the neurotransmitter glutamate in the hippocampus. This means that there are fewer receivers for the information crossing between neurons.
The research is also significant because it adds to the growing evidence for the role of astrocytes in neural transmission of information.
This is shown by the finding that genetically-engineered mice who lack type-1 cannabinoid receptors in their astroglia do not show impaired working memory when exposed to THC, while those who instead lacked the receptors in their neurons do. The activation of the cannabinoid receptor expressed by astroglia sends a signal to the neurons to begin the process that removes AMPA receptors, leading to long-term depression (a type of synaptic plasticity that weakens, rather than strengthens, neural connections).
(2012). Acute Cannabinoids Impair Working Memory through Astroglial CB1 Receptor Modulation of Hippocampal LTD.
Cell. 148(5), 1039 - 1050.
Quarter of British children performing poorly due to family disadvantage
A British study involving over 18,000 very young children (aged 9 months to 5 years) has found that those exposed to two or more “disadvantages” (28% of the children) were significantly more likely to have impaired intellectual development, expressed in a significantly reduced vocabulary and behavioral problems.
These differences were significant at three, and for the most part tended to widen between ages three or five (cognitive development, hyperactivity, peer problems and prosocial behaviors; the gap didn’t change for emotional problems, and narrowed for conduct problems). However, only the narrowing of the conduct problem gap and the widening of the peer problem gap was statistically significant.
Ten disadvantages were identified: living in overcrowded housing; having a teenage mother; having one or more parents with depression, parent with a physical disability; parent with low basic skills; maternal smoking during pregnancy; excessive alcohol intake; financial stress, unemployment; domestic violence..
Around 41% of the children did not face any of these disadvantages, and 30% faced only one of these disadvantages. Of those facing two or more, half of those (14%) only had two, while 7% of the total group experienced three risk factors, and fewer than 2% had five or more.
There was no dominant combination of risks, but parental depression was the most common factor (19%), followed by parental disability (15%). Violence was present in only 4% of families, and both parents unemployed in only 5.5%. While there was some correlation between various risk factors, these correlations were relatively modest for the most part. The highest correlations were between unemployment and disability; violence and depression; unemployment and overcrowding.
There were ethnic differences in rate: at 48%, Bangladeshi children were most likely to be exposed to multiple disadvantages, followed by Pakistani families (34%), other (including mixed) (33%), black African (31%), black Caribbean (29%), white (28%) and Indian (20%).
There were also differences depending on family income. Among those in the lowest income band (below £10,400 pa) — into which 21% of the families fell, the same proportion as is found nationally — nearly half had at least two risk factors, compared to 27% of those in families above this threshold. Moreover, children in families with multiple risk factors plus low income showed the lowest cognitive development (as measured by vocabulary).
Childhood maltreatment reduces size of hippocampus
In this context, it is interesting to note a recent finding that three key areas of the hippocampus were significantly smaller in adults who had experienced maltreatment in childhood. In this study, brain scans were taken of nearly 200 young adults (18-25), of whom 46% reported no childhood adversity and 16% reported three or more forms of maltreatment. Maltreatment was most commonly physical and verbal abuse from parents, but also included corporal punishment, sexual abuse and witnessing domestic violence.
Reduced volume in specific hippocampus regions (dentate gyrus, cornu ammonis, presubiculum and subiculum) was still evident after such confounding factors as a history of depression or PTSD were taken into account. The findings support the theory that early stress affects the development of subregions in the hippocampus.
While mother’s nurturing grows the hippocampus
Supporting this, another study, involving 92 children aged 7 to 10 who had participated in an earlier study of preschool depression, has found that those children who received a lot of nurturing from their parent (generally mother) developed a larger hippocampus than those who didn’t.
‘Nurturing’ was assessed in a videotaped interaction at the time of the preschool study. In this interaction, the parent performed a task while the child waited for her to finish so they could open an attractive gift. How the parent dealt with this common scenario — the degree to which they helped the child through the stress — was evaluated by independent raters.
Brain scans revealed that children who had been nurtured had a significantly larger hippocampus than those whose mothers were not as nurturing, and (this was the surprising bit), this effect was greater among the healthy, non-depressed children. Among this group, those with a nurturing parent had hippocampi which were on average almost 10% larger than those whose parent had not been as nurturing.
Sabates, R., Dex, S., Sabates, R., & Dex, S. (2012). Multiple risk factors in young children’s development. CLS Cohort Studies Working paper 2012/1.
Full text available at http://www.cls.ioe.ac.uk/news.aspx?itemid=1661&itemTitle=More+than+one+i...
(2012). Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum.
Proceedings of the National Academy of Sciences.
Full text available at http://www.pnas.org/content/early/2012/02/07/1115396109.abstract?sid=f73...
(2012). Maternal support in early childhood predicts larger hippocampal volumes at school age.
Proceedings of the National Academy of Sciences.
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).
(Submitted). Acquiring “the Knowledge” of London's Layout Drives Structural Brain Changes.
So-called ‘Gulf War syndrome’ is a poorly understood chronic condition associated with exposure to neurotoxic chemicals and nerve gas, and despite its name is associated with three main syndromes: impaired cognition (syndrome 1); confusion-ataxia (syndrome 2); central neuropathic pain (syndrome 3). Those with syndrome 2 are the most severely affected. Note that the use of the term ‘impaired cognition’ for syndrome 1 is not meant to indicate that the other syndromes show no impaired cognition; rather, it signals the absence of other primary symptoms such as ataxia and pain.
Symptoms of Gulf War syndrome include fatigue, neuropathic pain, memory and concentration deficits, balance disturbances and depression. Many of these symptoms suggest impairment of the hippocampus (among other regions, in particular the basal ganglia).
The new study follows up on an earlier study, with many of the same participants involved. A new, more sensitive, technique for assessing blood flow in the hippocampus was used to assess 35 patients with Gulf War syndromes and 13 controls. In the study of eleven years previous, those with syndrome 1 (impaired cognition) showed similar responses as the controls, while those with syndrome 2 (confusion-ataxia) showed abnormal blood flow in the right hippocampus.
In the present study, that abnormal hippocampal blood flow had progressed to the left hippocampus for those with syndrome 2 and to both hippocampi for those with syndrome 3. The results indicate that this alteration of hippocampal blood flow persists and can even worsen.
Around a quarter of U.S. military personnel deployed to the 1991 Persian Gulf War are estimated to be affected by Gulf War syndrome. Previous research has suggested genetic variation may underlie individuals’ vulnerability to neurotoxins.
(2011). Hippocampal Dysfunction in Gulf War Veterans: Investigation with ASL Perfusion MR Imaging and Physostigmine Challenge.
Radiology. 261(1), 218 - 225.
Previous research has found that carriers of the so-called KIBRA T allele have been shown to have better episodic memory than those who don’t carry that gene variant (this is a group difference; it doesn’t mean that any carrier will remember events better than any non-carrier). A large new study confirms and extends this finding.
The study involved 2,230 Swedish adults aged 35-95. Of these, 1040 did not have a T allele, 932 had one, and 258 had two. Those who had at least one T allele performed significantly better on tests of immediate free recall of words (after hearing a list of 12 words, participants had to recall as many of them as they could, in any order; in some tests, there was a concurrent sorting task during presentation or testing).
There was no difference between those with one T allele and those with two. The effect increased with increasing age. There was no effect of gender. There was no significant effect on performance of delayed category cued recall tests or a visuospatial task, although a trend in the appropriate direction was evident.
It should also be noted that the effect on immediate recall, although statistically significant, was not large.
Brain activity was studied in a subset of this group, involving 83 adults aged 55-60, plus another 64 matched on sex, age, and performance on the scanner task. A further group of 113 65-75 year-olds were included for comparison purposes. While in the scanner, participants carried out a face-name association task. Having been presented with face-name pairs, participants were tested on their memory by being shown the faces with three letters, of which one was the initial letter of the name.
Performance on the scanner task was significantly higher for T carriers — but only for the 55-60 age group, not for the 65-75 age group. Activity in the hippocampus was significantly higher for younger T carriers during retrieval, but not encoding. No such difference was seen in the older group.
This finding is in contrast with an earlier, and much smaller, study involving 15 carriers and 15 non-carriers, which found higher activation of the hippocampus in non-T carriers. This was taken at the time to indicate some sort of compensatory activity. The present finding challenges that idea.
Although higher hippocampal activation during retrieval is generally associated with faster retrieval, the higher activity seen in T carriers was not fully accounted for by performance. It may be that such activity also reflects deeper processing.
KIBRA-T carriers were neither more nor less likely to carry other ‘memory genes’ — APOEe4; COMTval158met; BDNFval66met.
The findings, then, fail to support the idea that non-carriers engage compensatory mechanisms, but do indicate that the KIBRA-T gene helps episodic memory by improving the hippocampus function.
BDNF gene variation predicts rate of age-related decline in skilled performance
In another study, this time into the effects of the BDNF gene, performance on an airplane simulation task on three annual occasions was compared. The study involved 144 pilots, of whom all were healthy Caucasian males aged 40-69, and 55 (38%) of whom turned out to have at least one copy of a BDNF gene that contained the ‘met’ variant. This variant is less common, occurring in about one in three Asians, one in four Europeans and Americans, and about one in 200 sub-Saharan Africans.
While performance dropped with age for both groups, the rate of decline was much steeper for those with the ‘met’ variant. Moreover, there was a significant inverse relationship between age and hippocampal size in the met carriers — and no significant correlation between age and hippocampal size in the non-met carriers.
Comparison over a longer time-period is now being undertaken.
The finding is more evidence for the value of physical exercise as you age — physical activity is known to increase BDNF levels in your brain. BDNF levels tend to decrease with age.
The met variant has been linked to higher likelihood of depression, stroke, anorexia nervosa, anxiety-related disorders, suicidal behavior and schizophrenia. It differs from the more common ‘val’ variant in having methionine rather than valine at position 66 on this gene. The BDNF gene has been remarkably conserved across evolutionary history (fish and mammalian BDNF have around 90% agreement), suggesting that mutations in this gene are not well tolerated.
(2011). KIBRA Polymorphism Is Related to Enhanced Memory and Elevated Hippocampal Processing.
The Journal of Neuroscience. 31(40), 14218 - 14222.
(2006). Common Kibra Alleles Are Associated with Human Memory Performance.
Science. 314(5798), 475 - 478.
(2011). BDNF polymorphism predicts the rate of decline in skilled task performance and hippocampal volume in healthy individuals.
Transl Psychiatry. 1, e51 - e51.
Full text is available at http://www.nature.com/tp/journal/v1/n10/full/tp201147a.html
Obesity has been linked to cognitive decline, but a new study involving 300 post-menopausal women has found that higher BMI was associated with higher cognitive scores.
Of the 300 women (average age 60), 158 were classified as obese (waist circumference of at least 88cm, or BMI of over 30). Cognitive performance was assessed in three tests: The Mini-Mental Statement Examination (MMSE), a clock-drawing test, and the Boston Abbreviated Test.
Both BMI and waist circumference were positively correlated with higher scores on both the MMSE and a composite cognitive score from all three tests. It’s suggested that the estrogen produced in a woman’s fat cells help protect cognitive function.
Interestingly, a previous report from the same researchers challenged the link found between metabolic syndrome and poorer cognitive function. This study, using data from a large Argentinean Cardiovascular Prevention Program, found no association between metabolic syndrome and cognitive decline — but the prevalence of metabolic syndrome and cognitive decline was higher in males than females. However, high inflammatory levels were associated with impairment of executive functions, and higher systolic blood pressure was associated with cognitive decline.
It seems clear that any connection between BMI and cognitive decline is a complex one. For example, two years ago I reported that, among older adults, higher BMI was associated with more brain atrophy (replicated below; for more recent articles relating obesity to cognitive impairment, click on the obesity link at the end of this report). Hypertension, inflammation, and diabetes have all been associated with greater risk of impairment and dementia. It seems likely that the connection between BMI and impairment is mediated through these and other factors. If your fat stores are not associated with such health risk factors, then the fat in itself is not likely to be harmful to your brain function — and may (if you’re a women) even help.
Overweight and obese elderly have smaller brains
Analysis of brain scans from 94 people in their 70s who were still "cognitively normal" five years after the scan has revealed that people with higher body mass indexes had smaller brains on average, with the frontal and temporal lobes particularly affected (specifically, in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus, in obese people, and in the basal ganglia and corona radiate of the overweight). The brains of the 51 overweight people were, on average, 6% smaller than those of the normal-weight participants, and those of the 14 obese people were 8% smaller. To put it in more comprehensible, and dramatic terms: "The brains of overweight people looked eight years older than the brains of those who were lean, and 16 years older in obese people." However, overall brain volume did not differ between overweight and obese persons. As yet unpublished research by the same researchers indicates that exercise protects these same brain regions: "The most strenuous kind of exercise can save about the same amount of brain tissue that is lost in the obese."
Zilberman, J.M., Del Sueldo, M., Cerezo, G., Castellino, S., Theiler, E. & Vicario, A. 2011. Association Between Menopause, Obesity, and Cognitive Impairment. Presented at the Physiology of Cardiovascular Disease: Gender Disparities conference, October 12, at the University of Mississippi in Jackson.
Vicario, A., Del Sueldo, M., Zilberman, J. & Cerezo, G.H. 2011. The association between metabolic syndrome, inflammation and cognitive decline. Presented at the European Society of Hypertension (ESH) 2011: 21st European Meeting on Hypertension, June 17 - 20, Milan, Italy.
(2010). Brain structure and obesity.
Human Brain Mapping. 31(3), 353 - 364.
Math-anxiety can greatly lower performance on math problems, but just because you suffer from math-anxiety doesn’t mean you’re necessarily going to perform badly. A study involving 28 college students has found that some of the students anxious about math performed better than other math-anxious students, and such performance differences were associated with differences in brain activity.
Math-anxious students who performed well showed increased activity in fronto-parietal regions of the brain prior to doing math problems — that is, in preparation for it. Those students who activated these regions got an average 83% of the problems correct, compared to 88% for students with low math anxiety, and 68% for math-anxious students who didn’t activate these regions. (Students with low anxiety didn’t activate them either.)
The fronto-parietal regions activated included the inferior frontal junction, inferior parietal lobule, and left anterior inferior frontal gyrus — regions involved in cognitive control and reappraisal of negative emotional responses (e.g. task-shifting and inhibiting inappropriate responses). Such anticipatory activity in the fronto-parietal region correlated with activity in the dorsomedial caudate, nucleus accumbens, and left hippocampus during math activity. These sub-cortical regions (regions deep within the brain, beneath the cortex) are important for coordinating task demands and motivational factors during the execution of a task. In particular, the dorsomedial caudate and hippocampus are highly interconnected and thought to form a circuit important for flexible, on-line processing. In contrast, performance was not affected by activity in ‘emotional’ regions, such as the amygdala, insula, and hypothalamus.
In other words, what’s important is not your level of anxiety, but your ability to prepare yourself for it, and control your responses. What this suggests is that the best way of dealing with math anxiety is to learn how to control negative emotional responses to math, rather than trying to get rid of them.
Given that cognitive control and emotional regulation are slow to mature, it also suggests that these effects are greater among younger students.
The findings are consistent with a theory that anxiety hinders cognitive performance by limiting the ability to shift attention and inhibit irrelevant/distracting information.
