Richer Fuller Lives: What Can We Learn from Einstein's Brain?

One of the more tragic aspects of human existence is the common loss of the brain's mental powers, just when a person has experienced enough of life to begin putting many of the pieces of the puzzle together.

Exceptional brains appear to see more of the big picture earlier, and to exhibit a greater resistance to dementia in later life. Why are some brains exceptional, and is it possible to learn enough about the genetics of brain anatomy and function to bring more human brains into an exceptional state of function?

Einstein's Brain
Detailed photographs of the brain of Albert Einstein taken at post-mortem have recently been re-examined by scientists, in an attempt to understand the differences in brain structure which contributed to the physicist's exceptional life and contributions to human knowledge. Einstein's brain displayed some remarkable features which were summarised in the images above, and in the caption below.

(A) Figure 2 [see image above] of the left lateral surface of Einstein’s brain highlighted to summarize interesting features, which have been darkened. These include a connected precentral superior and inferior sulcus, a long unnamed sulcus in the inferior primary somatosensory cortex, and a posterior ascending limb of the Sylvian fissure that, contrary to the literature, is not confluent with the postcentral inferior sulcus. Unusually expanded primary somatosensory (posterior to the central sulcus) and primary motor cortices (rectangular region below the precentral inferior sulcus) are highlighted in yellow, as are the unusually convoluted surface of the pars triangularis (part of Broca’s speech area) and the frontal polar region.

(B) Figure 7 of an occipital view of Einstein’s brain coloured to indicate the approximate boundaries of the superior parietal lobule (purple), inferior parietal lobule (aqua/blue) and occipital lobes (salmon). Presence of four transverse occipital sulci (darkened) is extremely rare, if not unique. Parts of the posterior temporal lobes are uncoloured below the inferior parietal lobules and rostral to the occipital lobes. Although the small striped patch between the superior and inferior parietal lobules on the right belongs with the superior parietal lobule rather than the angular gyrus of the inferior parietal lobule, its relationship with the bordering intraparietal sulcus is usually associated with a location in the angular gyrus. It would therefore be interesting to study the cytoarchitecture of this enigmatic patch of cortex. Notice that the inferior parietal lobule is favoured on the left (and see Fig. 4), while the superior parietal lobule is relatively greater on the right. There is also an asymmetry that favours the right posterior temporal region, and the right occipital lobe is shifted forward relative to the left.

(C) Figure 2 of the right lateral surface of Einstein’s brain highlighted to summarize interesting features, including sulci that are darkened. Unusual sulcal patterns include a connected precentral superior and inferior sulcus, a caudal segment of the inferior frontal sulcus that is connected with both the diagonal and precentral inferior sulci, and a long midfrontal sulcus that terminates in the fronto-marginal sulcus of Wernicke. The midfrontal sulcus divides the middle frontal region into two distinct gyri (highlighted in yellow), which causes Einstein’s right frontal lobe to have four rather than the typical three gyri. The enlarged ‘knob’ that probably represents motor cortex for the left hand and the highly convoluted frontal polar region are also highlighted in yellow.

(D) Figure 8 of the right medial surface of Einstein’s brain with unusual features highlighted in yellow. The cingulate gyrus has a long unnamed sulcus, the transverse parietal sulcus seems relatively elongated and the cuneus appears to be unusually convoluted.

(E) Figure 6 of the basal surface of Einstein’s brain highlighted to show that the left collateral sulcus is divided into two segments, and that part of the fusiform gyrus bridges between these segments to merge with the parahippocampal gyrus.

(F) Figure 8 of the left medial surface of Einstein’s brain with unusual features highlighted in yellow. The cingulate gyrus has a long unnamed sulcus, and the cingulate sulcus gives off four inferiorly directed branches (two of which are tiny), which suggest that the cingulate gyrus may be relatively convoluted. The cuneus appears to be unusually convoluted. The figures are reproduced with permission from the National Museum of Health and Medicine. _Cerebral Cortex of Albert Einstein _ Oxford Journals

Figure 8

Figure 8 from the recent journal Brain study of Einstein's brain photographs is only partially described in the captions "D" and "F" above. The photographs reveal far more detail than the drawings.

Both brain volume and brain gyral patterns are under significant genetic control (PDF), although brain volume heritability appears to be greater -- over 90%. Heritability of brain gyral patterns may be closer to 50%.

One interesting gyral pattern variation is the presence or absence of a "paracingulate gyrus" which exists in many people in parallel with the cingulate gyrus. Einstein appears to demonstrate some very interesting variations on the cingulate / paracingulate pattern.

In dementia of various types, brain volume tends to shrink significantly, along with a number of other gross and microscopic changes in morphology. All of these structural changes are also accompanied by changes in gene expression in both neurons and in glial support cells.

The question then arises as to how we might be able to influence gene expression -- in both the healthy and the diseased brain -- in order to improve brain function above and beyond what is currently being experienced.

A rich and full life benefits not only from many years of existence, but also from a depth of understanding of the world around us. Understanding exceptional brains such as Einstein's, may help us to learn what we need to do to enrich the lives of more ordinary humans.

Unconventional Brain Modifications

A team of neuroscientists had discovered a genetic manipulation which provides a long term increase in brain neurogenesis in mice, and which appears to boost learning and reduce anxiety and depression.

...genetic deletion of neurofibromin (Nf1), a tumor suppressor with RAS-GAP activity, in adult NPCs enhanced DG proliferation and increased generation of new neurons in mice. Nf1 loss-associated neurogenesis had the functional effect of enhancing behavioral responses to subchronic antidepressants and, over time, led to spontaneous antidepressive-like behaviors. Thus, our findings establish an important role for the Nf1-Ras pathway in regulating adult hippocampal neurogenesis, and demonstrate that activation of adult NPCs is sufficient to modulate depression- and anxiety-like behaviors. _Journal of Neuroscience

More from ScienceDaily news service:

The researchers found that the test group mice formed more neurons over time compared to controls, and that young mice lacking the Nf1 protein required much lower amounts of anti-depressants to counteract the effects of stress. Behavioral differences between the groups persisted at three months, six months and nine months. "Older mice lacking the protein responded as if they had been taking antidepressants all their lives," said Dr. Parada.

"In summary, this work suggests that activating neural precursor cells could directly improve depression- and anxiety-like behaviors, and it provides a proof-of-principle regarding the feasibility of regulating behavior via direct manipulation of adult neurogenesis," Dr. Parada said. _SD

This type of genetic manipulation will necessarily require further development before it is suitable for use in humans. In particular, it will have to be both reversible, and adjustable in effect.

The increase in hippocampal neurons also suggests the potential for augmenting learning ability in the altered mice over their full lifetimes.

Another interesting brain manipulation studied recently, is the use of the hallucinogenic drug LSD (lysergic acid diethylamide) to aid alcoholics in overcoming their addiction to ethanol. LSD has previously been used effectively to reduce cancer associated pain in terminal cancer patients, as well as to reduce or eliminate the fear of death in terminal cancer patients.

Here is more on a recent meta-analysis of the use of LSD for treating alcohol dependency:

Krebs and Johansen set out to independently extract data from previous randomized, controlled clinical trials, pooling their results. They identified six eligible trials, all carried out in the late 1960s and early 1970s. These included 536 participants, the vast majority of whom were male in-patients enrolled in alcohol-focused treatment programs. Individuals with a history of schizophrenia or psychosis were excluded from the original trials. The control conditions included low-dose LSD, stimulants, or non-drug control conditions. Each trial used clearly defined treatment-independent and standardized methods to assess outcomes on alcohol misuse.

While the experiments varied in the dosage used and the type of placebo physicians administered to patients, LSD had a beneficial effect on alcohol misuse in every trial. On average, 59 percent of LSD patients and 38 percent of control patients were improved at follow-up using standardized assessment of problem alcohol use. There was also a similar beneficial effect on maintained abstinence from alcohol. The positive effects of a single LSD dose -- reported both in these and in other, non-randomized trials -- lasts at least six months and appears to fade by 12 months. _ScienceDaily

Full study in Journal of Psychopharmacology (PDF)

Other hallucinogenic drugs besides LSD which may prove to have beneficial clinical uses include psilocybin, ketamine, and marijuana.

