hippocampus

means "sea horse", and is named for its shape. It is one of the oldest parts of the brain, and is buried deep inside, within the limbic lobe. The hippocampus is important for the forming, and perhaps long-term storage, of associative and episodic memories. Specifically, the hippocampus has been implicated in (among other things) the encoding of face-name associations, the retrieval of face-name associations, the encoding of events, the recall of personal memories in response to smells. It may also be involved in the processes by which memories are consolidated during sleep.

How cognitive reserve helps protect seniors from cognitive decline

May, 2012
  • Greater cognitive activity doesn’t appear to prevent Alzheimer’s brain damage, but is associated with more neurons in the prefrontal lobe, as well as other gender-specific benefits.

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.

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Genes, brain size, brain atrophy, and Alzheimer’s risk

May, 2012

A round-up of genetic news.

  • Several genes are linked to smaller brain size and faster brain atrophy in middle- & old age.
  • The main Alzheimer's gene is implicated in leaky blood vessels, and shown to interact with brain size, white matter lesions, and dementia risk.
  • Some evidence suggests early-onset Alzheimer's is not so dissimilar to late-onset Alzheimer's.

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.

http://www.eurekalert.org/pub_releases/2006-04/vfii-rda041906.php

Evidence that Alzheimer's protein switches on genes

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

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

http://www.eurekalert.org/pub_releases/2001-07/aaft-eta070201.php

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.

http://www.eurekalert.org/pub_releases/2004-04/cp-ioa032904.php

Reference: 

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

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

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

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

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

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

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

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

Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031039

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

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

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How marijuana impairs working memory

April, 2012

A mouse study indicates that the psychoactive component of marijuana, TCP, impairs working memory by initiating a process that ends with neural connections being weakened.

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).

See the Guardian and Scientific American articles for more detail on the study and the processes involved.

For more on the effects of marijuana on memory

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How family circumstance impacts learning and memory in children

February, 2012

A large study shows the impact of having multiple family disadvantages on cognitive development. A brain scan study finds childhood maltreatment significantly reduces the size of the hippocampus, while another finds parental care can increase it.

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.

Reference: 

First study:
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...

Second study:
[2741] Teicher, M. H., Anderson C. M., & Polcari A.
(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...

Third study:
[2734] Luby, J. L., Barch D. M., Belden A., Gaffrey M. S., Tillman R., Babb C., et al.
(2012).  Maternal support in early childhood predicts larger hippocampal volumes at school age.
Proceedings of the National Academy of Sciences.

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Latest London taxi driver study shows brain changes driven by learning

January, 2012
  • A comparison of the brains of London taxi drivers before and after their lengthy training shows clearly that the increase in hippocampal gray matter develops with training, but this may come at the expense of other brain functions.

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).

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Abnormal brain blood flow persisting in some Gulf War veterans

December, 2011

In a small study, some Gulf War syndromes are shown to have effects on the hippocampus that have persisted for 20 years, and in some cases worsened.

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.

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Memory genes vary in protecting against age-related cognitive decline

November, 2011

New findings show the T variant of the KIBRA gene improves episodic memory through its effect on hippocampal activity. Another study finds the met variant of the BDNF gene is linked to greater age-related cognitive decline.

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.

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Obesity linked to better cognition in post-menopausal women

November, 2011
  • A new study suggests fat might help protect women from age-related cognitive decline.

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.

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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."

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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.

[733] Thompson, P. M., Raji C. A., Ho A. J., Parikshak N. N., Becker J. T., Lopez O. L., et al.
(2010).  Brain structure and obesity.
Human Brain Mapping. 31(3), 353 - 364.

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Dealing with math anxiety

November, 2011

A new study shows that some math-anxious students can overcome performance deficits through their ability to control their negative responses. The finding indicates that interventions should focus on anticipatory cognitive control.

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.

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Cannabis disrupts synchronized brain activity

November, 2011

Effects of a cannabis-like drug on rats explain why cannabis is linked to schizophrenia and how it might impair cognition, as well as supporting our understanding of how working memory works.

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.

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