Note that students in the two groups (high and low anxiety) did not differ in working memory capacity or in general levels of anxiety.
(2011). Mathematics Anxiety: Separating the Math from the Anxiety.
You can download a copy of the study here: Math anxiety.pdf
Research into the effects of cannabis on cognition has produced inconsistent results. Much may depend on extent of usage, timing, and perhaps (this is speculation) genetic differences. But marijuana abuse is common among sufferers of schizophrenia and recent studies have shown that the psychoactive ingredient of marijuana can induce some symptoms of schizophrenia in healthy volunteers.
Now new research helps explain why marijuana is linked to schizophrenia, and why it might have detrimental effects on attention and memory.
In this rat study, a drug that mimics the psychoactive ingredient of marijuana (by activating the cannabinoid receptors) produced significant disruption in brain networks, with brain activity becoming uncoordinated and inaccurate.
In recent years it has become increasingly clear that synchronized brainwaves play a crucial role in information processing — especially that between the hippocampus and prefrontal cortex (see, for example, my reports last month on theta waves improving retrieval and the effect of running on theta and gamma rhythms). Interactions between the hippocampus and prefrontal cortex seem to be involved in working memory functions, and may provide the mechanism for bringing together memory and decision-making during goal-directed behaviors.
Consistent with this, during decision-making on a maze task, hippocampal theta waves and prefrontal gamma waves were impaired, and the theta synchronization between the two was disrupted. These effects correlated with impaired performance on the maze task.
These findings are consistent with earlier findings that drugs that activate the cannabinoid receptors disrupt the theta rhythm in the hippocampus and impair spatial working memory. This experiment extends that result to coordinated brainwaves beyond the hippocampus.
Similar neural activity is observed in schizophrenia patients, as well as in healthy carriers of a genetic risk variant.
The findings add to the evidence that working memory processes involve coordination between the prefrontal cortex and the hippocampus through theta rhythm synchronization. The findings are consistent with the idea that items are encoded and indexed along the phase of the theta wave into episodic representations and transferred from the hippocampus to the neocortex as a theta phase code. By disrupting that code, cannabis makes it more difficult to retain and index the information relevant to the task at hand.
(2011). Dysfunctional Prefrontal Cortical Network Activity and Interactions following Cannabinoid Receptor Activation.
The Journal of Neuroscience. 31(43), 15560 - 15568.
When a middle-aged woman loses her memory after sex, it naturally makes the headlines. Many might equate this sort of headline to “Man marries alien”, but this is an example of a rare condition — temporary, you will be relieved to hear — known as transient global amnesia. Such abrupt, localized loss of autobiographical memory is usually preceded by strenuous physical activity or stressful events. It generally occurs in middle-aged or older adults, but has been known to occur in younger people. In those cases, there may be a history of migraine or head trauma.
Following an earlier study in which 29 of 41 TGA patients were found to have small lesions in the CA1 region of the hippocampus, scanning of another 16 TGA patients has revealed 14 had these same lesions. It seems likely that all the patients had such lesions, but because they are very small and don’t last long, they’re easy to miss. The lesion is best seen after 24-72 hours, but is gone after 5-6 days.
At the start of one of these attacks, memory for the first 30 years of life was significantly impaired, but still much better than memory for the years after that. There was a clear temporal gradient, with memory increasingly worse for events closer in time. There was no difference between events in the previous year and events in the previous five years, but a clear jump at that five-year point.
The exact location of the lesions was significant: when the lesion was in the anterior part of the region, memory for recent events was more impaired.
The hippocampus is known to be crucially involved in episodic memory (memory for events), and an integral part of the network for autobiographical memory. In recent years, it has come to be thought that such memories are only hosted temporarily by the hippocampus, and over a few years come to be permanently lodged in the neocortex (the standard consolidation model). Evidence from a number of studies of this change at the five-year mark has been taken as support for this theory. According to this, then, older memories should be safe from hippocampal damage.
An opposing theory, however, is that the hippocampus continues to be involved in such memories, with both the neocortex and the hippocampus involved in putting together reconsolidated memories (the multiple trace model). According to this model, each retrieval of an episodic memory creates a new version in the hippocampus. The more versions, the better protected a memory will be from any damage to the hippocampus.
The findings from this study show that while there is indeed a significant difference between older and more recent memories, the CA1 region of the hippocampus continues to be crucial for retrieving older memories, and for our sense of self-continuity.
Interestingly, some studies have also found a difference between the left and right hemispheres, with the right hippocampus showing a temporal gradient and the left hippocampus showing constant activation across all time periods. Such a hemisphere difference was not found in the present study. The researchers suggest that the reason may lie in the age of the participants (average age was 68), reflecting a reduction in hemispheric asymmetry with age.
There’s another message in this study. In these cases of TGA, memory function is restored within 24 hours (and generally sooner, within 6-10 hours). This shows how fast the brain can repair damage. Similarly, the fact that such tiny lesions have temporary effects so much more dramatic than the more lasting effects of larger lesions, is also a tribute to the plasticity of the brain.
The findings are consistent with findings of a preferential degeneration of CA1 neurons in the early stages of Alzheimer's disease, and suggest a target for treatment.
(2011). “Forgettable” Sex: A Case of Transient Global Amnesia Presenting to the Emergency Department.
The Journal of Emergency Medicine. 41, 257 - 260.
(2011). CA1 neurons in the human hippocampus are critical for autobiographical memory, mental time travel, and autonoetic consciousness.
Proceedings of the National Academy of Sciences. 108(42), 17562 - 17567.
A ten-year study involving 7,239 older adults (65+) has found that each common health complaint increased dementia risk by an average of about 3%, and that these individual risks compounded. Thus, while a healthy older adult had about an 18% chance of developing dementia after 10 years, those with a dozen of these health complaints had, on average, closer to a 40% chance.
It’s important to note that these complaints were not for serious disorders that have been implicated in Alzheimer’s. The researchers constructed a ‘frailty’ index, involving 19 different health and wellbeing factors: overall health, eyesight, hearing, denture fit, arthritis/rheumatism, eye trouble, ear trouble, stomach trouble, kidney trouble, bladder control, bowel control, feet/ankle trouble, stuffy nose/sneezing, bone fractures, chest problems, cough, skin problems, dental problems, other problems.
Not all complaints are created equal. The most common complaint — arthritis/rheumatism —was only slightly higher among those with dementia. Two of the largest differences were poor eyesight (3% of the non-demented group vs 9% of those with dementia) and poor hearing (3% and 6%).
At the end of the study, 4,324 (60%) were still alive, and of these, 416 (9.6%) had Alzheimer's disease, 191 (4.4%) had another sort of dementia and 677 (15.7%) had other cognitive problems (but note that 1,023 were of uncertain cognitive ability).
While these results need to be confirmed in other research — the study used data from broader health surveys that weren’t specifically designed for this purpose, and many of those who died during the study will have probably had dementia — they do suggest the importance of maintaining good general health.
Common irregular heartbeat raises risk of dementia
In another study, which ran from 1994 to 2008 and followed 3,045 older adults (mean age 74 at study start), those with atrial fibrillation were found to have a significantly greater risk of developing Alzheimer’s.
At the beginning of the study, 4.3% of the participants had atrial fibrillation (the most common kind of chronically irregular heartbeat); a further 12.2% developed it during the study. Participants were followed for an average of seven years. Over this time, those with atrial fibrillation had a 40-50% higher risk of developing dementia of any type, including probable Alzheimer's disease. Overall, 18.8% of the participants developed some type of dementia during the course of the study.
While atrial fibrillation is associated with other cardiovascular risk factors and disease, this study shows that atrial fibrillation increases dementia risk more than just through this association. Possible mechanisms for this increased risk include:
- weakening the heart's pumping ability, leading to less oxygen going to the brain;
- increasing the chance of tiny blood clots going to the brain, causing small, clinically undetected strokes;
- a combination of these plus other factors that contribute to dementia such as inflammation.
The next step is to see whether any treatments for atrial fibrillation reduce the risk of developing dementia.
Stress may increase risk for Alzheimer's disease
And a rat study has shown that increased release of stress hormones leads to cognitive impairment and that characteristic of Alzheimer’s disease, tau tangles. The rats were subjected to stress for an hour every day for a month, by such means as overcrowding or being placed on a vibrating platform. These rats developed increased hyperphosphorylation of tau protein in the hippocampus and prefrontal cortex, and these changes were associated with memory deficits and impaired behavioral flexibility.
Previous research has shown that stress leads to that other characteristic of Alzheimer’s disease: the formation of beta-amyloid.
(2011). Nontraditional risk factors combine to predict Alzheimer disease and dementia.
Neurology. 77(3), 227 - 234.
(2011). Atrial Fibrillation and Risk of Dementia: A Prospective Cohort Study.
Journal of the American Geriatrics Society. 59(8), 1369 - 1375.
(2011). Stress Acts Cumulatively To Precipitate Alzheimer's Disease-Like Tau Pathology and Cognitive Deficits.
The Journal of Neuroscience. 31(21), 7840 - 7847.
The very large and long-running Women's Health Initiative study surprised everyone when it produced its finding that hormone therapy generally increased rather than decreased stroke risk as well as other health problems. But one explanation for that finding might be that many of the women only received hormone replacement therapy years after menopause. There are indications that timing is crucial.
This new rat study involved female rats equivalent to human 60-65 year olds, about a decade past menopause. An enzyme called CHIP (carboxyl terminus of Hsc70 interacting protein) was found to increase binding with estrogen receptors, resulting in about half the receptors getting hauled to the cell's proteosome to be chopped up and degraded. When some of the aged rats were later treated with estrogen, mortality increased. When middle-aged rats were treated with estrogen, on the other hand, results were positive.
In other words, putting in extra estrogen after the number of estrogen receptors in the brain has been dramatically decreased is a bad idea.
While this study focused on mortality, other research has produced similar conflicting results as to whether estrogen therapy helps fight age-related cognitive impairment in women (see my report). It’s interesting to note that this effect only occurred in the hippocampus — estrogen receptors in the uterus were unaffected.
(2011). C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection.
Proceedings of the National Academy of Sciences. 108(35), E617 -E624 - E617 -E624.
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.
(2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function.
Nature. 477(7362), 90 - 94.
(2011). Voluntary exercise protects hippocampal neurons from trimethyltin injury: Possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity.
Brain, Behavior, and Immunity. 25(6), 1063 - 1077.
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.
(Submitted). Sodium intake and physical activity impact cognitive maintenance in older adults: the NuAge Study.
Neurobiology of Aging.
(2011). Little Exercise, Big Effects: Reversing Aging and Infection-Induced Memory Deficits, and Underlying Processes.
The Journal of Neuroscience. 31(32), 11578 - 11586.
In the experiment, rats learned which lever to press to receive water, where the correct lever depended on which lever they had pressed previously (the levers were retractable; there was a variable delay between the first and second presentation of the levers). Microelectrodes in the rats’ brains provided data that enabled researchers to work out the firing patterns of neurons in CA1 that resulted from particular firing patterns in CA3 (previous research had established that long-term memory involves CA3 outputs being received in CA1).
Normal neural communication between these two subregions of the hippocampus was then chemically inhibited. While the rats still remembered the general rule, and still remembered that pressing the levers would gain them water, they could only remember which lever they had pressed for 5-10 seconds.
An artificial hippocampal system that could reproduce effective firing patterns (established in earlier training) was then implanted in the rats’ brains and long-term memory function was restored. Furthermore, when the ‘memory prosthetic’ was implanted in animals whose hippocampus was functioning normally, their memory improved.
The findings open up amazing possibilities for ameliorating brain damage. There is of course the greatly limiting factor that effective memory traces (spatiotemporal firing patterns) need to be recorded for each activity. This will be particularly problematic for individuals with significant damage. Perhaps one day we will all ‘record’ ourselves as a matter of course, in the same way that we might put by blood or genetic material ‘in case’! Still, it’s an exciting development.
The next step will be to repeat these results in monkeys.
(2011). A cortical neural prosthesis for restoring and enhancing memory.
Journal of Neural Engineering. 8(4), 046017 - 046017.
I’ve always felt that better thinking was associated with my brain working ‘in a higher gear’ — literally working at a faster rhythm. So I was particularly intrigued by the findings of a recent mouse study that found that brainwaves associated with learning became stronger as the mice ran faster.
In the study, 12 male mice were implanted with microelectrodes that monitored gamma waves in the hippocampus, then trained to run back and forth on a linear track for a food reward. Gamma waves are thought to help synchronize neural activity in various cognitive functions, including attention, learning, temporal binding, and awareness.
We know that the hippocampus has specialized ‘place cells’ that record where we are and help us navigate. But to navigate the world, to create a map of where things are, we need to also know how fast we are moving. Having the same cells encode both speed and position could be problematic, so researchers set out to find how speed was being encoded. To their surprise and excitement, they found that the strength of the gamma rhythm grew substantially as the mice ran faster.
The results also confirmed recent claims that the gamma rhythm, which oscillates between 30 and 120 times a second, can be divided into slow and fast signals (20-45 Hz vs 45-120 Hz for mice, consistent with the 30-55 Hz vs 45-120 Hz bands found in rats) that originate from separate parts of the brain. The slow gamma waves in the CA1 region of the hippocampus were synchronized with slow gamma waves in CA3, while the fast gamma in CA1 were synchronized with fast gamma waves in the entorhinal cortex.
The two signals became increasingly separated with increasing speed, because the two bands were differentially affected by speed. While the slow waves increased linearly, the fast waves increased logarithmically. This differential effect could have to do with mechanisms in the source regions (CA3 and the medial entorhinal cortex, respectively), or to mechanisms in the different regions in CA1 where the inputs terminate (the waves coming from CA3 and the entorhinal cortex enter CA1 in different places).
In the hippocampus, gamma waves are known to interact with theta waves. Further analysis of the data revealed that the effects of speed on gamma rhythm only occurred within a narrow range of theta phases — but this ‘preferred’ theta phase also changed with running speed, more so for the slow gamma waves than the fast gamma waves (which is not inconsistent with the fact that slow gamma waves are more affected by running speed than fast gamma waves). Thus, while slow and fast gamma rhythms preferred similar phases of theta at low speeds, the two rhythms became increasingly phase-separated with increasing running speed.
What’s all this mean? Previous research has shown that if inputs from CA3 and the entorhinal cortex enter CA1 at the same time, the kind of long-term changes at the synapses that bring about learning are stronger and more likely in CA1. So at low speeds, synchronous inputs from CA3 and the entorhinal cortex at similar theta phases make them more effective at activating CA1 and inducing learning. But the faster you move, the more quickly you need to process information. The stronger gamma waves may help you do that. Moreover, the theta phase separation of slow and fast gamma that increases with running speed means that activity in CA3 (slow gamma source) increasingly anticipates activity in the medial entorhinal cortex (fast gamma source).
What does this mean at the practical level? Well at this point it can only be speculation that moving / exercising can affect learning and attention, but I personally am taking this on board. Most of us think better when we walk. This suggests that if you’re having trouble focusing and don’t have time for that, maybe walking down the hall or even jogging on the spot will help bring your brain cells into order!
Pushing speculation even further, I note that meditation by expert meditators has been associated with changes in gamma and theta rhythms. And in an intriguing comparison of the effect of spoken versus sung presentation on learning and remembering word lists, the group that sang showed greater coherence in both gamma and theta rhythms (in the frontal lobes, admittedly, but they weren’t looking elsewhere).