The human brain is an incredibly complex and dynamic organ. We should not be surprised when such a complex device sometimes "malfunctions." And we should maintain relatively open minds when in pursuit of ways to stabilise and improve brain function.

We are playing for very high stakes.

Good News on the Alzheimer's Front

The number of Alzheimer’s victims worldwide is expected to double every 20 years... MIT neuroscientists have shown that an enzyme overproduced in the brains of Alzheimer’s patients creates a blockade that shuts off genes necessary to form new memories. Furthermore, by inhibiting that enzyme in mice, the researchers were able to reverse Alzheimer’s symptoms.

The finding suggests that drugs targeting the enzyme, known as HDAC2, could be a promising new approach to treating the disease, which affects 5.4 million Americans.

Histone deacetylases (HDACs) are a family of 11 enzymes that control gene regulation by modifying histones — proteins around which DNA is spooled, forming a structure called chromatin. When HDACs alter a histone through a process called deacetylation, chromatin becomes more tightly packaged, making genes in that region less likely to be expressed.

HDAC inhibitors can reverse this effect, opening up the DNA and allowing it to be transcribed.

In previous studies, Tsai had shown that HDAC2 is a key regulator of learning and memory. In the new study, her team discovered that inhibiting HDAC2 can reverse Alzheimer’s symptoms in mice._MIT

As the populations of the developed and emerging nations grow progressively older, the number of Alzheimer's sufferers -- and sufferers of other debilitating diseases of old age -- threaten to cripple these societies. Affordable means of preventing and treating dementias and other disabling diseases of senescence could make the difference between prosperity or poverty for many nations. The recent MIT discovery may be an important step forward in this regard.

... the team subsequently showed that using RNAi to reduce HDAC2 build up in the hippocampus of a mouse neurodegenerative disease model removed this repression, reinstated neuronal structural and synaptic plasticity, and eradicated neurodegeneration-associated memory deficits. Li-Huei Tsai, Ph.D., and colleagues report their findings in Nature in a paper titled “an epigenetic blockade of cognitive functions in the neurodegenerating brain.”

Epigenetic modifications in the nervous system that are mediated by histone acetylation have been unequivocally associated with facilitating learning and memory, the researchers state. Multiple studies have in addition reported that reduced histone acetylation is associated with cognitive decline in animal models of neurodegeneration including AD.

To further investigate the role of HDAC2 in neurodegeneration-related cognition, the team looked at levels of the enzyme in CK-p25 mice. These animals can be induced to overexpress p25, in the forebrain. p25 is a truncated version of p35 and is implicated in a range of neurodegenerative diseases. Their studies showed that animals induced to overexpress p25 demosntrated significant increases in HDAC2 in neuronal nuclei, specifically hippocampal area CA1 but not CA3 or the dentate gyrus, and also in the prefrontal cortex. In contrast, levels of the HDAC1 and HDAC3, were not changed.

The researchers then moved on to carry out chromatin immunopreciptation studies to assess the functional consequences of HDAC2 elevation, primarily in a range of known HDAC2 targets that have been shown to be downregulated in human AD brains, including learning- and memory-related genes, and those involved in synaptic plasticity. They found elevated HDAC2 enrichment at the majority of these genes induced CK-p25 hippocampus, whereas again, HDAC1 and HDAC3 binding wasn’t affected. “Interestingly, in agreement with previous reports showing that HDAC2 can also bind to a gene’s coding region, we also found HDAC2 more abundantly bound to the coding sequence of the same genes,” they note. _GenengNews

The researchers found that in mice with Alzheimer’s symptoms, HDAC2 (but not other HDACs) is overly abundant in the hippocampus, where new memories are formed. HDAC2 was most commonly found clinging to genes involved in synaptic plasticity — the brain’s ability to strengthen and weaken connections between neurons in response to new information, which is critical to forming memories. In the affected mice, those genes also had much lower levels of acetylation and expression.

“It’s not just one or two genes, it’s a group of genes that work in concert to control different phases of memory formation,” Tsai says. “With such a blockade, the brain really loses the ability to quickly respond to stimulation. You can imagine that this creates a huge problem in terms of learning and memory functions, and perhaps other cognitive functions.”

The researchers then shut off HDAC2 in the hippocampi of mice with Alzheimer’s symptoms, using a molecule called short hairpin RNA, which can be designed to bind to messenger RNA — the molecule that carries genetic instructions from DNA to the rest of the cell.

With HDAC2 activity reduced, histone acetylation resumed, allowing genes required for synaptic plasticity and other learning and memory processes to be expressed. In treated mice, synaptic density was greatly increased and the mice regained normal cognitive function. _MIT

The MIT researchers have utilised a number of different advances in cell and molecular biology to make these discoveries. As scientists close in on the discovery of meaningful interventions in destructive pathological processes, the importance of pre-existing replicated "off the shelf" research grows.

This is good news for all mice who suffer from Alzheimer's. Now, scientists must confront the immense government-made mine field and obstacle course which obstructs modern efforts to affordably develop life saving interventions in the biomedical fields, for humans. In this sense -- as in many others -- government is the greatest enemy of the future.

Cross-posted from Al Fin

A Brain Zapping Method of Removing Unwanted Nerve Connections

Scientists at the University of Western Australia have devised an intriguing method of removing unwanted neural connections in mice. Whether or not this procedure is directly applicable to humans, it opens a world of possibilities for improving the mental lives of a wide range of persons at every stage of life, from early onset schizophrenia through the brain maladaptations of senescence.

One of the pillars of Aubrey de Grey's Sens approach to anti-ageing is the removal of malfunctioning cells in the body. There is an analogous need in the brains of many individuals to remove malfunctioning or excess nerves and nerve connections, to optimise or improve brain functioning. Here is more on the experiments in mouse brains:

Jennifer Rodger from the University of Western Australia in Crawley and colleagues have found that stimulating the brain at intensities lower than would make a neuron fire can remove unwanted neural connections in mice.

As children, our brains produce too many connections between cells. As we develop, some connections are pruned away while others are strengthened. Inept pruning has been implicated in schizophrenia.

Rodger's team used genetically modified mice with abnormal connections in an area of the brain called the superior colliculus (SC), which is involved in motion detection. In these mice, 90 per cent of the axons in the SC had extended into the wrong areas. These bad connections make it difficult for the rodents to follow moving objects in their line of sight.

Rodger used low-intensity, pulsed magnetic field stimulation (PMF) on the rodents' SC for 10 minutes a day over two weeks. It is thought that PMF is too weak to make healthy neurons fire. But after treatment, tissue analysis showed that only 45 per cent of the abnormal axons were still there. "The axons that weren't in the right place were wiped out," says Rodger. After treatment the mice were also better at tracking objects.

"PMF is awakening unwanted connections, so the brain can detect and remove them," says Rodger.

Unwanted neurons generally express high levels of a specific NMDA glutamate receptor. According to Rodger, this makes them sensitive to changes in electrical activity and so even low-intensity pulses can activate these neurons.

NMDA receptors send out signals that trigger the recruitment of two chemicals called nitric oxide and brain-derived neurotrophic factor (BDNF), which help remove abnormal circuitry in healthy brains. Indeed, modified mice given PMF expressed higher levels of both chemicals, while only minor changes were found in healthy mice or those given a sham procedure (The FASEB Journal, DOI: 10.1096/fj.11-194878).

"I think it is a very promising avenue for treatment of nervous system disorders that involve abnormally abundant and inaccurate connections," says Rodger. _NewScientist

The brain is in a constant state of plasticity and re-shaping throughout life. But the brain often ends up in malfunctioning or maladaptive states which can be difficult to re-shape, without outside assistance. Part of the problem may lie in the genomics or gene expression of receptors or ion channels -- leading to consequent problems at higher levels of neuron function and the function of neuronal assemblies. Optimally, the underlying genetic or epigenetic cause would be corrected. But that isn't possible in most cases -- not yet.

In the meantime, workaround solutions such as the one discovered by the Australian researchers, may well allow for cruder fixes that can still add significantly to the quality of a person's mental existence.

The challenge in this case is to not only remove unwanted nerves or neural connections. One must also be able to stimulate growth of new neural connections in more optimal configurations.

Salk Researchers Take a Stab at New Approach to Alzheimer's Tx

At present, there are few drugs that improve the memory deficits associated with normal aging and none that prevent cognitive decline in chronic neurodegenerative conditions such as Alzheimer's disease (AD). Except for the rare cases of familial AD, the cause of AD is not known, but the disease is highly correlated with aging, a process involving a wide variety of physiological changes. Therefore, it is likely that the cells in the aging brain are compromised not from a single cause but from the convergence of multiple insults. However, the currently most widely used approach to drug discovery is to identify a single molecular target and then make a drug that alters this target [1]. Unfortunately, drugs for AD that were developed through this approach have all failed in clinical trials, perhaps because one target is not sufficient or because the targets are also critical for normal brain function so that their inactivation results in toxicity. Therefore, a different approach to drug discovery for AD is needed [2], [3]. _PLoS

Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD), the focus is the amyloid beta peptide (Aß) that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model. _PLoS

The "amyloid hypothesis" has not been a productive research pathway for finding cures for Alzheimer's -- at least not yet. Salk researchers chose to develop a new series of pharmacological agents based upon the neuroprotective action of the herb curcumin. Curcumin does not enter the brain in high enough concentrations to reverse the symptoms of Alzheimer's Disease, once the disease has progressed to the symptomatic stage. But the new Salk molecules, based upon curcumin's effect, are able to reverse some of the signs of neurodegeneration in aging animal brains.

If the new drug -- J147 -- proves to be effective, and is as safe as curcumin itself, it is likely to become the prototype for a new approach to treating neurodegeneration of aging in general, and Alzheimer's in particular.

H/T Gizmag

Brain Restoration in Alzheimer's Disease: Deep Brain Stimulates Reversal of Brain Shrinkage

BRAIN shrinkage in people with Alzheimer's disease can be reversed in some cases - by jolting the degenerating tissue with electrical impulses. Moreover, doing so reduces the cognitive decline associated with the disease. _NS

NS
Alzheimer's disease is an increasingly common cause of total disability in the ageing population. One of the manifestations of Alzheimer's is a shrinking and shutting down of activity in multiple centres of the brain which are critical to memory function. Cells die and crucial brain tissue is lost, as part of the disease process. Now scientists at Toronto Western Hospital in Ontario, believe they may have found an effective approach -- for some.

The group inserted electrodes into the brains of six people who had been diagnosed with Alzheimer's at least a year earlier. They placed the electrodes next to the fornix - a bundle of neurons that carries signals to and from the hippocampus - and left them there, delivering tiny pulses of electricity 130 times per second.

Follow-up tests a year later showed that the reduced use of glucose by the temporal lobe and posterior cingulate had been reversed in all six people (Annals of Neurology, DOI: 10.1002/ana.22089).

The researchers have now begun to investigate the effects on the hippocampus. At the Society for Neuroscience annual meeting in Washington DC last week they announced that while they saw hippocampal shrinking in four of the volunteers, the region grew in the remaining two participants.

"Not only did the hippocampus not shrink, it got bigger - by 5 per cent in one person and 8 per cent in the other," says Lozano. It's an "amazing" result, he adds.

Tests showed that these two individuals appeared to have better than expected cognitive function, although the other four volunteers did not.

Though Lozano is not sure exactly how the treatment works, his team's recent work in mice suggests that the electrical stimulation might drive the birth of new neurons in the brain. Deep brain stimulation in mice also triggers the production of proteins that encourage neurons to form new connections _NS

This approach is worth pursuing further. It is too invasive to be used on a wide scale, but it is likely that there will be no shortage of volunteers for the procedure. What is learned from this research can be used to devise less invasive approaches which will be more appropriate for use in larger populations.

In the meantime, research into the use of pharmaceuticals, growth factors, and stem cell therapies for Alzheimer's will continue.

Cognitive Enhancers In Health and Disease

Cognitive enhancer	Neuromodulatory mechanism	Cognitive functions improved	Known brain systems most affected	Currently recommended clinical use
Methylphenidate, amphetamine	Dopamine and noradrenaline reuptake inhibitors	Response inhibition, working memory, attention, vigilance	Frontoparietal attentional systems, striatum, default mode networks	ADHD, wake-promoting agent
Caffeine	Non-selective adenosine receptor antagonist	Vigilance, working memory, incidental learning	Frontal lobe attentional systems	–
Nicotine	Nicotinic cholinergic receptor agonist	Working memory, episodic memory, attention	Fronto-parietal attentional systems, medial temporal lobe, default mode networks	–
Modafinil	Unknown, but effects on dopamine, noradrenaline and orexin systems proposed	Working memory, episodic memory, attention	Frontal lobe attentional systems	Wake-promoting agent
Atomoxetine, reboxetine	Noradrenaline reuptake inhibitors	Response inhibition, working memory, attention	Frontoparietal attentional systems	ADHD, depression
Donepezil, galantamine, rivastigmine (AChEI)	Blocks enzymatic breakdown of acetylcholine	Episodic memory, attention	Frontal lobe attentional systems	Alzheimer's disease, PDD, DLB
Memantine	Noncompetitive, low-affinity, open channel blocker of the NMDA receptor	Episodic memory, attention	Frontal and parietal lobe	Alzheimer's disease

Table SourceThe ongoing process of ageing in all advanced societies around the world presents the unhappy prospect of a veritable global epidemic of Alzheimer's and other neurodegenerative conditions. Such an ominous prospect makes the quest for cognitive enhancers somewhat urgent, for all modern nations. We will look at the nature of current cognitive enhancers, and consider the prospects for future enhancers of cognition. The focus will be on long-term enhancement and neuroprotection, rather than the short-term performance enhancers which are popular on college campuses.

It would probably be fair to say that we are still in the first generation of studies to examine the potential for cognitive enhancement in humans. In both healthy individuals and many patient groups, the overall effects of drugs generally seem to be modest. However, there is evidence that there might be more significant effects in subgroups, such as those whose baseline performance is poorest or individuals with a particular genotype. Moreover, new drugs aimed at enhancing the phasic response of neurotransmitter systems, such as direct nicotinic agonists for the cholinergic system [34], might prove to have greater effects than existing modulators that globally increase levels of a neurotransmitter in a tonic fashion. The neurobiology underpinning the effects of cognitive enhancers and the mechanisms that determine responsiveness across individuals promise to be the focus of research in health and brain disorders in the future. _Source

The ongoing study of current cognitive enhancers such as those in the table above, have given us scattered hints as to what future therapies might offer. Here is a short list of possible future targets for cognitive therapies:

Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABAA α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population. _Source

It is important for us, at the outset, to take as realistic a viewpoint toward the possibility of meaningful cognitive enhancement as possible. The Likelihood of Cognitive Enhancement (Lynch et al 2011 PDF) is a useful introduction to many of the practical issues that need to be faced from the very beginning of this enterprise. Cognitive Enhacement: Promises and Perils (Hyman 2011 PDF) is a less technical introduction to the topic, perhaps more accessible to most laymen.

Cognitive Enhancement as a Pharmacotherapy Target for Stimulant Addiction (Sofuoglu 2010) looks at the use of cognitive enhancers as possible treatments for cocaine and methamphetamine addictions. Long term and heavy use of these drugs leads to cognitive deficits which make it even more difficult for a person to stop using these drugs and lead a "normal" life. The restoration of cognitive function is likely to provide a certain amount of "mental fortification" to allow at least some addicts to turn away from the dead end lifestyle. Similarly, restoration of cognitive function in persons suffering from age-related neurodegeneration is more likely to allow the person to participate in normal social interaction, and to undertake some level of responsibility, and perhaps productive activity.