So, while we’re a long way from pinning any of this down, it may be that all of these — movement, meditation, music — can be useful in synchronizing your brain rhythms in a way that helps attention and learning. This exciting discovery will hopefully be the start of an exploration of these possibilities.
(2011). Speed Controls the Amplitude and Timing of the Hippocampal Gamma Rhythm.
PLoS ONE. 6(6), e21408 - e21408.
Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0021408
(2010). From alpha to gamma: Electrophysiological correlates of meditation-related states of consciousness.
Medical Hypotheses. 75, 218 - 224.
(2007). Music increases frontal EEG coherence during verbal learning.
Neuroscience Letters. 412(3), 217 - 221.
Trying to learn two different things one after another is challenging. Almost always some of the information from the first topic or task gets lost. Why does this happen? A new study suggests the problem occurs when the two information-sets interact, and demonstrates that disrupting that interaction prevents interference. (The study is a little complicated, but bear with me, or skip to the bottom for my conclusions.)
In the study, young adults learned two memory tasks back-to-back: a list of words, and a finger-tapping motor skills task. Immediately afterwards, they received either sham stimulation or real transcranial magnetic stimulation to the dorsolateral prefrontal cortex or the primary motor cortex. Twelve hours later the same day, they were re-tested.
As expected from previous research, word recall (being the first-learned task) declined in the control condition (sham stimulation), and this decline correlated with initial skill in the motor task. That is, the better they were at the second task, the more they forgot from the first task. This same pattern occurred among those whose motor cortex had been stimulated. However, there was no significant decrease in word recall for those who had received TMS to the dorsolateral prefrontal cortex.
Learning of the motor skill didn't differ between the three groups, indicating that this effect wasn't due to a disruption of the second task. Rather, it seems that the two tasks were interacting, and TMS to the DLPFC disrupted that interaction. This hypothesis was supported when the motor learning task was replaced by a motor performance task, which shouldn’t interfere with the word-learning task (the motor performance task was almost identical to the motor learning task except that it didn’t have a repeating sequence that could be learned). In this situation, TMS to the DLPFC produced a decrease in word recall (as it did in the other conditions, and as it would after a word-learning task without any other task following).
In the second set of experiments, the order of the motor and word tasks was reversed. Similar results occurred, with this time stimulation to the motor cortex being the effective intervention. In this case, there was a significant increase in motor skill on re-testing — which is what normally happens when a motor skill is learned on its own, without interference from another task (see my blog post on Mempowered for more on this). The word-learning task was then replaced with a vowel-counting task, which produced a non-significant trend toward a decrease in motor skill learning when TMS was applied to the motor cortex.
The effect of TMS depends on the activity in the region at the time of application. In this case, TMS was applied to the primary motor cortex and the DLPFC in the right hemisphere, because the right hemisphere is thought to be involved in integrating different types of information. The timing of the stimulation was critical: not during learning, and long before testing. The timing was designed to maximize any effects on interference between the two tasks.
The effect in this case mimics that of sleep — sleeping between tasks reduces interference between them. It’s suggested that both TMS and sleep reduce interference by reducing the communication between the prefrontal cortex and the mediotemporal lobe (of which the hippocampus is a part).
Here’s the problem: we're consolidating one set of memories while encoding another. So, we can do both at the same time, but as with any multitasking, one task is going to be done better than the other. Unsurprisingly, encoding appears to have priority over consolidation.
So something needs to regulate the activity of these two concurrent processes. Maybe something looks for commonalities between two actions occurring at the same time — this is, after all, what we’re programmed to do: we link things that occur together in space and time. So why shouldn’t that occur at this level too? Something’s just happened, and now something else is happening, and chances are they’re connected. So something in our brain works on that.
If the two events/sets of information are connected, that’s a good thing. If they’re not, we get interference, and loss of data.
So when we apply TMS to the prefrontal cortex, that integrating processor is perhaps disrupted.
The situation may be a little different where the motor task is followed by the word-list, because motor skill consolidation (during wakefulness at least) may not depend on the hippocampus (although declarative encoding does). However, the primary motor cortex may act as a bridge between motor skills and declarative memories (think of how we gesture when we explain something), and so it may this region that provides a place where the two types of information can interact (and thus interfere with each other).
In other words, the important thing appears to be whether consolidation of the first task occurs in a region where the two sets of information can interact. If it does, and assuming you don’t want the two information-sets to interact, then you want to disrupt that interaction.
Applying TMS is not, of course, a practical strategy for most of us! But the findings do suggest an approach to reducing interference. Sleep is one way, and even brief 20-minute naps have been shown to help learning. An intriguing speculation (I just throw this out) is that meditation might act similarly (rather like a sorbet between courses, clearing the palate).
Failing a way to disrupt the interaction, you might take this as a warning that it’s best to give your brain time to consolidate one lot of information before embarking on an unrelated set — even if it's in what appears to be a completely unrelated domain. This is particularly so as we get older, because consolidation appears to take longer as we age. For children, on the other hand, this is not such a worry. (See my blog post on Mempowered for more on this.)
(2011). Preventing interference between different memory tasks.
Nat Neurosci. 14(8), 953 - 955.
What governs whether or not you’ll retrieve a memory? I’ve talked about the importance of retrieval cues, of the match between the cue and the memory code you’re trying to retrieve, of the strength of the connections leading to the code. But these all have to do with the memory code.
Theta brainwaves, in the hippocampus especially, have been shown to be particularly important in memory function. It has been suggested that theta waves before an item is presented for processing lead to better encoding. Now a new study reveals that, when volunteers had to memorize words with a related context, they were better at later remembering the context of the word if high theta waves were evident in their brains immediately before being prompted to remember the item.
In the study, 17 students made pleasantness or animacy judgments about a series of words. Shortly afterwards, they were presented with both new and studied words, and asked to indicate whether the word was old or new, and if old, whether the word had been encountered in the context of “pleasant” or “alive”. Each trial began with a 1000 ms presentation of a simple mark for the student to focus on. Theta activity during this fixation period correlated with successful retrieval of the episodic memory relating to that item, and larger theta waves were associated with better source memory accuracy (memory for the context).
Theta activity has not been found to be particularly associated with greater attention (the reverse, if anything). It seems more likely that theta activity reflects a state of mind that is oriented toward evaluating retrieval cues (“retrieval mode”), or that it reflects reinstatement of the contextual state employed during study.
The researchers are currently investigating whether you can deliberately put your brain into a better state for memory recall.
(2011). Prestimulus theta activity predicts correct source memory retrieval.
Proceedings of the National Academy of Sciences. 108(26), 10702 - 10707.
Binge drinking occurs most frequently among young people, and there has been concern that consequences will be especially severe if the brain is still developing, as it is in adolescence. Because of the fact that it is only some parts of the brain — most crucially the prefrontal cortex and the hippocampus — that are still developing, it makes sense that only some functions will be affected.
I recently reported on a finding that binge drinking university students, performed more poorly on tests of verbal memory, but not on a test of visual memory. A new study looks at another function: spatial working memory. This task involves the hippocampus, and animal research has indicated that this region may be especially vulnerable to binge drinking. Spatial working memory is involved in such activities as driving, figural reasoning, sports, and navigation.
The study involved 95 adolescents (aged 16-19) from San Diego-area public schools: 40 binge drinking (27 males, 13 females) and 55 control (31 males, 24 females). Brain scans while performing a spatial working memory task revealed that there were significant gender differences in brain activation patterns for those who engaged in binge drinking. Specifically, in eight regions spanning the frontal cortex, anterior cingulate, temporal cortex, and cerebellum, female binge drinkers showed less activation than female controls, while male bingers exhibited greater activation than male controls. For female binge drinkers, less activation was associated with poorer sustained attention and working memory performances, while for male binge drinkers, greater activation was linked to better spatial performance.
The differences between male binge drinkers and controls were smaller than that seen in the female groups, suggesting that female teens may be particularly vulnerable. This is not the first study to find a gender difference in the brains’ response to excess alcohol. In this case it may have to do, at least partly, with differences in maturity — female brains mature earlier than males’.
(Submitted). Adolescent Binge Drinking Linked to Abnormal Spatial Working Memory Brain Activation: Differential Gender Effects.
Alcoholism: Clinical and Experimental Research.
Following on from research showing that long-term meditation is associated with gray matter increases across the brain, an imaging study involving 27 long-term meditators (average age 52) and 27 controls (matched by age and sex) has revealed pronounced differences in white-matter connectivity between their brains.
The differences reflect white-matter tracts in the meditators’ brains being more numerous, more dense, more myelinated, or more coherent in orientation (unfortunately the technology does not yet allow us to disentangle these) — thus, better able to quickly relay electrical signals.
While the differences were evident among major pathways throughout the brain, the greatest differences were seen within the temporal part of the superior longitudinal fasciculus (bundles of neurons connecting the front and the back of the cerebrum) in the left hemisphere; the corticospinal tract (a collection of axons that travel between the cerebral cortex of the brain and the spinal cord), and the uncinate fasciculus (connecting parts of the limbic system, such as the hippocampus and amygdala, with the frontal cortex) in both hemispheres.
These findings are consistent with the regions in which gray matter increases have been found. For example, the tSLF connects with the caudal area of the temporal lobe, the inferior temporal gyrus, and the superior temporal gyrus; the UNC connects the orbitofrontal cortex with the amygdala and hippocampal gyrus
It’s possible, of course, that those who are drawn to meditation, or who are likely to engage in it long term, have fundamentally different brains from other people. However, it is more likely (and more consistent with research showing the short-term effects of meditation) that the practice of meditation changes the brain.
The precise mechanism whereby meditation might have these effects can only be speculated. However, more broadly, we can say that meditation might induce physical changes in the brain, or it might be protecting against age-related reduction. Most likely of all, perhaps, both processes might be going on, perhaps in different regions or networks.
Regardless of the mechanism, the evidence that meditation has cognitive benefits is steadily accumulating.
The number of years the meditators had practiced ranged from 5 to 46. They reported a number of different meditation styles, including Shamatha, Vipassana and Zazen.
(2011). Enhanced brain connectivity in long-term meditation practitioners.
NeuroImage. 57(4), 1308 - 1316.
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.
(2011). Division-Coupled Astrocytic Differentiation and Age-Related Depletion of Neural Stem Cells in the Adult Hippocampus.
Cell Stem Cell. 8(5), 566 - 579.
Sleep can boost classroom performance of college students
There’s a lot of evidence that memories are consolidated during sleep, but most of it has involved skill learning. A new study extends the findings to complex declarative information — specifically, information from a lecture on microeconomics.
The study involved 102 university undergraduates who had never taken an economics course. In the morning or evening they completed an introductory, virtual lecture that taught them about concepts and problems related to supply and demand microeconomics. They were then tested on the material either immediately, after a 12-hour period that included sleep, after 12 hours without sleep, or after one week. The test included both basic problems that they had been trained to solve, and "transfer" problems that required them to extend their knowledge to novel, but related, problems.
Performance was better for those who slept, and this was especially so for the novel, 'transfer' integration problems.
Rule-learning task also benefits from sleep
Another complex cognitive task was investigated in a study of 54 college undergraduates who were taught to play a card game for rewards of play money in which wins and losses for various card decks mimic casino gambling (the Iowa Gambling Task is typically used to assess frontal lobe function). Those who had a normal night’s sleep as part of the study drew from decks that gave them the greatest winnings four times more often than those who spent the 12-hour break awake, and they better understood the underlying rules of the game.
The students were given a brief morning or afternoon preview of the gambling task (too brief to learn the underlying rule). They returned twelve hours later (i.e., either after a normal night’s sleep, or after a day of their usual activities), when they played the full gambling task for long enough to learn the rules. Those who got to sleep between the two sessions played better and showed a better understanding of the rules when questioned.
To assure that time of day didn’t explain the different performance, two groups of 17 and 21 subjects carried out both the preview and the full task either in the morning or the evening. Time of day made no difference.
Sleep problems may be a link between perceived racism and poor health
Analysis of data from the 2006 Behavioral Risk Factor Surveillance System, involving 7,093 people in Michigan and Wisconsin, suggests that sleep deprivation may be one mediator of the oft-reported association between discrimination and poorer cognitive performance.
The survey asked the question: "Within the past 12 months when seeking health care, do you feel your experiences were worse than, the same as, or better than for people of other races?" Taking this as an index of perceived racism, and comparing it with reports of sleep disturbance (difficulty sleeping at least six nights in the past two weeks), the study found that individuals who perceived racial discrimination were significantly more likely to experience sleep difficulties, even after allowing for socioeconomic factors and depression. Risk of sleep disturbance was nearly doubled in those who perceived themselves as discriminated against, and although this was reduced after depression was taken into account, it remained significant.
Sleep problems more prevalent than expected in urban minority children
Ten families also underwent sleep monitoring at home for five to seven days. All children who completed actigraphy monitoring had shortened sleep duration, with an average sleep duration of 8 hours, significantly less than the 10 to 11 hours recommended for children in this age group.
It’s worth noting that parents consistently overestimated sleep duration. Although very aware of bedtime and wake time, parents are less aware of time spent awake during the night.
(Also note that the figures I quote are taken from the conference abstract, which differ from those quoted in the press release.)
Rocking really does help sleep
If you or your loved one is having troubles getting to sleep, you might like to note an intriguing little study involving 12 healthy males (aged 22-38, and good sleepers). The men twice took a 45-minute afternoon nap on a bed that could slowly rock. On one occasion, it was still; on the other, it rocked. Rocking brought about faster sleep, faster transition to deeper sleep, and increased slow oscillations and sleep spindles (hallmarks of deep sleep). All these results were evident in every participant.
Sleep helps long-term memory in two ways
A fruit fly study points to two dominant theories of sleep being correct. The two theories are (a) that synapses are pruned during sleep, ensuring that only the strongest connections survive (synaptic homeostasis), and (b) that memories are replayed and consolidated during sleep, so that some connections are reactivated and thus made stronger (memory consolidation).
The experiment was made possible by the development of a new strain of fruit fly that can be induced to fall asleep when temperatures rise. The synaptic homeostasis model was supported when flies were placed in socially enriched environments, then either induced to sleep or not, before being taught a courtship ritual. Those that slept developed long-term memories of the ritual, while those that didn’t sleep didn’t remember it. The memory consolidation theory was supported when flies trained using a protocol designed to give them short-term memories retained a lasting memory, if sleep was induced immediately after the training.
In other words, it seems that both pruning and replaying are important for building long-term memories.
Mouse studies identify the roots of memory impairment resulting from sleep deprivation
Sleep deprivation in known to result in increased levels of adenosine in the brain, whether fruit fly or human (caffeine blocks the effects of adenosine). New mice studies now reveal the mechanism.
Mice given a drug that blocked a particular adenosine receptor in the hippocampus (the A1 receptor) failed to show the normal memory impairment evoked by sleep deprivation (being woken halfway through their normal 12-hour sleep schedule). The same results occurred if mice were genetically engineered to lack a gene involved in the production of glial transmitters (necessary to produce adenosine).
Memory was tested by the mice being allowed to explore a box with two objects, and then returned to the box on the next day, where one of the two objects had been moved. They would normally explore the moved object more than other objects, but sleep-deprived mice don’t usually react to the change, because they don’t remember where the object had been. In both these cases, the sleep-deprived mice showed no memory impairment.