Emerging Pharmacotherapies for Neurodevelopmental Disorders (Wetmore et Garner 2010) looks at the use of cognitive enhancers for persons who suffer from neurodevelopmental disorders such as Down's Syndrome, Fragile X, autism, etc. Given the overlap of mechanisms between some of the cognitive deficits in developmental disorders and ageing-related cognitive deficits, some of the coming developments in this area of pharmacotherapy should also prove quite helpful for treating age-related dementias.

As more is learned about the time-course of dysfunction in NDDs [neurodevelopmental disorders], targeting of therapies to the existing brain state may be improved. Moreover, individuals with NDDs have multiple cognitive and behavioral disabilities, and a particular drug therapy may improve only a subset of cognitive functions. Thus, a combination of complementary drugs may offer the most benefit by addressing deficits in attention, arousal, information processing, or depression.
...
The NDDs discussed here are phenotypically diverse yet linked by common mechanisms of dysfunction, including abnormal gene dosage, imbalance among neurotransmitter systems, and local protein translation (Fig. 2). A particular NDD can be caused by mutations in multiple genes, underscoring the convergence of dysfunction in key biochemical pathways. _Source

Finally, I would like to append to this entry some material from an earlier Al Fin article, which provides a few hints of future drug targets, as well as links to related material:

AMPAkines
CREB
PDE Inhibitors(4,10)
Nicotinic Alpha-7 agonists
mGluR antagonists
5HT6 antagonists

Frontrunners in the pharmaceutical race for smarter, better memory drugs include Memory Pharmaceuticals, Cortex Pharmaceuticals, Saegis Pharmaceuticals, Helicon, Lilly, Pfizer, Wyeth, Merck, Sention and many others. The precedent of approving drugs for erectile dysfunction (ED)--a lifestyle drug--suggests that smart drugs will eventually be approved for drooping memories as well.

Further Reading:

Molecules for Memory

Nootropics

Smart Drugs: What Are the Prospects?

Shaping the Brain with Smart Drugs (Gazzaniga)

CREB and Memory (basic neuroscience)

CREB, Synapses, and Memory Disorders

Hat tip Advanced Nano and Kurzweilai.net

Brain Implants are Coming: Can They Repair Stroke Damage?

Recent research on rats at Tel Aviv University is offering hope that we may soon have access to brain implants which could help to bypass damaged areas of brain, and allow relatively normal functioning after stroke and other types of brain damage.

Matti Mintz of Tel Aviv University in Israel and his colleagues have created a synthetic cerebellum which can receive sensory inputs from the brainstem - a region that acts as a conduit for neuronal information from the rest of the body. Their device can interpret these inputs, and send a signal to a different region of the brainstem that prompts motor neurons to execute the appropriate movement.

"It's proof of concept that we can record information from the brain, analyse it in a way similar to the biological network, and return it to the brain," says Mintz, who presented the work this month at the Strategies for Engineered Negligible Senescence meeting in Cambridge, UK.

...The team analysed brainstem signals feeding into a real cerebellum and the output it generated in response. They then used this information to generate a synthetic version on a chip that sits outside the skull and is wired into the brain using electrodes.

To test the chip, they anaesthetised a rat and disabled its cerebellum before hooking up their synthetic version. They then tried to teach the anaesthetised animal a conditioned motor reflex - a blink - by combining an auditory tone with a puff of air on the eye, until the animal blinked on hearing the tone alone. They first tried this without the chip connected, and found the rat was unable to learn the motor reflex. But once the artificial cerebellum was connected, the rat behaved as a normal animal would, learning to connect the sound with the need to blink.

...The next step is to model larger areas of the cerebellum that can learn a sequence of movements and test the chip in a conscious animal - a much greater challenge. "This is very demanding because of the decrease of [neural] signal quality due to artefacts caused by movement," says Robert Prueckl of Guger Technologies in Graz, Austria, who is working with Mintz. He thinks this can be achieved, though, by developing improved software to tune out noise and better techniques for implanting the electrodes. Ultimately, the goal is to build chips that can replicate complex areas of the brain _NewScientist

Yes, the implant used by the researchers was only able to substitute for a small part of the cerebellum -- which is only one part of the brain. Still, it is a start. The challenge is to enlarge and consolidate this understanding of the motor system. Then we can move beyond these early victories to the far more complex and difficult challenges of substituting for more complex signaling that occurs in the cortical and subcortical tissues.

And yet it would be best not to underestimate this achievement. The cerebellum helps to control and coordinate body movement, which is a very important function of being human. Those who have lost the ability to initiate, control, coordinate, and terminate basic movements, understand how important the motor system is to quality of life.

Cyborg brain part replacement is not the end goal, of course. We really want to re-grow any damaged brain parts or nerve connections which have been lost. But cyborg replacements will be an important bridge between where we are now and where we would like to go.

Why Do Old Brains Prefer Young Blood?

A paper published today in Nature finds that when younger mice are exposed to the blood of older mice, their brain cells behave more like those found in aging brains, and vice versa. The researchers who carried out the work also uncovered chemical signals in aged blood that can dampen the growth of new brain cells, suggesting that the decline in brain function with age could be caused in part by blood-borne factors rather than an intrinsic failure of brain cells. _TechnologyReview

Many things change in the human body as we age. Our cells lose their ability to repair incidental damage, and produce less and less energy for our ever-less efficient muscles. We produce lower levels of hormones which help us, and higher levels of chemicals that cause inflammation and cellular damage.

It has been found that young blood can reverse certain signs of aging in the circulatory systems of old mice. Now there is evidence that young blood can help rejuvenate old brains.

To arrive at the discovery, the researchers studied pairs of old and young mice that were literally joined at the hip. They used a technique called parabiosis, in which two mice are surgically joined together along the flank, which causes them to develop a shared circulatory system. The technique has been used to study the development of the blood system, and more recently has been used to investigate the effects of age by joining old and young mice.

Lead author Tony Wyss-Coray, a neuroscientist at Stanford University, says that five weeks after creating these May-December pairings, "we found striking effects both on the young and old brains." The young mice had a reduction in the production of new neurons (neurogenesis), an increase in brain inflammation, and less activity in synapses connecting neurons.

The older mice, in contrast, had an increase in new neurons, less inflammation, and greater activity at synapses. "You could almost call this a rejuvenation effect," Wyss-Coray says.

...To see whether the effect could influence behavior, they injected, in separate experiments, young mice with plasma from older mice and vice versa, and found that old plasma impaired the younger animals' ability to perform learning and memory tasks, whereas young plasma improved the abilities of older mice.

Blood cells from one mouse cannot travel into the brain of the other because of the blood-brain barrier, so the team concluded that free-floating molecules in the blood, capable of passing through, must be responsible for the effects. By comparing more than 60 chemokines—chemical messengers secreted by cells that circulate in the blood—the researchers identified several associated with the detrimental effect of old blood. Administering one of these chemicals, called CCL11, to young mice dampened neurogenesis and impaired learning and memory. CCL11 has been studied for its role in allergies and asthma, but it's not clear how it influences neurons. _TechnologyReview

Does this mean that those of us who wish to stay young will have to prey on our young like vampires, sucking their life's blood for our own sustenance? No. For we are learning how to take our old cells and make them young again, in vitro -- in the test tube. The goal is to do the same thing, only better, and in vivo.

Such cellular rejuvenation treatments are likely to excellent stopgap methods of anti-aging, with significant -- but limited -- effects. The lifespans we live will be lived as younger, more vital monkey-men. And that is worth a very great deal.

But if we wish to live significantly longer lives, at significantly higher levels of awareness, intellect, and invention, we will need to go deeper than cellular replacement and humoral replacement therapies of this type.

Extending Brain Plasticity and Learning into Later Life

Dendrites integrate synaptic inputs to neurons, and their branching is thought to be related to their representational capacity [24]. Branching patterns of dendritic trees are related to the degree of compartmentalization of inputs to the cell and a stronger potential for compartmentalization (i.e. more complex branching) has been proposed to increase the representational power of the cell resulting in greater learning and memory capacity [24]. Dendritic structure appears to be regulated during development in part by calcineurin [26]. Dendritic spines, which comprise the post synaptic element of over 90% of cortical excitatory synapses, are thought to be particularly important for learning and memory [18]. _ScienceDirect

ScienceDirect
An international team of researchers from Yale, University of Zagreb, and VU University in Amsterdam, have discovered that plasticity and pruning of dendritic spines in the human prefrontal cortex continues well into adulthood, throughout the 20s.

Pasko Rakic at Yale University and colleagues at the University of Zagreb, Croatia, and the VU University Medical Center in Amsterdam, the Netherlands, have now found that the brains of adults in their 20s are still subject to synaptic pruning.

Rakic's team analysed post-mortem tissue from a brain region called the prefrontal cortex (PFC) in 32 people aged between 1 week old and 91 years. Specifically, they calculated the density of dendritic spines – the tiny projections that protrude from the neuron's long dendrites, each of which facilitates communication with other neurons through a synapse.

As expected, Rakic's team found that spine density increased rapidly during infancy, reaching a peak before the 9th birthday. It then began to fall away as pruning began. Intriguingly, though, spine density did not plateau after adolescence, as might have been expected, but continued to fall gradually until the late 20s.

Rakic says the result could be good news for those hoping to gain new skills in their third decade. The period of pruning is associated with a heightened ability to learn – whether that is in picking up language skills or understanding new concepts, he says. "You should not give up learning just because you're in your 20s – it isn't too late," he says. _NewScientist

Abstract for PNAS paper

It has been shown that in rats, age related loss of normal dendritic density in prefrontal cortical neurons, occurred at the same time as loss of experience-related dendritic plasticity.

The goal of researchers is to develop ways to extend the optimal periods of brain learning well beyond young adulthood, into middle age and beyond. A Harvard - Mass General study published in Neuroscience Letters in Jan. 2011, discusses the use of a calcineurin inhibitor -- FK 506 -- to effectively increase dendritic density in cortical pyramidal neurons (all sites) of adult rats.

Such drugs provide clues as to how dendritic plasticity in the brain is regulated, and are likely to help lead to effective ways of beating back the growing impact of Alzheimer's disease and other dementias. Interestingly, calcineurin upregulation has been implicated in Alzheimer's Disease models as being responsible for amyloid related loss of glutamate receptors and decreased dendritic spine density. In such conditions, the inhibition of calcineurin (as in FK506) might well partially reverse the Alzheimer-like effects.

The mechanisms of brain development, plasticity, and disease are highly complex. We will need to learn as much as possible about signaling pathways, genetic and epigenetic mechanisms, cytoskeletal dynamics, and a number of other cellular and intercellular activities, before we will be ready to intervene in a definitive way. But things look promising, if a bit slower than we would like.

Restoring Lost Memories: Hope for Long-Lived Brains?

Our brains were not really meant to last for 80, 90, 100 years. Metabolic debris accumulates, DNA repair mechanisms break down, and function tends to degenerate at variable rates -- depending upon the individual's lifestyle and genetic complement. Now scientists at USC in Los Angeles are learning how to restore lost memories -- at least in rats.

Theodore Berger at the University of Southern California in Los Angeles, and colleagues, used electrodes implanted within the hippocampus to record patterns of brain activity while rats learned how to operate a sequence of levers to gain a reward.

Next, the team obliterated the memory of the task by injecting chemicals into the hippocampus that block the signalling between neurons needed to access long-term memories. When tested, the rats could no longer perform the task.

However, when the team used the electrodes to stimulate the brain with the same pattern of activity recorded when the rats first learned the task, their ability to operate the levers in the correct sequence was restored. The rats could temporarily access the original memory, even though the chemical blockade was still in place. When fed scrambled versions of the code, the rats could no longer perform the task.

Ultimately, the researchers hope to create implants that contain codes for 20 to 30 simple tasks, enabling people with brain damage to recover basic abilities that have been lost, such as speaking or dressing themselves.

Berger says that encoding these tasks will be very difficult. "These are very basic capabilities that we are investigating, and it has taken us a lot of effort to get this far," he says. _NewScientist

It is unlikely that the USC team actually encoded rat brain activity with any accuracy. Rather, the team was able to encode a sufficient "hint" so as to allow the rats to internally re-assemble or approximate their former memories. Even in a rat's brain, mental codes are more difficult than even the best scientists understand.

But it is a promising beginning that provides hope for the long-lived brains of the future.

Article Abstract from Jnl of Neural Engineering

More on Sleep, ATP, and Adenosine

Sleep Phases and Progression

Levels of adenosine triphosphate (ATP), the energy currency of cells, in rats increased in four key brain regions normally active during wakefulness. Shown here is the energy surge measured in the frontal cortex, a brain region associated with higher-level thinking. Credit: Courtesy, with permission: Dworak et al. The Journal of Neuroscience 2010.
We spend roughly 1/3 of our lives in the state of sleep. Researchers are beginning to learn why we must do this, and are gleaning hints of possible technologies for bypassing at least part of the sleep imperative, and doing well on less sleep.

“For a long time, researchers have known that sleep deprivation results in increased levels of adenosine in the brain, and has this effect from fruit flies to mice to humans.” Abel said. “There is accumulating evidence that this adenosine is really the source of a number of the deficits and impact of sleep deprivation, including memory loss and attention deficits. One thing that underscores that evidence is that caffeine is a drug that blocks the effects of adenosine, so we sometimes refer to this as ‘the Starbucks experiment.’”

Abel’s research actually involved two parallel experiments on sleep-deprived mice, designed to test adenosine’s involvement in memory impairment in different ways.

One experiment involved genetically engineered mice. These mice were missing a gene involved in the production of glial transmitters, chemicals signals that originate from glia, the brain cells that support the function of neurons. Without these gliatransmitters, the engineered mice could not produce the adenosine the researchers believed might cause the cognitive effects associated sleep deprivation.

The other experiment involved a pharmacological approach. The researchers grafted a pump into the brains of mice that hadn’t been genetically engineered; the pump delivered a drug that blocked a particular adenosine receptor in the hippocampus. If the receptor was indeed involved in memory impairment, sleep-deprived mice would behave as if the additional adenosine in their brains was not there.

...To see whether these mice showed the effects of sleep deprivation, the researchers used an object recognition test. On the first day, mice were placed in a box with two objects and were allowed to explore them while being videotaped. That night, the researchers woke some of the mice halfway through their normal 12-hour sleep schedule.

On the second day, the mice were placed back in the box, where one of the two objects had been moved, and were once again videotaped as they explored to see how they reacted to the change.

“Mice would normally explore that moved object more than other objects, but, with sleep deprivation, they don’t,” Abel said. “They literally don’t know where things are around them.”

Both sets of treated mice explored the moved object as if they had received a full night’s sleep.

“These mice don’t realize they’re sleep-deprived,” Abel said.

Abel and his colleagues also examined the hippocampi of the mice, using electrical current to measure their synaptic plasticity, or how strong and resilient their memory-forming synapses were. The pharmacologically and genetically protected mice showed greater synaptic plasticity after being sleep deprived than the untreated group.

Combined, the two experiments cover both halves of the chemical pathway involved in sleep deprivation. The genetic engineering experiment shows where the adenosine comes from: glia’s release of adenosine triphosphate, or ATP, the chemical by which cells transfer energy to one another. And the pharmacological experiment shows where the adenosine goes: the A1 receptor in the hippocampus. _MedicalXpress

Abel's is a sophisticated experiment which covers a lot of possiblities. Combining the findings of this experiment with findings of previous experiments gives one a fuller picture of what is going on.
The brain has evolved certain activity in N2 sleep (sleep spindles) which apparently promotes the production of ATP from adenosine and phosphate groups. As ATP levels rise in N2 sleep, adenosine levels drop. So the sound sleeper receives both the benefits of higher ATP energy levels and the improved learning that results from lower hippocampal free adenosine levels.