Both the drugged and genetically protected mice also showed greater synaptic plasticity in the hippocampus after being sleep deprived than the untreated group.
The two groups reveal two parts of the chemical pathway involved in sleep deprivation. The genetic engineering experiment shows that the adenosine comes from glia's release of adenosine triphosphate (ATP). The drug experiment shows that the adenosine goes to the A1 receptor in the hippocampus.
The findings provide the first evidence that astrocytic ATP and adenosine A1R activity contribute to the effects of sleep deprivation on hippocampal synaptic plasticity and hippocampus-dependent memory, and suggest a new therapeutic target to reverse the cognitive deficits induced by sleep loss.
Scullin M, McDaniel M, Howard D, Kudelka C. 2011. Sleep and testing promote conceptual learning of classroom materials. Presented Tuesday, June 14, in Minneapolis, Minn., at SLEEP 2011, the 25th Anniversary Meeting of the Associated Professional Sleep Societies LLC (APSS).
(Submitted). Sleep‐dependent modulation of affectively guided decision‐making.
Journal of Sleep Research.
Grandner MA, Hale L, Jackson NJ, Patel NP, Gooneratne N, Troxel WM. 2011. Sleep disturbance and daytime fatigue associated with perceived racial discrimination. Presented Tuesday, June 14, in Minneapolis, Minn., at SLEEP 2011, the 25th Anniversary Meeting of the Associated Professional Sleep Societies LLC (APSS).
Sheares, B.J., Dorsey, K.B., Lamm, C.I., Wei, Y., Kattan, M., Mellins, R.B. & Evans, D. 2011. Sleep Problems In Urban Minority Children May Be More Prevalent Than Previously Recognized. Presented at the ATS 2011 International Conference in Denver.
(2011). Rocking synchronizes brain waves during a short nap.
Current Biology. 21(12), R461-R462 - R461-R462.
(2011). Inducing Sleep by Remote Control Facilitates Memory Consolidation in Drosophila.
Science. 332(6037), 1571 - 1576.
(2011). Astrocyte-Derived Adenosine and A1 Receptor Activity Contribute to Sleep Loss-Induced Deficits in Hippocampal Synaptic Plasticity and Memory in Mice.
The Journal of Neuroscience. 31(19), 6956 - 6962.
Sleep can boost classroom performance of college students http://www.eurekalert.org/pub_releases/2011-06/aaos-scb060611.php Rule-learning task also benefits from sleep http://medicalxpress.com/news/2011-05-excellent-science-based-advice.html Sleep problems may be a link between perceived racism and poor health http://medicalxpress.com/news/2011-06-problems-link-racism-poor-health.html Sleep problems more prevalent than expected in urban minority children http://medicalxpress.com/news/2011-05-problems-prevalent-urban-minority-... Rocking really does help sleep http://www.scientificamerican.com/podcast/episode.cfm?id=rocking-increas... Sleep helps long-term memory in two ways http://the-scientist.com/2011/06/23/sleep-on-it/ Mouse studies identify the roots of memory impairment resulting from sleep deprivation http://www.eurekalert.org/pub_releases/2011-05/uop-pri051711.php
The brain tends to shrink with age, with different regions being more affected than others. Atrophy of the hippocampus, so vital for memory and learning, is associated with increased risk of developing Alzheimer’s, and has also been linked to depression.
In a study involving 268 older adults (58+), the hippocampus of those reporting a life-changing religious experience was found to be shrinking significantly more compared to those not reporting such an experience. Significantly greater hippocampal atrophy was also found among born-again Protestants, Catholics, and those with no religious affiliation, compared with Protestants not identifying as born-again.
The participants are not a general sample — they were originally recruited for the NeuroCognitive Outcomes of Depression in the Elderly. However, some of the participants were from the control group, who had no history of depression. Brain scans were taken at the beginning of the study, and then every two years. The length of time between the baseline scan and the final scan ranged from 2 to 8 years (average was 4).
Questions about religious experiences were asked in an annual survey, so could change over time. Two-thirds of the group was female, and 87% were white. The average age was 68. At baseline, 42% of the group was non-born-again Protestant, 36% born-again Protestant; 8% Catholic; 6% other religion. Only 7% reported themselves as having no religion. By the end of the study, 44% (119 participants) reported themselves born-again, and 13% (36) reported having had life-changing religious experiences.
These associations persisted after depression status, acute stress, and social support were taken into account. Nor did other religious factors (such as prayer, meditation, or Bible study) account for the changes.
It is still possible that long-term stress might play a part in this association — the study measured acute rather than cumulative stress. The researchers suggest that life-changing religious experiences can be stressful, if they don’t fit in with your existing beliefs or those of your family and friends, or if they lead to new social systems that add to your stress.
Of course, the present results can be interpreted in several ways — is it the life-changing religious experience itself that is the crucial factor? Or the factors leading up to that experience? Or the consequences of that experience? Still, it’s certainly an intriguing finding, and it will be interesting to see more research expanding and confirming (or not!) this result.
More generally, the findings may help clarify the conflicting research about the effects of religion on well-being, by pointing to the fact that religion can’t be considered a single factor, but one subject to different variables, some of which may be positive and others not.
(2011). Religious Factors and Hippocampal Atrophy in Late Life.
PLoS ONE. 6(3), e17006 - e17006.
Following animal research indicating that binge drinking damages the hippocampus, and other research showing that this learning and memory center is still developing during adolescence, a new study has investigated the effects of binge drinking on learning in university students. The study, involving 122 Spanish university students (aged 18-20), of whom half engaged in binge drinking, found a clear association between binge drinking and a lower ability to learn new verbal information.
Specifically, binge drinkers were more affected by interference in the Rey Auditory Verbal Learning Test, and remembered fewer words; they also performed worse on the Weschler Memory Scale-3rd ed. (WMS-III) Logical Memory subtest, both on immediate and delayed recall. However, there were no differences between the two groups on the WMS-III Family Pictures subtest (measuring visual declarative memory).
These results persisted even after controlling for other possible confounding variables such as intellectual levels, history of neurological or psychopathological disorders, other drug use, or family history of alcoholism.
The genders were evenly represented in both groups. Interestingly, and in contradiction of some other research, women were not found to be more vulnerable to the neurotoxic effects of binge drinking.
(Submitted). Binge Drinking and Declarative Memory in University Students.
Alcoholism: Clinical and Experimental Research.
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.
(2011). Air Pollution Around Schools Is Linked To Poorer Student Health And Academic Performance.
Health Affairs. 30(5), 852 - 862.
(2011). Air pollution impairs cognition, provokes depressive-like behaviors and alters hippocampal cytokine expression and morphology.
As we get older, when we suffer memory problems, we often laughingly talk about our brain being ‘full up’, with no room for more information. A new study suggests that in some sense (but not the direct one!) that’s true.
To make new memories, we need to recognize that they are new memories. That means we need to be able to distinguish between events, or objects, or people. We need to distinguish between them and representations already in our database.
We are all familiar with the experience of wondering if we’ve done something. Is it that we remember ourselves doing it today, or are we remembering a previous occasion? We go looking for the car in the wrong place because the memory of an earlier occasion has taken precedence over today’s event. As we age, we do get much more of this interference from older memories.
In a new study, the brains of 40 college students and older adults (60-80) were scanned while they viewed pictures of everyday objects and classified them as either "indoor" or "outdoor." Some of the pictures were similar but not identical, and others were very different. It was found that while the hippocampus of young students treated all the similar pictures as new, the hippocampus of older adults had more difficulty with this, requiring much more distinctiveness for a picture to be classified as new.
Later, the participants were presented with completely new pictures to classify, and then, only a few minutes later, shown another set of pictures and asked whether each item was "old," "new" or "similar." Older adults tended to have fewer 'similar' responses and more 'old' responses instead, indicating that they could not distinguish between similar items.
The inability to recognize information as "similar" to something seen recently is associated with “representational rigidity” in two areas of the hippocampus: the dentate gyrus and CA3 region. The brain scans from this study confirm this, and find that this rigidity is associated with changes in the dendrites of neurons in the dentate/CA3 areas, and impaired integrity of the perforant pathway — the main input path into the hippocampus, from the entorhinal cortex. The more degraded the pathway, the less likely the hippocampus is to store similar memories as distinct from old memories.
Apart from helping us understand the mechanisms of age-related cognitive decline, the findings also have implications for the treatment of Alzheimer’s. The hippocampus is one of the first brain regions to be affected by the disease. The researchers plan to conduct clinical trials in early Alzheimer's disease patients to investigate the effect of a drug on hippocampal function and pathway integrity.
(2011). Age-related memory deficits linked to circuit-specific disruptions in the hippocampus.
Proceedings of the National Academy of Sciences.
Imaging the brains of 10 young men who were long term users of ecstasy and seven of their healthy peers with no history of ecstasy use has revealed a significantly smaller hippocampus in those who used ecstasy. The overall proportion of gray matter was also lower, suggesting the effects of ecstasy may not be restricted to the hippocampus.
Both groups had used similar amounts of recreational drugs other than ecstasy, and drank alcohol regularly. The ecstasy group had not taken ecstasy for more than two months before the start of the study on average.
(2011). Preliminary evidence of hippocampal damage in chronic users of ecstasy.
Journal of Neurology, Neurosurgery & Psychiatry.
Following previous research suggesting that the volume of the hippocampus was reduced in some people with chronic PTSD, a twin study indicated that this may not be simply a sign that stress has shrunk the hippocampus, but that those with a smaller hippocampus are at greater risk of PTSD. Now a new study has found that Gulf War veterans who recovered from PTSD had, on average, larger hippocampi than veterans who still suffer from PTSD. Those who recovered had hippocampi of similar size to control subjects who had never had PTSD.
The study involved 244 Gulf War veterans, of whom 82 had lifetime PTSD, 44 had current PTSD, and 38 had current depression.
Because we don’t know hippocampal size prior to trauma, the findings don’t help us decide whether hippocampal size is a cause or an effect (or perhaps it would be truer to say, don’t help us decide the relative importance of these factors, because it seems most plausible that both are significant).
The really important question, of course, is whether an effective approach to PTSD treatment would be to work on increasing hippocampal volume. Exercise and mental stimulation, for example, are known to increase the creation of new brain cells in the hippocampus. In this case, the main mediator is probably the negative effects of stress (which reduces neurogenesis). There is some evidence that antidepressant treatment might increase hippocampal volume in people with PTSD.
The other conclusion we can derive from these findings is that perhaps we should not simply think of building hippocampal volume / creating new brain cells as a means of building cognitive reserve, thus protecting us from cognitive decline and dementia. We should also think of it as a means of improving our emotional resilience and protecting us from the negative effects of stress and trauma.
(2011). Hippocampal Volume Differences in Gulf War Veterans with Current Versus Lifetime Posttraumatic Stress Disorder Symptoms.
Biological Psychiatry. 69(6), 541 - 548.
(2002). Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma.
Nature neuroscience. 5(11), 1242 - 1247. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819093/
In a study involving 44 young adults given a rigorous memorizing task at noon and another such task at 6pm, those who took a 90-minute nap during the interval improved their ability to learn on the later task, while those who stayed awake found it harder to learn.
The degree to which the nappers were refreshed correlated with the amount of stage 2 non-REM sleep they experienced. This sleep phase is characterized by sleep spindles, which are associated with brain activity between the hippocampus and prefrontal cortex. Spindle-rich sleep occurs mostly in the second half of the night, so those who don’t get their quota of sleep are probably getting less.
The finding confirms the idea that learning ability decreases the more time you spend awake.
(2011). Wake deterioration and sleep restoration of human learning.
Current Biology. 21(5), R183-R184 - R183-R184.
Another study has come out proclaiming the cognitive benefits of walking for older adults. Previously sedentary adults aged 55-80 who walked around a track for 40 minutes on three days a week for a year increased the size of their hippocampus, as well as their level of BDNF. Those assigned to a stretching routine showed no such growth. There were 120 participants in the study.
The growth of around 2% contrasts with the average loss of 1.4% hippocampal tissue in the stretching group — an amount of atrophy considered “normal” with age. Although both groups improved their performance on a computerized spatial memory test, the walkers improved more.
The findings are consistent with a number of animal studies showing aerobic exercise increases neurogenesis and BDNF in the hippocampus, and human studies pointing to a lower risk of cognitive decline and dementia in those who walk regularly.
(Submitted). Exercise training increases size of hippocampus and improves memory.
Proceedings of the National Academy of Sciences.
Brain images of 16 participants in an 8-week mindfulness meditation program, taken two weeks before and after the program, have found measurable changes in brain regions associated with memory, sense of self, empathy and stress. Specifically, they showed increased grey-matter density in the left hippocampus, posterior cingulate cortex, temporo-parietal junction, and cerebellum, as well as decreased grey-matter density in the amygdala. Similar brain scans of a control group of non-meditators (those on a waiting list for the program) showed no such changes over time.
Although a number of studies have found differences in the brains of experienced meditators and those who don’t practice meditation, this is the first to demonstrate that those differences are actually produced by meditation.
The Mindfulness-Based Stress Reduction program involved weekly meetings that included practice of mindfulness meditation and audio recordings for guided meditation practice. Participants reported spending an average of 27 minutes each day practicing mindfulness exercises.
(2011). Mindfulness practice leads to increases in regional brain gray matter density.
Psychiatry Research: Neuroimaging. 191(1), 36 - 43.
In a study in which 78 healthy elders were given 5 different tests and then tested for cognitive performance 18 months later, two tests combined to correctly predict nearly 80% of those who developed significant cognitive decline. These tests were a blood test to identify presence of the ‘Alzheimer’s gene’ (APOE4), and a 5-minute fMRI imaging scan showing brain activity during mental tasks.
The gene test in itself correctly classified 61.5% of participants (aged 65-88; mean age 73), showing what a strong risk factor this is, but when taken with activity on the fMRI test, the two together correctly classified 78.9% of participants. Age, years of education, gender and family history of dementia were not accurate predictors of future cognitive decline. A smaller hippocampus was also associated with a greater risk of cognitive decline.
These two tests are readily available and not time-consuming, and may be useful in identifying those at risk of MCI and dementia.
Woodard, J.L. et al. 2010. Prediction of Cognitive Decline in Healthy Older Adults using fMRI. Journal of Alzheimer’s Disease, 21 (3), 871-885.
We know active learning is better than passive learning, but for the first time a study gives us some idea of how that works. Participants in the imaging study were asked to memorize an array of objects and their exact locations in a grid on a computer screen. Only one object was visible at a time. Those in the "active study” group used a computer mouse to guide the window revealing the objects, while those in the “passive study” group watched a replay of the window movements recorded in a previous trial by an active subject. They were then tested by having to place the items in their correct positions. After a trial, the active and passive subjects switched roles and repeated the task with a new array of objects.
The active learners learned the task significantly better than the passive learners. Better spatial recall correlated with higher and better coordinated activity in the hippocampus, dorsolateral prefrontal cortex, and cerebellum, while better item recognition correlated with higher activity in the inferior parietal lobe, parahippocampal cortex and hippocampus.
The critical role of the hippocampus was supported when the experiment was replicated with those who had damage to this region — for them, there was no benefit in actively controlling the viewing window.