More on sleep spindles (PDF)

Adenosine is a potent pharmacological agent, powerfully affecting heart rhythms. It also affects central nervous system activity in a largely inhibitory function, and also exhibits anti-inflammatory effects.

Adenosine and deep brain stimulation (DBS)

Why Do We Sleep? A brief look at stages of sleep, and possible benefits of sleep.

Cross posted to Al Fin, the Next Level

How could we manage on less sleep? The fastest route to achieving high-functioning sleep reduction would seem to involve electromagnetic brain stimulation or inhibition over particular brain areas at specific pulse frequencies. The aim would be to reduce adenosine levels -- and increase ATP levels -- in specific areas of the brain including the hippocampus.

Pharmacological methods for blocking adenosine's effect, such as used in the experimental mice in the study above, offer another possiblity -- although a time delay before approval for a new drug of at least 10 years is to be expected.

Genetic techniques for modifying adenosine production or re-uptake and ATP synthesis, are another likely approach -- eventually. At the present time, genetic (and epigenetic) treatment methods are far too primitive and clumsy to risk for such an objective as sleep reduction, for most people.

Other neuromolecules are likely involved in this puzzle, but at least this information offers a place to start.

Refurbishing the Brain, Making Humans Smarter and Happier

“I think we’re getting closer to harnessing neurogenesis to improve cognition and mood in humans. This research may also help explain a bit of a mystery in the field, which we still don’t understand, regarding how the hippocampus can be involved with both cognition – which is its classic function – and in mood and anxiety-related functions. Perhaps the fact that pattern separation affects both the cognitive and mood domains is the beginning of an answer to that paradox,” said Dr. Hen. _StemCells

René Hen, PhD, professor of Neuroscience and Pharmacology, in the Departments of Neuroscience and Psychiatry at Columbia University and the New York State Psychiatric Institute, has discovered a possible escape hatch by which some members of society might escape the Idiocracy. It involves the use of chemicals called "BAX inhibitors." Particular members of that class of drugs have the potential to preserve newborn stem cells in the brain's hippocampus. And doing that could make all the difference in the course of a person's life success and happiness.

After boosting the number of neurons in the hippocampus, an area of the brain involved in memory and mood, the researchers tested the mice in both learning and mood-related tasks and looked for changes in behavior. The researchers found specific effects on learning tasks that involve a process called pattern separation, which is the ability to distinguish between similar places, events and experiences.

“This process is crucial for learning because it enables us to know whether something is familiar or novel,” said Dr. Hen. “If it is familiar, you move on to the next bit of information; if it’s novel, you want to be able to recognize that it’s new and give it meaning. These mice, with just more adult-born neurons, and no other changes in the brain, basically learn better in tasks where they have to discriminate between similar contexts.”

Earlier strategies for manipulating neurogenesis, according to the investigators, were broader and less specific. “In addition to stimulating neurogenesis, these earlier methods exerted many other effects on the brain. As a result, you never knew with these older manipulations what’s due to neurogenesis, or what’s due to the other effects that these manipulations cause, and, indeed, what we find is that when you stimulate just adult neurogenesis, you actually get a subtle effect. Unlike broader manipulations, it does not affect all forms of learning, it’s very specific to tasks that require pattern separation,” said Dr. Hen.

Pattern separation is not only important for learning; it may also be important for anxiety disorders, including post traumatic stress disorder (PTSD) and panic disorder. People with PTSD, say the researchers, have a more generalized fear response, so that when they are placed in a situation that reminds them of even one aspect of their trauma, they frequently have a full fear response.

...The researchers say that the genetic strategy used to stimulate neurogenesis in their experiments can be mimicked pharmacologically, potentially leading to the development of new drugs to reverse pattern separation deficits. One such class of drugs the investigators are currently testing – BAX inhibitors – works by blocking cell death.

“These drugs are basically doing the same thing that we did with our genetic manipulation-namely, increasing the survival of the young neurons which normally undergo a process of cell death that eliminates at least half of these neurons. Now instead of dying, the neurons will go on to survive,” said Dr. Sahay.

Some BAX inhibitors have been developed for stroke research, where the goal has also been to prevent neurons from dying. The Columbia researchers plan to begin testing the BAX inhibitors in mice shortly. And if they produce cognitive benefits, the testing will be extended to clinical trials to determine if there’s also a beneficial effect in humans. _StemCells

This is all related to the length of time required before antidepressants are able to bring about a full "antidepressive response." The full effect of modern antidepressants requires new stem cell production in the hippocampus -- but that takes time to achieve. Drugs capable of rapid and prolonged increases of hippocampal stem cells could conceivably keep anxiety and depression at bay, while improving a person's cognitive capacity.

No, this is not NZT. As mentioned here previously, a drug that could achieve the effect of the fictional NZT would have to stimulate changes in gene expression on multiple levels, and across a wide range of brain centers.

Smart drugs alone will not achieve the goal of smarter, better-rounded, and happier humans. Educational and environmental interventions would also be necessary, to blunt the Idiocratic brainwashing effect of modern media, modern academia, and modern popular culture, while allowing the brain to develop newer, more functional pathways.

Realistically, it will take 15 years at the earliest to see the early promise of this type of medication come to fulfillment. But a single ray of hope in the distance is worth a lot to a person immersed in the modern rush to Idiocracy.

More 5April2001: An example of rapid brain plasticity in human adults
The PNAS Abstract from the actual study

Previously published at Al Fin

As noted here before, improved neurogenesis in the hippocampus is associated with antidepressant and anti-anxiety behaviours in animal studies -- and probably in humans. It does no good to live longer with younger brains if we are unable to enjoy our added time and brainpower.

Total Brain Network Imaging Reveals Efficiency Loss w/ Ageing

“While particular brain regions are important for specific functions, the capacity of information flow within and between regions is also crucial,” said study leader Scientia Professor Perminder Sachdev from UNSW’s School of Psychiatry.

“We all know what happens when road or phone networks get clogged or interrupted. It’s much the same in the brain.

“With age, the brain network deteriorates and this leads to slowing of the speed of information processing, which has the potential to impact on other cognitive functions.” _Science Alert

University of New South Wales researchers have utilised advanced diffusion tensor imaging (PDF research article) along with powerful computational tools to assess the efficiency of the total brain network of white matter, and watched overall brain processing speeds as they slow due to ageing.

The research team, led by Scientia Professor Perminder Sachdev from the UNSW School of Psychiatry, has mapped the network of fibres or ‘white matter’ for the first time, allowing them to examine the strength of connections between different cortical regions, or ‘grey matter’, which are responsible for specific functions. In the past, most research has focused on the more complicated grey matter without looking at how information flows between separate regions.

A new type of magnetic resonance imaging (MRI) called diffusion tensor imaging (DTI) combined with powerful computers allowed the team to create the map and see the whole network in great detail.

“Using a mathematical theory you can see how strongly the different regions are connected to each other,” Professor Sachdev said. “You can basically look at the efficiency of the network and with ageing, we can see a reduction in the efficiency of these networks.”

“What we wanted to see is how this relates to cognitive function, and we found that the best relationship was with processing speed, which makes sense because we’re talking about strength of information connections.”

Other areas strongly affected by the efficiency of neural networks were executive functions that manage other brain processes and the ability to navigate in space, known as visuospatial function.

Sachdev said the findings could help to some extent with dementia research, by offering another way of looking at the condition, but had already helped explain what happens in the brain when physical reaction time slows down in older people.

“It’s not that they can’t do the task, it just takes longer, and we have shown that this is related to structural changes in the brain, in terms of its neural networks.”

“The next step is looking at what determines the efficiency of these networks. We want to see if they are flexible or plastic, and whether maybe we can intervene.”

...The results of the study, which was based on a sample of 342 healthy people aged between 72 and 92, have been published in the January edition of the Journal of Neuroscience. _AustralianAgeingAgenda

Here is more from science alert Australia:

In the study, the researchers performed magnetic resonance imaging (MRI) scans on 342 healthy individuals aged 72 to 92, using a new imaging technique called diffusion tensor imaging (DTI).