This is something of a surprise to researchers. Although the hippocampus plays a crucial role in memory, it has been thought of as a passive participant in the learning process. This finding suggests that it is actually part of an active network that controls behavior dynamically.
(2011). Hippocampal brain-network coordination during volitional exploratory behavior enhances learning.
Nat Neurosci. 14(1), 115 - 120.
A rat study using powerful imaging techniques has revealed how an injured brain continues to change long after the original trauma. Widespread decreases in brain functioning over a period of months were seen in specific brain regions, in particular the hippocampus, amygdala, and ipsilateral cortex, even when these were remote from the site of direct trauma and unaccompanied by signs of injury.
The findings indicate that there is a time window during which intervention could reduce these processes and protect against some of the disabling consequences of TBI.
(2010). Progressive Metabolic and Structural Cerebral Perturbations After Traumatic Brain Injury: An In Vivo Imaging Study in the Rat.
J Nucl Med. 51(11), 1788 - 1795.
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.
(2010). Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters.
PLoS ONE. 5(12), e15267 - e15267.
Comparison of 17 people with severe obstructive sleep apnea (OSA) with 15 age-matched controls has revealed that those with OSA had reduced gray matter in several brain regions, most particularly in the left parahippocampal gyrus and the left posterior parietal cortex, as well as the entorhinal cortex and the right superior frontal gyrus. These areas were associated with deficits in abstract reasoning and executive function. Deficits in the left posterior parietal cortex were also associated with daytime sleepiness.
Happily, however, three months of treatment with continuous positive airway pressure (CPAP), produced a significant increase in gray matter in these regions, which was associated with significant improvement in cognitive function. The researchers suggest that the hippocampus, being especially sensitive to hypoxia and innervation of small vessels, is the region most strongly and quickly affected by hypoxic episodes.
The findings point to the importance of diagnosing and treating OSA.
(2010). Obstructive Sleep Apnea: Brain Structural Changes and Neurocognitive Function Before and After Treatment.
Am. J. Respir. Crit. Care Med.. 201005-0693OC - 201005-0693OC.
The role of sleep in consolidating memory is now well-established, but recent research suggests that sleep also reorganizes memories, picking out the emotional details and reconfiguring the memories to help you produce new and creative ideas. In an experiment in which participants were shown scenes of negative or neutral objects at either 9am or 9pm and tested 12 hours later, those tested on the same day tended to forget the negative scenes entirely, while those who had a night’s sleep tended to remember the negative objects but not their neutral backgrounds.
Follow-up experiments showed the same selective consolidation of emotional elements to a lesser degree after a 90-minute daytime nap, and to a greater degree after a 24-hour or even several-month delay (as long as sleep directly followed encoding).
These findings suggest that processes that occur during sleep increase the likelihood that our emotional responses to experiences will become central to our memories of them. Moreover, additional nights of sleep may continue to modify the memory.
In a different approach, another recent study has found that when volunteers were taught new words in the evening, then tested immediately, before spending the night in the sleep lab and being retested in the morning, they could remember more words in the morning than they did immediately after learning them, and they could recognize them faster. In comparison, a control group who were trained in the morning and re-tested in the evening showed no such improvement on the second test.
Deep sleep (slow-wave sleep) rather than rapid eye movement (REM) sleep or light sleep appeared to be the important phase for strengthening the new memories. Moreover, those who experienced more sleep spindles overnight were more successful in connecting the new words to the rest of the words in their mental lexicon, suggesting that the new words were communicated from the hippocampus to the neocortex during sleep. Sleep spindles are brief but intense bursts of brain activity that reflect information transfer between the hippocampus and the neocortex.
The findings confirm the role of sleep in reorganizing new memories, and demonstrate the importance of spindle activity in the process.
Taken together, these studies point to sleep being more important to memory than has been thought. The past decade has seen a wealth of studies establishing the role of sleep in consolidating procedural (skill) memory, but these findings demonstrate a deeper, wider, and more ongoing process. The findings also emphasize the malleability of memory, and the extent to which they are constructed (not copied) and reconstructed.
(2010). Sleep’s Role in the Consolidation of Emotional Episodic Memories.
Current Directions in Psychological Science. 19(5), 290 - 295.
(2010). Sleep Spindle Activity is Associated with the Integration of New Memories and Existing Knowledge.
J. Neurosci.. 30(43), 14356 - 14360.
Carriers of the so-called ‘Alzheimer’s gene’ (apoE4) comprise 65% of all Alzheimer's cases. A new study helps us understand why that’s true. Genetically engineered mice reveal that apoE4 is associated with the loss of GABAergic interneurons in the hippocampus. This is consistent with low levels of GABA (produced by these neurons) typically found in Alzheimer’s brains. This loss was associated with cognitive impairment in the absence of amyloid beta accumulation, demonstrating it is an independent factor in the development of this disease.
The relationship with the other major characteristic of the Alzheimer’s brain, tau tangles, was not independent. When the mice’s tau protein was genetically eliminated, the mice stopped losing GABAergic interneurons, and did not develop cognitive deficits. Previous research has shown that suppressing tau protein can also prevent amyloid beta from causing memory deficits.
Excitingly, daily injections of pentobarbital, a compound that enhances GABA action, restored cognitive function in the mice.
The findings suggest that increasing GABA signaling and reducing tau are potential strategies to treat or prevent apoE4-related Alzheimer's disease.
(2010). Apolipoprotein E4 Causes Age- and Tau-Dependent Impairment of GABAergic Interneurons, Leading to Learning and Memory Deficits in Mice.
J. Neurosci.. 30(41), 13707 - 13717.
Because people with damage to their hippocampus are sometimes impaired at remembering spatial information even over extremely short periods of time, it has been thought that the hippocampus is crucial for spatial information irrespective of whether the task is a working memory or a long-term memory task. This is in contrast to other types of information. In general, the hippocampus (and related structures in the mediotemporal lobe) is assumed to be involved in long-term memory, not working memory.
However, a new study involving four patients with damage to their mediotemporal lobes, has found that they were perfectly capable of remembering for one second the relative positions of three or fewer objects on a table — but incapable of remembering more. That is, as soon as the limits of working memory were reached, their performance collapsed. It appears, therefore, that there is, indeed, a fundamental distinction between working memory and long-term memory across the board, including the area of spatial information and spatial-objection relations.
The findings also underscore how little working memory is really capable of on its own (although absolutely vital for what it does!) — in real life, long-term memory and working memory work in tandem.
(2010). Intact Working Memory for Relational Information after Medial Temporal Lobe Damage.
J. Neurosci.. 30(41), 13624 - 13629.
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.
(2010). A neuroimaging investigation of the association between aerobic fitness, hippocampal volume, and memory performance in preadolescent children.
Brain Research. 1358, 172 - 183.
Children’s ability to remember past events improves as they get older. This has been thought by many to be due to the slow development of the prefrontal cortex. But now brain scans from 60 children (8-year-olds, 10- to 11-year-olds, and 14-year-olds) and 20 young adults have revealed marked developmental differences in the activity of the mediotemporal lobe.
The study involved the participants looking at a series of pictures (while in the scanner), and answering a different question about the image, depending on whether it was drawn in red or green ink. Later they were shown the pictures again, in black ink and mixed with new ones. They were asked whether they had seen them before and whether they had been red or green.
While the adolescents and adults selectively engaged regions of the hippocampus and posterior parahippocampal gyrus to recall event details, the younger children did not, with the 8-year-olds indiscriminately using these regions for both detail recollection and item recognition, and the 10- to 11-year-olds showing inconsistent activation. It seems that the hippocampus and posterior parahippocampal gyrus become increasingly specialized for remembering events, and these changes may partly account for long-term memory improvements during childhood.
(2010). Developmental Differences in Medial Temporal Lobe Function during Memory Encoding.
J. Neurosci.. 30(28), 9548 - 9556.
A small study comparing 18 obese adolescents with type 2 diabetes and equally obese adolescents without diabetes or pre-diabetes has found that those with diabetes had significantly impaired cognitive performance, as well as clear abnormalities in the integrity of their white matter (specifically, reduced white matter volume, especially in the frontal lobe, as well as impaired integrity in both white and grey matter). Similar abnormalities have previously been found in adults with type 2 diabetes, but the subjects were elderly and, after many years of diabetes, generally had significant vascular disease. One study involving middle-aged diabetics found a reduction in the volume of the hippocampus, which was directly associated with poor glycaemic control.
It remains to be seen whether such changes can be reversed by exercise and diet interventions. While those with diabetes performed worse in all cognitive tasks tested, the differences were only significant for intellectual functioning, verbal memory and psychomotor efficiency.
(2010). Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus.
(2007). Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes.
Diabetologia. 50(4), 711 - 719.
A three-year study involving 169 people with mild cognitive impairment has found that those who later developed Alzheimer's disease showed 10-30% greater atrophy in two specific locations within the hippocampus, the cornu ammonis (CA1) and the subiculum. A second study comparing the brains of 10 cognitively normal elderly people and seven who were diagnosed with MCI between two and three years after their initial brain scan and with Alzheimer's some seven years after the initial scan, has confirmed the same pattern of hippocampal atrophy, from the CA1 to the subiculum, and then other regions of the hippocampus.
Apostolova, L.G. et al. In press. Subregional hippocampal atrophy predicts Alzheimer's dementia in the cognitively normal. Neurobiology of Aging, Available online 24 September 2008.
(2010). 3D comparison of low, intermediate, and advanced hippocampal atrophy in MCI.
Human Brain Mapping. 9999(9999), NA - NA.
It is now well established that memories are consolidated during sleep. Now a new study has found that restful periods while you are awake are also times when consolidation can occur. The imaging study revealed that during resting (allowed to think about anything), there was correlated activity between the hippocampus and part of the lateral occipital complex. This activity was associated with improved memory for the previous experience. Moreover, the degree of activity correlated with how well it was remembered. You can watch a 4 ½ minute video where the researchers explain their study at http://www.cell.com/neuron/abstract/S0896-6273%2810%2900006-1
Tambini, A., Ketz, N. & Davach, L. 2010. Enhanced Brain Correlations during Rest Are Related to Memory for Recent Experiences. Neuron, 65 (2), 280-290.
A rat study reveals that, for rats at least, an understanding of place and a sense of direction appears within two weeks of being born, seemingly independently of any experience of the world. The directional signal, which allows the animal to know which way it is facing, is already at adult levels as soon as it can be measured in newborn rats. Sense of place is also present early, but improves with age. Representations of distance appear a few days later. These processes depend on specialized cells in the hippocampus, which in humans plays a crucial role in long-term memory for events as well as spatial navigation. The findings fit in with the theory that a pre-wired spatial framework may provide a conceptual framework for experience.
(2010). Development of the Hippocampal Cognitive Map in Preweanling Rats.
Science. 328(5985), 1573 - 1576.
Several reports have come out in recent years on how recent events replay in the hippocampus, a process thought to be crucial for creating long-term memories. Now a rat study suggests that these replays are not merely echoes of past events, but a dynamic process aimed at improving decision-making. Rather than being solely replays of recent or frequent paths through the maze, the replays were often paths that the rats had rarely taken or, in some cases, had never taken, as if the rats were trying to build maps to help them make better navigation decisions.
(2010). Hippocampal Replay Is Not a Simple Function of Experience.
Neuron. 65(5), 695 - 705.
Supporting the idea that repeated anaesthesia in children can lead to memory impairment, a rodent study has revealed that repeated anaesthesia wiped out a large portion of the stem cells in the hippocampus. This was associated with impaired memory in young animals, which worsened as they got older. The effect did not occur in adult animals. A similar effect has also been found with radiotherapy, and animal studies have found physical activity after radiotherapy results in a greater number of new stem cells that partly replace those that have been lost.
An imaging study reveals why older adults are better at remembering positive events. The study, involving young adults (ages 19-31) and older adults (ages 61-80) being shown a series of photographs with positive and negative themes, found that while there was no difference in brain activity patterns between the age groups for the negative photos, there were age differences for the positive photos. In older adult brains, but not the younger, two emotion-processing regions (the ventromedial prefrontal cortex and the amygdala) strongly influenced the memory-encoding hippocampus.
(2010). There are age-related changes in neural connectivity during the encoding of positive, but not negative, information.
Cortex. 46(4), 425 - 433.
A study involving five patients with severe amnesia due to damage in the hippocampus, resulting in a condition comparable to Alzheimer's, has found that memory tests given 5-10 minutes after sad and happy film clips showed little (if any) memory of the details, but the generated emotion lasted for 20 to 30 minutes afterward. Interestingly, normal controls also felt happy for about the same length of time, but the impact of sad scenes was shorter. The findings challenge the idea that by minimizing a specific memory of past trauma, associated sadness will also decrease. Indeed, it may be that forgetting the details of unhappy events prolongs the effects. The findings also point to the need for care in dealing with those with impaired memory — don’t assume that any induced emotion will vanish as quickly as their memory of it.
(2010). Sustained experience of emotion after loss of memory in patients with amnesia.
Proceedings of the National Academy of Sciences. 107(17), 7674 - 7679.
Older news items (pre-2010) brought over from the old website
The importance of retrieval cues
An imaging study has revealed that it is retrieval cues that trigger activity in the hippocampus, rather than, as often argued, the strength of the memory. The study involved participants learning unrelated word pairs (a process which included making up sentences with the words), then being asked whether various familiar words had been previously seen or not — the words being shown first on their own, and then with their paired cue word. Brain activity for words judged familiar on their own was compared with activity for the same items when shown with context cues. Increased hippocampal activity occurred only with cued recall. Moreover, the amount of activity was not associated with familiarity strength, and recollected items were associated with greater activity relative to highly familiar items.
Cohn, M., Moscovitch, M., Lahat, A., & McAndrews, M. P. (2009). Recollection versus strength as the primary determinant of hippocampal engagement at retrieval. Proceedings of the National Academy of Sciences, 106(52), 22451-22455. doi: 10.1073/pnas.0908651106.
Children’s PTSD symptoms linked to poor hippocampus function
An imaging study comparing brain activity during a verbal memory task of 16 10- to 17-year-olds who had PTSD symptoms with a control group of 11 young people, has found that while hippocampal activity was similar in both groups when the word list was presented, those with PTSD symptoms made more errors on the recall part of the test and showed less hippocampus activity than control subjects doing the same task. Additionally, those with the worst hippocampus function were also most likely to experience a specific set of PTSD symptoms — "avoidance and numbing", including difficulty remembering the trauma, feeling cut off from others and lack of emotion. The research helps explain why traumatized children behave as they do and could improve treatments.
Carrion, V. G., Haas, B. W., Garrett, A., Song, S., & Reiss, A. L. (2009). Reduced Hippocampal Activity in Youth with Posttraumatic Stress Symptoms: An fMRI Study. J. Pediatr. Psychol., jsp112. doi: 10.1093/jpepsy/jsp112.
Higher levels of leptin associated with lower risk of dementia
A new study has showed that higher levels of leptin—a hormone involved in fat metabolism and appetite—is linked to reduced risk of Alzheimer's disease. The study used data from the large long-running Framingham Heart Study, and found that higher leptin levels were not only associated with a dose-related lower incidence of dementia and Alzheimer’s, but also with higher total cerebral brain volume. The findings are consistent with recent evidence that leptin improves memory function through direct effects on the hippocampus. The strength of the association was striking (an Alzheimer’s risk of 25% for those with the lowest levels of leptin compared to 6% for those with the highest levels), and if confirmed will emphasize the role of lifestyle in preventing and treating Alzheimer’s.
Lieb, W., Beiser, A. S., Vasan, R. S., Tan, Z. S., Au, R., Harris, T. B., et al. (2009). Association of Plasma Leptin Levels With Incident Alzheimer Disease and MRI Measures of Brain Aging. JAMA, 302(23), 2565-2572. doi: 10.1001/jama.2009.1836.
High protein diet shrinks brain in Alzheimer’s mice
A study using genetically engineered mice has tested the effects of four diets for their effects on Alzheimer’s pathology: a regular diet, a high fat/low carbohydrate custom diet, a high protein/low carb version, or a high carbohydrate/low fat option. Unexpectedly, mice fed the high protein/low carbohydrate diet had brains 5% lighter that all the others, and regions of their hippocampus were less developed. Mice on the high fat diet had higher levels of amyloid-beta protein, although no effect on plaque burden was detected.
Franciosi, S., Gama Sosa, M., English, D., Oler, E., Oung, T., Janssen, W., et al. (2009). Novel cerebrovascular pathology in mice fed a high cholesterol diet. Molecular Neurodegeneration, 4(1), 42. doi: 10.1186/1750-1326-4-42.
Full text available at http://www.molecularneurodegeneration.com/content/4/1/40
Why smells can be so memorable
Confirming the common experience of the strength with which certain smells can evoke emotions or memories, an imaging study has found that, when people were presented with a visual object together with one, and later with a second, set of pleasant and unpleasant odors and sounds, then presented with the same objects a week later, there was unique activation in particular brain regions in the case of their first olfactory (but not auditory) associations. This unique signature existed in the hippocampus regardless of how strong the memory was — that is, it was specific to olfactory associations. Regardless of whether they were smelled or heard, people remembered early associations more clearly when they were unpleasant.
The study appeared online on November 5 in Current Biology.
Why sleep deprivation causes cognitive impairment, and how to fix it
A mouse study has found a molecular pathway in the brain that is the cause of cognitive impairment due to sleep deprivation, and points to a way of preventing the cognitive deficits caused by sleep deprivation. The study showed that mice deprived of sleep had increased levels of the enzyme phosphodiesterase 4 (PDE4) and reduced levels of cAMP, crucial in forming new synaptic connections in the hippocampus. Treatment with phosphodiesterase inhibitors rescued the sleep deprivation-induced deficits in cAMP signaling, synaptic plasticity and hippocampus-dependent memory, counteracting some of the memory consequences of sleep deprivation.
Vecsey, C. G., Baillie, G. S., Jaganath, D., Havekes, R., Daniels, A., Wimmer, M., et al. (2009). Sleep deprivation impairs cAMP signalling in the hippocampus. Nature, 461(7267), 1122-1125. doi: 10.1038/nature08488.
Concepts are born in the hippocampus
Concepts are at the heart of cognition. A study showed 25 people pairs of fractal patterns that represented the night sky and asked them to forecast the weather – either rain or sun – based on the patterns. The task could be achieved by either working out the conceptual principles, or simply memorizing which patterns produced which effects. However, the next task required them to make predictions using new patterns (but based on the same principles). Success on this task was predictable from the degree of activity in the hippocampus during the first, learning, phase. In the second phase, the ventromedial prefrontal cortex, important in decision-making, was active. The results indicate that concepts are learned and stored in the hippocampus, and then passed on to the vMPFC for application.
Kumaran, D. et al. 2009. Tracking the Emergence of Conceptual Knowledge during Human Decision Making. Neuron, 63 (6), 889-901.
How sleep consolidates memory
A rat study provides clear evidence that "sharp wave ripples", brainwaves that occur in the hippocampus when it is "off-line", most often during stage four sleep, are responsible for consolidating memory and transferring the learned information from the hippocampus to the neocortex, where long-term memories are stored. The study found that when these waves were eliminated during sleep, the rats were less able to remember a spatial navigation task.
Girardeau, G. et al. 2009. Selective suppression of hippocampal ripples impairs spatial memory. Nature Neuroscience, 12 (10), 1222-1223.
New insights into memory without conscious awareness
An imaging study in which participants were shown a previously studied scene along with three previously studied faces and asked to identify the face that had been paired with that scene earlier has found that hippocampal activity was closely tied to participants' tendency to view the associated face, even when they failed to identify it. Activity in the lateral prefrontal cortex, an area required for decision making, was sensitive to whether or not participants had responded correctly and communication between the prefrontal cortex and the hippocampus was increased during correct, but not incorrect, trials. The findings suggest that conscious memory may depend on interactions between the hippocampus and the prefrontal cortex.
Hannula, D.E. & Ranganath, C. 2009. The Eyes Have It: Hippocampal Activity Predicts Expression of Memory in Eye Movements. Neuron, 63 (5), 592-599.
Healthy older brains not significantly smaller than younger brains
A study using healthy older adults from Holland's long-term Maastricht Aging Study found that the 35 cognitively healthy people who stayed free of dementia showed no significant decline in gray matter, but the 30 people who showed substantial cognitive decline although still dementia-free showed a significant reduction in brain tissue in the hippocampus and parahippocampal areas, and in the frontal and cingulate cortices. The findings suggest that atrophy in the normal older brain may have been over-estimated in earlier studies, by not screening out people whose undetected, slowly developing brain disease was killing off cells in key areas.
Burgmans, S. et al. 2009. The Prevalence of Cortical Gray Matter Atrophy May Be Overestimated In the Healthy Aging Brain. Neuropsychology, 23 (5), 541-550.
Overweight and obese elderly have smaller brains
Analysis of brain scans from 94 people in their 70s who were still "cognitively normal" five years after the scan has revealed that people with higher body mass indexes had smaller brains on average, with the frontal and temporal lobes particularly affected (specifically, in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus, in obese people, and in the basal ganglia and corona radiate of the overweight). The brains of the 51 overweight people were, on average, 6% smaller than those of the normal-weight participants, and those of the 14 obese people were 8% smaller. To put it in more comprehensible, and dramatic terms: "The brains of overweight people looked eight years older than the brains of those who were lean, and 16 years older in obese people." However, overall brain volume did not differ between overweight and obese persons. As yet unpublished research by the same researchers indicates that exercise protects these same brain regions: "The most strenuous kind of exercise can save about the same amount of brain tissue that is lost in the obese."
Raji, C.A. et al. 2009. Brain structure and obesity. Human Brain Mapping, Published Online: Aug 6 2009
Alcoholics show abnormal brain activity when processing facial expressions
Excessive chronic drinking is known to be associated with deficits in comprehending emotional information, such as recognizing different facial expressions. Now an imaging study of abstinent long-term alcoholics has found that they show decreased and abnormal activity in the amygdala and hippocampus when looking at facial expressions. They also show increased activity in the lateral prefrontal cortex, perhaps in an attempt to compensate for the failure of the limbic areas. The finding is consistent with other studies showing alcoholics invoking additional and sometimes higher-order brain systems to accomplish a relatively simple task at normal levels. The study compared 15 abstinent long-term alcoholics and 15 healthy, nonalcoholic controls, matched on socioeconomic backgrounds, age, education, and IQ.
Marinkovic, K. et al. 2009. Alcoholism and Dampened Temporal Limbic Activation to Emotional Faces. Alcoholism: Clinical and Experimental Research, Published Online: Aug 10 2009
Memories practiced throughout the day, not just while sleeping
It is known that a certain amount of replaying of experiences occurs in the hippocampus immediately afterwards, but it has been thought that this is confined to the immediate past, while the replaying that occurs during sleep and is thought to be part of the memory consolidation process, ranges far more widely. Now a new rat study indicates that the replaying that occurs while the animal is awake is more extensive than thought, and more accurate than that which occurs during sleep. Data from the neurons indicated that the events being replayed (repeatedly) were from 20 to 30 minutes earlier, and involved different settings, indicating the replay wasn’t dependent on incoming sensory cues. It’s suggested that the less-accurate replays seen during sleep are more aimed at making connections, rather than consolidating the actual experience. The waking replays occurred during pauses in activity, perhaps suggesting the importance of making pauses for reflection during your day!
Karlsson, M.P. & Frank, L.M. 2009. Awake replay of remote experiences in the hippocampus. Nature Neuroscience, 12, 913–918.
Measuring brain atrophy in patients with mild cognitive impairment
A study involving 269 patients with mild cognitive impairment provides evidence that a fully automated procedure called Volumetric MRI (that can be done in a clinical setting) can accurately and quickly measure parts of the medial temporal lobe and compare them to expected size. It also found that not only atrophy in the hippocampus but also the amygdala is associated with a greater risk of conversion to Alzheimer’s.
Kovacevic, S. et al. 2009. High-throughput, Fully Automated Volumetry for Prediction of MMSE and CDR Decline in Mild Cognitive Impairment. Alzheimer Disease & Associated Disorders, 23 (2), 139-145.
New insight into how information is encoded in the hippocampus
Theta brain waves are known to orchestrate neuronal activity in the hippocampus, and for a long time it’s been thought that these oscillations were "in sync" across the hippocampus, timing the firing of neurons like a sort of central pacemaker. A new rat study reveals that rather than being in sync, theta oscillations actually sweep along the length of the hippocampus as traveling waves. This changes our notion of how spatial information is represented in the rat brain (and presumably has implications for our brains: theta waves are ubiquitous in mammalian brains). Rather than neurons encoding points in space, it seems that what is encoded are segments of space. This would make it easier to distinguish between representations of locations from different times. It also may have significant implications for understanding how information is transmitted from the hippocampus to other areas of the brain, since different areas of the hippocampus are connected to different areas in the brain. The fact that hippocampal activity forms a traveling wave means that these target areas receive inputs from the hippocampus in a specific sequence rather than all at once.
Lubenov, E.V. & Siapas, A.G. 2009. Hippocampal theta oscillations are travelling waves. Nature, 459, 534-539.
Meditation may increase gray matter
Adding to the increasing evidence for the cognitive benefits of meditation, a new imaging study of 22 experienced meditators and 22 controls has revealed that meditators showed significantly larger volumes of the right hippocampus and the right orbitofrontal cortex, and to a lesser extent the right thalamus and the left inferior temporal gyrus. There were no regions where controls had significantly more gray matter than meditators. These areas of the brain are all closely linked to emotion, and may explain meditators' improved ability in regulating their emotions.
Luders, E. et al. 2009. The underlying anatomical correlates of long-term meditation: Larger hippocampal and frontal volumes of gray matter. NeuroImage, 45 (3), 672-678.
Carriers of Alzheimer's gene show different brain activity as young adults
Possession of the ApoE4 gene variant associated with Alzheimer’s risk is found in about a quarter of the population, and has been shown to be associated with differences in the hippocampus in middle-aged and elderly healthy carriers. Now a new study of 36 younger adults (20-35) has revealed that differences in brain activity patterns between carriers and non-carriers are also evident at this stage, not only when performing a memory task, but even when the brain was at rest. Carriers of the gene had more brain activity in the hippocampus during the memory task, and more activity in the default mode network during rest. The findings support a theory that the brain's memory function may gradually wear itself out in those who go on to develop Alzheimer's.
Filippini, N. et al. 2009. Distinct patterns of brain activity in young carriers of the APOE-ε4 allele. Proceedings of the National Academy of Sciences, 106, 7209-7214.
How the brain translates memory into action
We know that the hippocampus is crucial for place learning, especially for the rapid learning of temporary events (such as where we’ve parked the car). Now a new study reveals more about how that coding for specific places connects to behaviour. Selective lesioning in rats revealed that the critical part is in the middle part of the hippocampus, where links to visuospatial information connect links to the behavioural control necessary for returning to that place after a period of time. Rats whose brain still maintained an accurate memory of place nevertheless failed to find their way when a sufficient proportion of the intermediate hippocampus was removed. The findings emphasise that memory failures are not only, or always, about actual deficits in memory, but can also be about being able to act on it.
Bast, T. et al. 2009. From Rapid Place Learning to Behavioral Performance: A Key Role for the Intermediate Hippocampus. PLoS Biology, 7(4), e1000089. doi:10.1371/journal.pbio.1000089
Shrinking in hippocampus precedes Alzheimer's
An imaging study of 64 Alzheimer's patients, 44 people with mild cognitive impairment, and 34 people with no memory or thinking problems, has found that those with smaller hippocampal volumes and higher rates of shrinkage were two to four times as likely to develop dementia over the study period (average 18 months) as those with larger volumes and a slower rate of atrophy. During that time, 23 of the people with MCI developed Alzheimer's, and three of the healthy participants.
Henneman, W.J.P. et al. 2009. Hippocampal atrophy rates in Alzheimer disease: Added value over whole brain volume measures. Neurology, 72, 999-1007.
Physical fitness improves memory in seniors
A study of 165 older adults (59-81) has found a significant association between physical fitness and performance on certain spatial memory tests. Fitness was also strongly correlated with hippocampus size. Although rodent studies have shown that exercise increases hippocampus size and spatial memory, this is the first study to show that in humans. The findings provide more evidence for the benefits of physical exercise in preventing memory loss in older adults.
Erickson, K.I. et al. 2009. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus, Published online 2 January
Aging brains allow negative memories to fade
Another study has found that older adults (average age 70) remember fewer negative images than younger adults (average age 24), and that this has to do with differences in brain activity. When shown negative images, the older participants had reduced interactions between the amygdala and the hippocampus, and increased interactions between the amygdala and the dorsolateral prefrontal cortex. It seems that the older participants were using thinking rather than feeling processes to store these emotional memories, sacrificing information for emotional stability. The findings are consistent with earlier research showing that healthy seniors are able to regulate emotion better than younger people.
St. Jacques, P.L., Dolcos, F. & Cabeza, R. 2009. Effects of Aging on Functional Connectivity of the Amygdala for Subsequent Memory of Negative Pictures: A Network Analysis of Functional Magnetic Resonance Imaging Data. Psychological Science, 20 (1), 74-84.
Why it’s so hard to disrupt your routine
New research has added to our understanding of why we find it so hard to break a routine or overcome bad habits. The problem lies in the competition between the striatum and the hippocampus. The striatum is involved with habits and routines, for example, it records cues or landmarks that lead to a familiar destination. It’s the striatum that enables you to drive familiar routes without much conscious awareness. If you’re travelling an unfamiliar route however, you need the hippocampus, which is much ‘smarter’. The mouse study found that when the striatum was disrupted, the mice had trouble navigating using landmarks, but they were actually better at spatial learning. When the hippocampus was disrupted, the converse was true. This may help us understand, and treat, certain mental illnesses in which patients have destructive, habit-like patterns of behavior or thought. Obsessive-compulsive disorder, Tourette syndrome, and drug addiction all involve abnormal function of the striatum. Cognitive-behavioral therapy may be thought of as trying to learn to use one of these systems to overcome and, ultimately, to re-train the other.
Lee, A.S. et al. 2008. A double dissociation revealing bidirectional competition between striatum and hippocampus during learning. Proceedings of the National Academy of Sciences, 105 (44), 17163-17168.