Using a mathematical technique called graph theory, they plotted and measured the properties of the neural connectivity they observed.

“We found that the efficiency of the whole brain network of cortical fibre connections had an influence on processing speed, visuospatial function – the ability to navigate in space – and executive function,” said study first author Dr Wei Wen.

“In particular greater processing speed was significantly correlated with better connectivity of nearly all the cortical regions of the brain.”

Professor Sachdev said the findings help explain how cognitive functions are organised in the brain, and the more highly distributed nature of some functions over others. _Science Alert

It is important to stress the difference between speed of nerve transmission and speed of information processing for the brain. The two are related, and both are measurable (or calculable) using the DTI computational techniques, but information processing is a much higher order process than mere nerve conduction velocities. Knowing processing speeds -- particularly being able to compare whole brain processing and subsystem processing speeds and efficiencies -- provides more information.

Diffusion Tensor Imaging (DTI) can be used to assess several aspects of brain functioning, including general intelligence and executive function. It can also be used to assess multiple types of brain pathology, including schizophrenia.

Better brain imaging techniques provide clinicians and researchers with better information with which to form theories and plan therapies. As brain ageing comes to be seen more as a reversible pathology, more advanced diagnostic tools and therapeutic methods will be made available more widely.

DNA for Healthy Aging, and Rebuilding the Brain After Stroke

We will look at two studies that relate to the quest for longer, healthier, more productive and fulfilling lives. First, researchers at the University of Miami looked at an Amish population and discovered that a certain genetic pattern in the mitochondria seems to allow for a much healthier lifespan into the 80s.

On Friday they will present a paper showing that 15 percent of healthy Amish octogenarians have "haplogroup X," a genetic pattern within the mitochondria, which are the regions of cells that generate energy and help guard against deterioration. Haplogroup X is generally found in only 2 percent of Europeans, from whom the Amish descended. In the University of Miami study, only 3 percent of the control group—Amish people who had made it to 80 but suffered from significant disease or disability—had the genetic variant. The paper will be featured during a session at the American Society of Human Genetics' annual meeting in Washington, D.C.

Researchers who study aging have long suspected that mitochondria play a role in aging. Mitochondria are responsible for processing metabolized food particles into adenosine triphosphate, which fuels vital cellular processes. They're also involved in cell growth and differentiation. But the ability of mitochondria to function properly seems to decline with age.

Understanding the reason for that decline—and the genes that might control it—has been challenging. Mitochondria have their own DNA, which is passed down from the mother only. This unique chromosome has variations, called haplogroups. Nine such haplogroups have been well characterized in people of European descent, Scott says. But only haplogroup X was found to be prevalent among healthy aged people in the University of Miami study. _TechnologyReview

The second study, from UCLA researchers, looks at the ability of the brain to re-build following stroke -- or brain infarct. The team appears to have discovered a drug target with significant promise, which may lead to drugs that help the brain to re-build itself following destructive lesions.

A stroke is usually caused by a clot that blocks blood flow to an area of the brain. Tissue in that part of the brain dies from lack of oxygen unless the clot is detected immediately and is either dissolved or removed. The dead tissue cannot be revived, but often the brain can be trained to redirect nerve impulses via still-living nearby neurons. But such training is difficult, can require months to years of arduous rehab, and is often not sufficient to overcome complex disability.

The new research, by neurologist S. Thomas Carmichael and his colleagues at the University of California at Los Angeles, shows that neurons in the areas of the brain closest to the site of a stroke are impaired after it occurs. The reason for that is a buildup of an inhibitory signaling molecule called GABA that prevents the neurons from firing. When those nerves are inhibited, it's harder for the brain to recruit them into its rerouted circuits.

In studies in mice, the researchers discovered that blocking a particular piece of the GABA signaling system with an existing drug allowed the nerves to reactivate, reversing the repressed excitability, allowing them to more easily respond to other neurons, and encouraging and enhancing early recovery after a stroke by as much as 50 percent. "At face value, it's a new pharmacological target for repair and recovery in stroke," Carmichael says.

...Carmichael and his colleagues identified the piece of the GABA signaling cascade that goes awry in the area of the brain adjacent to the stroke: reduced levels of a transporter responsible for moving the inhibitory molecule out of the vicinity. Without that transporter, GABA is allowed to reach such high levels that the nearby neurons are prevented from firing.

In studies in mice, the researchers induced a stroke in the motor cortex, the movement center of the brain, and then gave them a drug that specifically reverses the post-stroke GABA uptake. The drug is not approved for use in people—it was an experimental molecule produced during the drug industry's search for memory enhancers. But just the fact that it works in mice means that stroke researchers have a new line of evidence to pursue.

"It's significant, because they're identifying a molecular mechanism that is keeping stroke survivors from recovering. And as a result, [Carmichael is] identifying targets for molecular manipulation," says Theresa Jones, a neurobiologist at the University of Texas at Austin. "Now we have potential to find drugs that aim at that target."

The scientists found that, as with other types of stroke treatments, timing was critical. During the first few days after a stroke, a brain injury is still stabilizing; prior studies have shown that any physical rehabilitation attempted during this period can aggravate the brain and actually make the damage worse. The same proved true for the drug.

But when the mice were given the drug three days later, it improved their recovery of movement by 40 to 50 percent. This implies that while the post-stroke inhibition of neurons in these areas may help with immediate recovery, but it is a harmful adaptation when it persists for weeks or months or even years after the initial injury. _TechnologyReview

Stroke is one of the major causes of death and disability in the developed world. A viable treatment for stroke rehabilitation would be a significant medical development.

Reversing Age Related Memory Loss

Researchers estimate that roughly 20 to 30 percent of people age 75 and older have elevated glucocorticoid levels (more precise figures aren't available). Most affected is so-called declarative memory, the ability to learn new facts and remember, for example, lists. People who suffer age-related memory loss are at higher risk for developing Alzheimer's and other forms of dementia, though the condition is not itself considered a form of dementia. _TechnologyReview

A research team at the University of Edinburgh have developed a new compound that appears to prevent and reverse age-related memory decline in mice. Their approach utilises a "gene knockout" approach against an amplifier of glucocorticoid effect present in brain cells.

"What's most surprising is that even short-term inhibition was able to reverse memory loss in old mice," says Jonathan Seckl, a professor of molecular medicine who was involved in the research. "I don't think people had realized this was so reversible. It takes [the animals] back to being relatively young."

The researchers hope to develop equivalent human therapies and are now more extensively studying the safety of a closely related compound in animals. They aim to begin human testing within a year.

Scientists have long known that glucocorticoids--a class of steroid hormones that mediate our response to stressful situations--play a role in age-related memory decline. Although short-term exposure to glucocorticoids enhances the formation of memories during stressful situations, chronically high levels of the hormones are linked to greater memory loss with age, both in humans and animals. The exact mechanism underlying this link is unclear, but researchers theorize that excess exposure to the hormones makes parts of the brain more vulnerable to damage.

Seckl and his collaborators focused on an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (11 β-HSD1). This enzyme generates an active version of the key glucocorticoid hormone within brain cells and some other tissues, providing a target for fine-tuning the system without blocking the overall stress response. Tinkering with the enzyme seems to have little effect on blood levels of glucocorticoids, which are produced in the adrenal glands. Instead, "this enzyme acts as an intracellular amplifier of glucocorticoids," says Seckl. "If you take out the amplifier, you still have stress hormones, but they shout less loudly and cause less wear and tear."