Occasional memory loss tied to lower brain volume
A study of 503 seniors (aged 50-85) with no dementia found that 453 of them (90%) reported having occasional memory problems such as having trouble thinking of the right word or forgetting things that happened in the last day or two, or thinking problems such as having trouble concentrating or thinking more slowly than they used to. Such problems have been attributed to white matter lesions, which are very common in older adults, but all of the participants in the study had white matter lesions in their brains, and the amount of lesions was not tied to occasional memory problems. However it was found that those who reported having such problems had a smaller hippocampus than those who had no cognitive problems. This was most noteworthy in subjects with good objective cognitive performance.
van Norden, A.G.W. et al. 2008. Subjective cognitive failures and hippocampal volume in elderly with white matter lesions. Neurology, 71, 1152-1159.
Drinking alcohol associated with smaller brain volume
It is estimated that brain volume decreases by 1.9% per decade, accompanied by an increase in white matter lesions. Because moderate alcohol consumption has been associated with a lower risk of cardiovascular disease, it’s been thought that small amounts of alcohol might also reduce age-related declines in brain volume, although it’s known that large amounts of alcohol will reduce brain volume. However, a large, long-running study, has now found that, even at low levels of alcohol consumption, brain volume was negatively affected. Moreover, although men were more likely to be heavier drinkers, the association between drinking and brain volume was stronger in women.
Paul, C.A. et al. 2008. Association of Alcohol Consumption With Brain Volume in the Framingham Study. Archives of Neurology, 65(10), 1363-1367.
Encoding isn’t solely in the hippocampus
Perhaps we can improve memory in older adults with a simple memory trick. The hippocampus is a vital region for learning and memory, and indeed the association of related details to form a complete memory has been thought to occur entirely within this region. However, a new imaging study has found that when volunteers memorized pairs of words such as "motor/bear" as new compound words ("motorbear") rather than separate words, then the perirhinal cortex, rather than the hippocampus, was activated, and this activity predicted whether the volunteers would be able to successfully remember the pairs in the future.
Haskins, A.L. et al. 2008. Perirhinal Cortex Supports Encoding and Familiarity-Based Recognition of Novel Associations. Neuron, 59, 554-560.
Long-term cannabis users may have structural brain abnormalities
An imaging study of 15 men who smoked more than five cannabis joints daily for more than 10 years has found that, compared with individuals who were not cannabis users, the heavy cannabis users tended to have a smaller hippocampus and amygdala. They also performed significantly worse on verbal learning, but this didn’t correlate with regional brain volumes.
Yücel, M. et al. 2008. Regional Brain Abnormalities Associated With Long-term Heavy Cannabis Use . Archives of General Psychiatry, 65(6), 694-701.
How Ritalin works to focus attention
Ritalin has been widely used for decades to treat attention deficit hyperactivity disorder (ADHD), but until now the mechanism of how it works hasn’t been well understood. Now a rat study has found that Ritalin, in low doses, fine-tunes the functioning of neurons in the prefrontal cortex, and has little effect elsewhere in the brain. It appears that Ritalin dramatically increases the sensitivity of neurons in the prefrontal cortex to signals coming from the hippocampus. However, in higher doses, prefrontal neurons stopped responding to incoming information, impairing cognition. Low doses also reinforced coordinated activity of neurons, and weakened activity that wasn't well coordinated. All of this suggests that Ritalin strengthens dominant and important signals within the prefrontal cortex, while lessening weaker signals that may act as distractors.
Devilbiss, D.M. & Berridge, C.W. 2008. Cognition-Enhancing Doses of Methylphenidate Preferentially Increase Prefrontal Cortex Neuronal Responsiveness. Biological Psychiatry, Available online 30 June 2008
Short-term stress can affect learning and memory
We know that long-lasting, severe stress can impair cell communication in the hippocampus. Now rodent studies have demonstrated that the same outcome can happen with short-term stress. But rather than involving the familiar stress hormone cortisol, acute stress activated corticotropin releasing hormones, which led to the rapid disintegration of dendritic spines in the hippocampus, thus limiting the ability of synapses to collect and store memories.
Chen, Y. et al. 2008. Rapid Loss of Dendritic Spines after Stress Involves Derangement of Spine Dynamics by Corticotropin-Releasing Hormone. Journal of Neuroscience, 28, 2903-2911.
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.
Bachstetter, A.D. et al. 2008. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain. BMC Neuroscience, 9, 22.
Stress hormone impacts memory, learning in diabetic rodents
A rodent study sheds light on why diabetes can impair cognitive function. The study found that increased levels of a stress hormone (called cortisol in humans) in diabetic rats impaired synaptic plasticity and reduced neurogenesis in the hippocampus. When levels returned to normal, the hippocampus recovered. Cortisol production is controlled by the hypothalamic-pituitary axis (HPA). People with poorly controlled diabetes often have an overactive HPA axis and excessive cortisol.
Stranahan, A.M et al. 2008. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nature Neuroscience, 11, 309–317.
Mouse study points to new therapy for Fragile X sufferers
A mouse study has found evidence that fragile X mutation produces a highly selective impairment to long-term potentiation in hippocampal cells, and that adding brain-derived neurotrophic factor (BNDF) proteins to the hippocampus restored it.
Lauterborn, J.C. et al. 2007. Brain-Derived Neurotrophic Factor Rescues Synaptic Plasticity in a Mouse Model of Fragile X Syndrome. Journal of Neuroscience, 27 (40), 10685-10694.
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.
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.
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.
Saxe, M.D. et al. 2007. Paradoxical influence of hippocampal neurogenesis on working memory. Proceedings of the National Academy of Sciences, 104 (11), 4642-4646.
Odor can help memory, in some circumstances
A study in which students played a computer version of a common memory game in which you turn over pairs of cards to find each one's match found that those who played in a rose-scented room and were later exposed to the same scent during slow-wave sleep, remembered the locations of the cards significantly better than people who didn't have that experience (97% vs 86%). Those exposed to the odor during REM sleep, however, saw no memory boost. Imaging revealed the hippocampus was activated when the odor was presented during slow-wave sleep. Having the smell available throughout sleep wouldn’t help, however, because we adapt to smells very quickly. Being exposed to the smell when being tested didn’t help either. Nor did experiencing the odor during slow-wave sleep help when the memory task involved a different type of memory — learning a finger-tapping sequence — probably because procedural memory doesn’t depend on the hippocampus.
Rasch, B., Büchel, C., Gais, S. & Born, J. 2007. Odor Cues During Slow-Wave Sleep Prompt Declarative Memory Consolidation. Science, 315 (5817), 1426-1429.
How we predict the future
A brain imaging study has revealed those regions involved in imagining future events are much the same as those regions involved in remembering past events, suggesting the brain apparently predicts the course of future events by imagining them taking place much like similar past ones. This is also consistent with observations from amnesic patients and very young children — that the capacity to predict the future depends on being able to remember the past. One set of regions that was more active while envisioning the future than while recollecting the past has been implicated in imagined (simulated) bodily movements, suggesting that we place future scenarios in well known visual–spatial contexts.
Szpunar, K.K., Watson, J.M. & McDermott, K.B. 2007. Neural substrates of envisioning the future. Proceedings of the National Academy of Sciences USA, 104, 642-647.
The finding is supported by another study, demonstrating that amnesic patients with primary damage to the hippocampus were markedly impaired at imagining new experiences in response to short verbal cues that outlined a range of simple commonplace scenarios. The patients were unable to visualize the whole experience in their mind's eye, seeing instead just a collection of separate images.
Hassabis, D., Kumaran, D., Vann, S.D. & Maguire, E.A. 2007. Patients with hippocampal amnesia cannot imagine new experiences. Proceedings of the National Academy of Sciences USA, 104 (5), 1726-1731.
Full text available at http://tinyurl.com/2jwpn3
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.
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 Science, 103 (50), 19170-19175.
More on how memories are consolidated during sleep
A new study sheds more light on how memory is consolidated during sleep. Using a new technique, the research confirms that new information is transferred between the hippocampus and the cerebral cortex, and, unexpectedly, provides evidence suggesting that the cerebral cortex actively controls this transfer.
Hahn, T., Sakmann, B. & Mehta, M.R. 2006. Phase-locking of hippocampal interneurons' membrane potential to neocortical up-down states. Nature Neuroscience, 9, 1359-1361.
Still more on how memories are consolidated during sleep
In research following up an earlier study in which rats were shown to form complex memories for sequences of events experienced while they were awake, and that these memories were replayed while they slept, it has been shown that these replayed memories do contain the visual images that were present during the running experience. By showing that the brain is replaying memory events in the visual cortex and in the hippocampus at the same time, the finding suggests that this process may contribute to or reflect the result of the memory consolidation process.
Ji, D. & Wilson, M.A. 2006. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nature Neuroscience, 10, 100-107.
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.
Hattiangady, B. & Shetty, A.K. 2006. Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus. Neurobiology of Aging, In Press, Corrected Proof, Available online 7 November 2006.
Rote learning may improve verbal memory in seniors
A study involving 24 older adults (aged 55—70) has found that six weeks of intensive rote learning (memorizing a newspaper article or poem of 500 words every week) resulted in measurable changes in N-acetylaspartate, creatine and choline, three metabolites in the brain that are related to memory performance and neural cell health, in the left posterior hippocampus — but only after a six-week rest period, at which time the participants also showed improvements in their verbal and episodic memory, and also only in one of the two learning groups. The group that didn’t show any change were said to have low compliance with the memorization task.
McNulty, J. et al. The Identification of Neurometabolic Sequelae Post-learning Using Proton Magnetic Resonance Spectroscopy. Presented November 26 at the annual meeting of the Radiological Society of North America (RSNA).
How the brain detects novelty
New research suggests that the hippocampus makes predictions of what will happen next by automatically recalling an entire sequence of events in response to a single cue, allowing us to anticipate future events and detect when things do not turn out as expected. Rather than reacting to novelty, the hippocampus seems to act as a comparison device, matching up past and present experience.
Kumaran, D. & Maguire, E.A. 2006. An unexpected sequence of events: Mismatch detection in the human hippocampus. PLoS Biol 4(12): e424. DOI: 10.1371/journal.pbio.0040424
Repeated common infections may lead to memory deficits over a lifetime
A mouse study suggests that over the lifetime of an individual, a picornavirus-related infection could have a permanent effect on memory late in life. Picornaviruses are the most common infectious viral agents in humans. They include rhinoviruses, enteroviruses, encephalitis, myocarditis, meningitis, and those that cause foot-and-mouth disease, polio and hepatitis A. Generally individuals contract two or three enterovirus and/or rhinovirus infections each year. In the study, mice infected with an encephalomyelitis virus (comparable to the human poliovirus) had difficulty learning to navigate a maze designed to test various components of spatial memory. The degree of memory impairment was directly correlated to the number of dead brain cells in the hippocampus. "Our findings suggest that picornavirus infections throughout the lifetime of an individual may chip away at the cognitive reserve, increasing the likelihood of detectable cognitive impairment as the individual ages. We hypothesize that mild memory and cognitive impairments of unknown etiology may, in fact, be due to accumulative loss of hippocampus function caused by repeated infection with common and widespread neurovirulent picornaviruses."
Buenz, E.J., Rodriguez, M. & Howe, C.L. 2006. Disrupted spatial memory is a consequence of picornavirus infection. Neurobiology of Disease, 24 (2), 266-273.
'Memory gene' identified
Analysis of the human genome has revealed a gene associated with memory performance. The gene is called Kibra, and is expressed in the hippocampus. According to brain scans, people with the version of the gene related to poorer memory potential had to tax their brains harder to remember the same amount of information.
Papassotiropoulos, A. 2006. Common Kibra Alleles Are Associated with Human Memory Performance. Science, 314 (5798), 475-478.
Why moderate drinking may boost memory
Another study has come out suggesting moderate amounts of alcohol are good for the brain, and explaining why. The rat study found that low levels of alcohol increased the expression of a particular receptor, NR1, on the surface of neurons in the hippocampus. Increasing the number of NR1 receptors in a different group of rats resulted in a memory boost similar to that seen in the rats given low doses of alcohol. There were no toxic effects of low-level alcohol consumption (1—2 drinks a day) on the brain, but a higher dose of alcohol did damage neurons.
The findings were presented at the Society for Neuroscience's annual meeting on October 14-18 in Atlanta, Georgia.
Chemo drugs for treating breast cancer may cause changes in cognitive function
A study involving female mice confirms the existence of "chemobrain", finding mild to moderate learning and memory deficits in mice receiving methotrexate and 5-fluorouracil (5FU), two drugs widely used in women to prevent recurrence of breast cancer. The deficits extended only to those types of memory that involve the hippocampus or the frontal lobes (spatial memory and working memory, in this instance). The study only looked at short-term effects (2—4 weeks).
Winocur, G., Vardy, J., Binns, M.A., Kerr, L. & Tannock, I. 2006. The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice. Pharmacology, Biochemistry and Behavior, 85 (1), 66-75.
Anticipation strengthens memory
An imaging study has revealed that the amygdala and the hippocampus become activated when a person is anticipating a difficult situation (some type of gruesome picture). Moreover, the higher the level of activation during this anticipation, the better the pictures were remembered two weeks later. The study demonstrates how expectancy can affect long-term memory formation, and suggests that the greater our anxiety about a situation, the better we’ll remember that situation. If it’s an unpleasant one, this will only reinforce the anxiety, setting up a vicious cycle. The study has important implications for the treatment of psychological conditions such as post-traumatic stress disorder and social anxiety.
Mackiewicz, K.L., Sarinopoulos, I., Cleven, K.L. & Nitschke, J.B. 2006. The effect of anticipation and the specificity of sex differences for amygdala and hippocampus function in emotional memory. PNAS, 103, 14200-14205.
Childhood sleep apnea linked to brain damage, lower IQ
It’s long been known that sleep apnea, characterized by fragmented sleep, interrupted breathing and oxygen deprivation, harms children's learning ability and school performance. Now a new study involving 19 children with severe obstructive sleep apnea has identified damage in the hippocampus and the right frontal cortex, and linked that to observable deficits in performance on cognitive tests. Children with OSA had an average IQ of 85 compared to 101 in matched controls. They also performed worse on standardized tests measuring executive functions, such as verbal working memory (8 versus 15) and word fluency (9.7 versus 12). Obstructive sleep apnea affects 2% of children in the United States, but it is unclear how many of these suffer from severe apnea.
Springer, M.V., McIntosh, A.R., Winocur, G. & Grady, C.L. 2005. The Relation Between Brain Activity During Memory Tasks and Years of Education in Young and Older adults. Neuropsychology and Aging, 19 (2)
A single memory is processed in three separate parts of the brain
A rat study has demonstrated that a single experience is indeed processed differently in separate parts of the brain. They found that when the rats were confined in a dark compartment of a familiar box and given a mild shock, the hippocampus was involved in processing memory for context, while the anterior cingulate cortex was responsible for retaining memories involving unpleasant stimuli, and the amygdala consolidated memories more broadly and influenced the storage of both contextual and unpleasant information.
Malin, E.L. & McGaugh, J.L. 2006. Differential involvement of the hippocampus, anterior cingulate cortex, and basolateral amygdala in memory for context and footshock. Proceedings of the National Academy of Sciences, 103 (6), 1959-1963.
Memory of fear more complex than supposed
It seems that fear memory is more complex than has been thought. A new mouse study has shown that not only the hippocampus and amygdala are involved, but that the prefrontal cortex is also critical. The development of the fear association doesn’t occur immediately after a distressing event, but develops over time. The process, it now seems, depends directly on a protein called NR2B.
Zhao, M-G. et al. 2005. Roles of NMDA NR2B Subtype Receptor in Prefrontal Long-Term Potentiation and Contextual Fear Memory. Neuron, 47, 859-872.
How trauma triggers long-lasting memories in the brain
A rat study sheds more light on why emotional experiences tend to be better remembered than emotionally neutral events. The study found that emotionally arousing events activated the amygdala, which then increased a specific protein — activity-regulated cytoskeletal protein ("Arc") — in the neurons in the hippocampus. It's thought that Arc helps store these memories by strengthening the synapses.
McIntyre, C.K., Miyashita, T., Setlow, B., Marjon, K.D., Steward, O., Guzowski, J.F. & McGaugh, J.L. 2005. Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus. Proceedings of the National Academy of Sciences, 102 (30), 10718-10723.
How sleep improves memory
While previous research has been conflicting, it does now seem clear that sleep consolidates learning of motor skills in particular. A new imaging study involving 12 young adults taught a sequence of skilled finger movements has found a dramatic shift in activity pattern when doing the task in those who were allowed to sleep during the 12 hour period before testing. Increased activity was found in the right primary motor cortex, medial prefrontal lobe, hippocampus and left cerebellum — this is assumed to support faster and more accurate motor output. Decreased activity was found in the parietal cortices, the left insular cortex, temporal pole and fronto-polar region — these are assumed to reflect less anxiety and a reduced need for conscious spatial monitoring. It’s suggested that this is one reason why infants need so much sleep — motor skill learning is a high priority at this age. The findings may also have implications for stroke patients and others who have suffered brain injuries.
Walker, M.P., Stickgold, R., Alsop, D., Gaab, N. & Schlaug, G. 2005. Sleep-dependent motor memory plasticity in the human brain.Neuroscience, 133 (4) , 911-917.
Why traumatic memories have the power they do
In the first imaging study to look at retrieval of emotional memories after a long period (one year after encoding), researchers found that people did recall emotional images, both pleasant and unpleasant, better than emotionally-neutral images. This recall was associated with higher activity in both the amygdala and the hippocampus. The synchronicity of activity between these two regions suggested that each region triggers the other, creating a self-reinforcing "memory loop" in which an emotional cue might trigger recall of the event, which then loops back to a re-experiencing of the emotion of the event. The findings suggest why people subject to traumatic events may be trapped in a cycle of emotion and recall that aggravates post-traumatic stress disorder, and may also suggest why therapies in which people relive such memories and reshape perspective to make it less traumatic can help people cope with such memories.
Dolcos, F., LaBar, K.S. & Cabeza, R. 2005. Remembering one year later: Role of the amygdala and the medial temporal lobe memory system in retrieving emotional memories. PNAS, 102 (7), 2626-2631.
Hippocampus and subiculum both critical for short-term memory
A new animal study has revealed that the hippocampus shares its involvement in short-term memory with an adjacent brain region, the subiculum. Both regions act together to establish and retrieve short-term memories. The process involves each region acting at different times, with the other region shutting off while the other is active. The shortest memories (10-15s) were found to be controlled almost exclusively by the subiculum. After 15s, the hippocampus took over. It was also found that the hippocampus appeared to respond in a way influenced by previous experiences, allowing it to anticipate future events on the basis of past outcomes. This is an advantage but can also cause errors.
Deadwyler, S.A. & Hampson, R.E. 2004. Differential but Complementary Mnemonic Functions of the Hippocampus and Subiculum. Neuron, 42 (3), 465-476.
Different brain regions for arousing and non-arousing words
An imaging study has found that words representing arousing events (e.g., “rape”, “slaughter”) activate cells in the amygdala, while nonarousing words (e.g., “sorrow”, “mourning”) activated cells in the prefrontal cortex. The hippocampus was active for both type of words. On average, people remembered more of the arousing words than the others, suggesting stress hormones, released as part of the response to emotionally arousing events, are responsible for enhancing memories of those events.
Kensinger, E.A. & Corkin, S. 2004. Two routes to emotional memory: Distinct neural processes for valence and arousal. PNAS, 101, 3310-3315. Published online before print February 23 2004, 10.1073/pnas.0306408101
More light shed on memory encoding
Anything we perceive contains a huge amount of sensory information. How do we decide what bits to process? New research has identified brain cells that streamline and simplify sensory information, markedly reducing the brain's workload. The study found that when monkeys were taught to remember clip art pictures, their brains reduced the level of detail by sorting the pictures into categories for recall, such as images that contained "people," "buildings," "flowers," and "animals." The categorizing cells were found in the hippocampus. As humans do, different monkeys categorized items in different ways, selecting different aspects of the same stimulus image, most likely reflecting different histories, strategies, and expectations residing within individual hippocampal networks.
Hampson, R.E., Pons, T.P., Stanford, T.R. & Deadwyler, S.A. 2004. Categorization in the monkey hippocampus: A possible mechanism for encoding information into memory. PNAS, 101, 3184-3189. Published online before print as 10.1073/pnas.0400162101
Now definite? Memories are consolidated during sleep
Researchers of a new study claim that their research finally settles the question of whether or not sleep consolidates new memories. The study involved detailed recording of specific learning- and memory- related areas (hippocampus and forebrain) in the brains of rats. The rats were exposed to four kinds of novel objects. Analysis of brain signals before, during, and after this experience, revealed "reverberations" of distinctive brain wave patterns across all the areas being monitored for up to 48 hours after the novel experience. This pattern was much more prevalent in slow-wave sleep than in REM sleep. Previous studies by the same researchers have found that the activation of genes that affect memory consolidation occurs during REM sleep, not slow-wave sleep. It is proposed that both stages of sleep are important for memory consolidation. Previous studies have tended to focus solely on the hippocampus, and have observed brain activity for a much shorter period.
Ribeiro, S., Gervasoni, D., Soares, E.S., Zhou, Y., Lin, S-C., Pantoja, J., Lavine, M. & Nicolelis, M.A.L. 2004. Long-Lasting Novelty-Induced Neuronal Reverberation during Slow-Wave Sleep in Multiple Forebrain Areas. PLoS Biol 2(1): e24 DOI:10.1371/journal.pbio.0020024.
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.
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.
Forgetting may sometimes be an active process
New evidence suggests that forgetting may not simply be the passive phenomenon it has always been thought. Rather than simply a failure to properly encode or consolidate memories, forgetting may also be an active process — a deliberate action to erase unwanted memories. The recent study involved seeing the effect of a memory-blocking drug called APV on slices of brain tissue taken from the hippocampus of rats. APV blocks receptors for the neurotransmitter NMDA, which mediates the strengthening of synapses. While, as expected, NMDA activity was reduced in the treated hippocampal neurons, it was also found that “sharp waves” doubled in magnitude. This type of electrical activity is little understood, but it is known that such waves occur when an animal is alert but not actively exploring its environment or receiving sensory input, and they do not occur when brain activity associated with memory processing is occurring. Thus, the fact that a drug known to block memory, enhances sharp waves, is suggestive. The researchers speculate that sharp waves might work by reversing long-term potentiation — the mechanism by which synapses are thought to be strengthened — and that their function is to erase some of the information that was encoded during the active phase.
More evidence for active forgetting
In an imaging study involving 24 people aged 19 to 31, participants were given pairs of words and told to remember some of the matched pairs but forget others. Trying to shut out memory appeared more demanding than remembering, in that some areas of the brain were significantly more when trying to suppress memory. Both the prefrontal cortex and the hippocampus were active. Those whose prefrontal cortex and hippocampus were most active during this time were most successful at suppressing memory.
Anderson, M.C., Ochsner, K.N., Kuhl, B., Cooper, J., Robertson, E., Gabrieli, S.W., Glover, G.H. & Gabrieli, J.D.E. 2004. Neural Systems Underlying the Suppression of Unwanted Memories. Science, 303 (5655), 232-235.
Gene essential for development of normal brain connections discovered
After birth, learning and experience change the architecture of the brain dramatically. The structure of individual neurons, or nerve cells, changes during learning to accommodate new connections between neurons. Neuroscientists believe these structural changes are initiated when neurons are activated, causing calcium ions to flow into cells and alter the activity of genes. Now the first gene, CREST, known to mediate these changes in the structure of neurons in response to calcium, has been discovered. In the study, it was found that mice lacking this gene didn’t develop normally in response to sensory experience, and their brains, while normal at birth, later showed far less interconnectivity between neurons. The gene produces a protein that, in adult humans, is produced in the hippocampus. It is therefore speculated that the protein may be necessary for learning and memory storage. The discovery of this gene may have implications for certain types of learning disorders in humans.
Aizawa, H., Hu, S-C., Bobb, K., Balakrishnan, K., Ince, G., Gurevich, I., Cowan, M. & Ghosh, A. 2004. Dendrite Development Regulated by CREST, a Calcium-Regulated Transcriptional Activator. Science, 303 (5655), 197-202.
Brain protein affecting learning and memory discovered
A significant new brain protein has been identified. Cypin is found throughout the body, but in the brain it now appears that it regulates neuron branching in the hippocampus. Such branching is thought to increase when learning occurs, and a reduction in branching is associated with certain neurological diseases. Discovery of this protein opens the possibility of new drug therapies for treating neurological disorders, and perhaps even memory-enhancing drugs.
Akum, B.F., Chen, M., Gunderson, S.I., Riefler, G.M., Scerri-Hansen, M.M. & Firestein, B.L. 2004. Cypin regulates dendrite patterning in hippocampal neurons by promoting microtubule assembly. Nature Neuroscience, 7(2), 145-152.
More learned about how spatial navigation works in humans
Researchers monitored signals from individual brain cells as patients played a computer game in which they drove around a virtual town in a taxi, searching for passengers who appeared in random locations and delivering them to their destinations. Previous research has found specific cells in the brains of rodents that respond to “place”, but until now we haven’t known whether humans have such specific cells. This study identifies place cells (primarily found in the hippocampus), as well as “view” cells (responsive to landmarks; found mainly in the parahippocampal region) and “goal” cells (responsive to goals, found throughout the frontal and temporal lobes). Some cells respond to combinations of place, view and goal — for example, cells that responded to viewing an object only when that object was a goal.
Ekstrom, A.D., Kahana, M.J., Caplan, J.B., Fields, T.A., Isham, E.A., Newman, E.L. & Fried, I. 2003. Cellular networks underlying human spatial navigation.Nature, 425 (6954), 184-7.
Another step in understanding how memories are formed
The electrical activity of individual neurons in the brains of two adult rhesus monkeys was monitored while the monkeys played a memory-based video game in which an image pops up on the computer screen with four targets—white dots—superimposed on it. The monkeys’ task was to learn which target on which image was associated with a reward (a drop of their favorite fruit juice). Dramatic changes in the activity of some hippocampal neurons, which the scientists called "changing cells", paralleled their learning, indicating that these neurons are involved in the initial formation of new associative memories. In some of the cells, activity continued after the animal had learned the association, suggesting that these cells may participate in the eventual storage of the associations in long-term memory.
Wirth, S., Yanike, M., Frank, L.M., Smith, A.C., Brown, E.N. & Suzuki, W.A. 2003. Single Neurons in the Monkey Hippocampus and Learning of New Associations. Science, 300, 1578-1581.
Brain implant may restore memory
An artificial hippocampus — a programmed silicone chip — is to be linked with live tissue taken from rat brains, and then will be tested on live animals. If all goes well, it will then be tested as a way to help people who have suffered brain damage due to stroke, epilepsy or Alzheimer's disease.
Another step in understanding how sleep affects memory
The value of sleep for memory takes a further step in being understood in new rodent research, which found that, as the rodents slept, the thalamus at the base of their brains originated bursts of electrical activity (“sleep spindles”), which were then detected in the somatosensory neocortex. Some 50 msec later, the hippocampus responded with a pulse of electricity (a “ripple”). "This neocortical-hippocampal dialogue may provide a selection mechanism for the time-compressed replay of information learned during the day." It’s suggested that the ripple is the hippocampus sending back neat, compact waves of memory to the neocortex where they are filed away for future reference. Most of this activity took place during slow wave sleep, the stage which makes up the majority of the sleep cycle.
Sirota, A., Csicsvari, J., Buhl, D. & Buzsáki, G. 2003. Communication between neocortex and hippocampus during sleep in rodents. Proc. Natl. Acad. Sci. USA, 100 (4), 2065-2069.
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.
Egan, M.F., Kojima, M., Callicott, J.H., Goldberg, T.E., Kolachana, B.S., Bertolino, A., Zaitsev, E., Gold, B., Goldman, D., Dean, M., Lu, B. & Weinberger, D.R. 2003. The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function. Cell, 112, 257-269.
More details about how memories are formed in the hippocampus
We know how important the hippocampus is in forming memories, but now, using newly developed imaging techniques, researchers have managed to observe how activity patterns within specific substructures of the hippocampus change during learning. The study identified areas within the hippocampus (the cornu ammonis and the dentate gyrus) as highly active during encoding of face-name pairs. This activity decreased as the associations were learned. A different area of the hippocampus (the subiculum) was active primarily during the retrieval of the face-name associations. Activity in the subiculum also decreased as retrieval became more practiced.
Zeineh, M.M., Engel, S.A., Thompson, P.M. & Bookheimer, S.Y. 2003. Dynamics of the Hippocampus During Encoding and Retrieval of Face-Name Pairs, Science, 299, 577-580.
Brain region involved in recalling memories from smell identified
We all know the power of smell in triggering the recall of memories. New research has found the specific area of the brain involved in this process - a section of the hippocampus called CA3. The hippocampus has long been known to play a crucial part in forming new memories. It appears that the CA3 region of the hippocampus is crucial for recalling memories from partial representations of the original stimulus.
Nakazawa, K., Quirk, M.C., Chitwood, R.A., Watanabe, M., Yeckel, M.F., Sun, L.D., Kato, A., Carr, C.A., Johnston, D., Wilson, M.A. & Tonegawa, S. 2002. Requirement for Hippocampal CA3 NMDA Receptors in Associative Memory Recall. Science 297, 211-218.
Rhythm rather than strength of neural activity may be crucial for memory formation
The strength of the electrical activity between neurons has long been thought to be the critical factor in forming memories, but new research suggests that at least in two critical brain areas, memory may hinge more on the timing than on the strength of neural activity. It seems that, as subjects studied word lists, clusters of neurons in the rhinal cortex and the hippocampus—adjacent brain areas already implicated in memory—fired synchronized electrical bursts that paved the way for remembering those words later. Moreover, the coordination of cell activity in the same two brain regions plummetted for a fraction of a second just after participants remembered a word from the list, possibly signaling an end to a coordinated neural effort. "Memory may emerge when rhinal and hippocampal neurons synchronously oscillate and then desynchronize."
Fell, J., Klaver, P., Lehnertz, K., Grunwald, T., Schaller, C., Elger, C.E. & Fernández, G. 2001. Human memory formation is accompanied by rhinal-hippocampal coupling and decoupling. Nature Neuroscience 4(12), 1259-1264.
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).
Kornack, D.R. & Rakic, P. 2001. Cell Proliferation Without Neurogenesis in Adult Primate Neocortex. Science, 294 (5549), 2127-2130.