The Edinburgh team showed that knocking out either one or both copies of the gene for this enzyme in mice preserved the animals' memory into old age. To determine whether blocking the enzyme could improve memory in already aged animals, researchers then developed a compound designed to cross into the brain and inhibit the enzyme. Just 10 days of treatment in two-year-old mice--the maximum lifespan for a typical lab mouse--was enough to improve the animals' performance on a test of spatial memory. The treatment "returned mice to the equivalent of when they were young and fully functioning," says Brian Walker, another researcher involved in the study. "It's important to emphasize that we are trying to target the pathology--the role that glucocorticoids play in age-related memory decline--not just globally improving memory." The research was published last week in the Journal of Neuroscience. _TechnologyReview

Brian Wang looks at another approach to augmenting human brainpower

Also published at Al Fin

Another Way to Add Years to Your Life

Physorg
Most people spend a third of their lives sleeping. Doing without sleep does not seem to work well, in terms of achieving optimal focus and concentration. The brain seems to need that "down time" for some reason. This may be the reason:

Levels of adenosine triphosphate (ATP), the energy currency of cells, in rats increased in four key brain regions normally active during wakefulness. Shown here is the energy surge measured in the frontal cortex, a brain region associated with higher-level thinking. Credit: Courtesy, with permission: Dworak et al. The Journal of Neuroscience 2010.

In the initial stages of sleep, energy levels increase dramatically in brain regions found to be active during waking hours, according to new research in the June 30 issue of the Journal of Neuroscience. These results suggest that a surge of cellular energy may replenish brain processes needed to function normally while awake.

The authors measured levels of adenosine triphosphate (ATP), the energy currency of cells, in rats. They found that ATP levels in four key brain regions normally active during wakefulness increased when the rats were in non-REM sleep, but were accompanied by an overall decrease in brain activity. When the animals were awake, ATP levels were steady. When the rats were gently nudged to stay awake three or six hours past their normal sleep times, there was no increase in ATP.
The authors conclude that sleep is necessary for this ATP energy surge, as keeping the rats awake prevented the surge. The energy increase may then power restorative processes absent during wakefulness, because brain cells consume large amounts of energy just performing daily waking functions. _Physorg

Now that scientists have a clue as to where to look for sleep's regenerative effects on the brain, they can begin to devise alternative ways of stimulating that regeneration -- other than to consume 1/3 of every 24 hour day for that purpose.

Alternative schedules of sleep / wake cycles, napping strategies, electromagnetic stimulation, nutritional or exercise strategies, etc -- there is likely to be workable ways by which an individual could achieve brain ATP regeneration AND redeem some of those 8 hours of sleep for productive or leisure activity. More living, in other words, without endangering one's health.

It is a mere glimpse behind the curtain of sleep, but it could prove to be a useful one. Two extra hours of productive wakefulness over 30 years can give you two and a half extra years of intentional living. If you are just as rested and just as healthy, then there are few reasons not to have more awake time.

Thymosin Beta 4 Helps Regenerate Damaged Brain in Rats

The small protein thymosin beta 4 has multiple functions: it moonlights to repair injured tissues [6], has anti-inflammatory efficacy in monocyte/macrophages [7], promotes wound healing [8] and mediates angiogenesis [9]. Tβ4 has been also shown to play a relevant role during the development of different neural cell types in the rat brain [10]. In particular, Tβ4 plays a neurotrophic and antiapoptotic role during the development of the nervous system [11]. __PLoSONE

New research to be reported June 3 at the Annual Meeting of the Society for Academic Emergency Medicine in Phoenix, showed that in adult rats, thymosin beta-4 assisted in the repair of nerve fibres in the brain and in growing new blood vessels.

A synthetic version of a naturally occurring peptide promoted the creation of new blood vessels and repaired damaged nerve cells in lab animals, according to researchers at Henry Ford Hospital in Detroit.

"This successful experiment holds promise for treating clot-induced strokes in humans," says study lead author Daniel C. Morris, M.D., senior staff physician in the Department of Emergency Medicine at Henry Ford Hospital. "Neurorestorative therapy is the next frontier in the treatment of stroke." _SD

This is a potentially important finding for regenerative medicine, given how common cerebral vascular accident is in humans, and how dismal the prognosis typically is afterward.

Thymosin beta-4 is an immune modulating protein, which demonstrates once again how important the brain and the immune system are to one another. Given that Thymosin beta-4 is not a growth factor, as such, it will be important to generate a picture of the entire mechanism involved, for a complete understanding of potential therapies for brain damage, using this protein.

Brain Cell Regeneration Using Reprogrammed Astroglia

The brain consists of two major cell types: neurons, which transmit information, and glial cells, which support and protect neurons. Interestingly, evidence suggests that some glial cells, including astroglia, can be directly converted into neurons by specific proteins, a transformation that may aid in the functional repair of damaged brain tissue. However, in order for the repaired brain areas to function properly, it is important that astroglia be directed into appropriate neuronal subclasses. In this study, we show that non-neurogenic astroglia from the cerebral cortex can be reprogrammed in vitro using just a single transcription factor to yield fully functional excitatory or inhibitory neurons. We achieved this result through forced expression of the same transcription factors that instruct the genesis of these distinct neuronal subtypes during embryonic forebrain development. Moreover we demonstrate that reactive astroglia isolated from the adult cortex after local injury can be reprogrammed into synapse-forming excitatory or inhibitory neurons following a similar strategy. Our findings provide evidence that endogenous glial cells may prove a promising strategy for replacing neurons that have degenerated due to trauma or disease. _PLOS

Scientists from the Helmholtz Center and Ludwig-Maximilians University in Munich, have used a virus to reprogram brain helper cells -- astroglia -- into actual neurons. They were able to convert astroglia from early post-natal and adult mouse brains into either excitatory or inhibitory neurons, depending upon the transcription factors which were introduced.

The study adds to growing evidence that certain cell types can be transformed directly into other cell types without first being converted into stem cells. Researchers have previously transformed skin cells into neurons, and one type of pancreatic cell into another. Marius Wernig, a coauthor of the skin cell study and a stem cell biologist at Stanford University, says there's a growing awareness that it may not be necessary to erase a cell's existing identity before giving it a new one.

...this latest study "means that these astroglial cells could be converted in the brain" without the need for a transplant. Berninger says that one of the next challenges is to determine whether these reprogrammed neurons can survive and function in a living brain.

Fortunately, the brain seems to have a ready source of astroglia. When the brain is injured, these cells proliferate, similar to the way the skin repairs itself after a wound. The researchers found they could also derive neurons from injury-induced astroglia taken from the brains of adult mice. _TechnologyReview

More:

we first aimed at a more potent neuronal reprogramming by inducing higher and more persistent expression of neurogenic fate determinants in astroglial cells. This allowed us not only to obtain fully functional neurons that also establish synapses from astroglial cells in vitro but also to demonstrate that distinct neurogenic transcription factors, such as on the one hand Neurog2 and on the other Dlx2 alone or in combination with Mash1, can indeed instruct the selective generation of different neuronal subtypes, such as glutamatergic and GABAergic neurons, respectively. Moreover, we found that the reprogramming efficiency of postnatal cortical astroglia towards GABAergic neurons by Dlx2 could be enhanced by first expanding the astroglial cells under neurosphere conditions prior to forced expression of Dlx2. Given that following brain injury reactive astroglia from the adult cerebral cortex de-differentiate, resume proliferation, and can give rise to self-renewing neurospheres in vitro [16], we finally show that neuronal reprogramming and subtype specification are not restricted to postnatal stages but can also be achieved from adult cortical astroglia responding to injury. _PLOS

The findings are a striking reminder that nature offers us many more possibilities than we can presently conceive of. But perhaps we will grow in our conceptual capacity, over time.

The possibility of regenerating brain tissue in situ -- without the need for inserting new cells from elsewhere -- offers new hope for brain trauma, infection, infarct, atrophy, and senility. But it also offers a distinctly new possibility which most observors are not quite ready to think about -- much less discuss.

I am referring to the possibility of growing entirely new neural networks in situ, from astroglia. The possibility that humans can induce their own brains to create entirely new brain centers and pathways, using more advanced forms of such techniques, should not be overlooked.

There is currently a race between biological methods of repairing and enhancing human organs, and technological methods of compensating for organ damage or loss -- the cyborg approach. A cyborg may utilise nano-technological enhancement, and thus manifest no outward sign of distinction from standard normal humans. The same would be true for most biological enhancements or remediation.

This lack of overt differences between ordinary persons and enhanced persons is quite important to most military uses of enhanced individuals, and to virtually all covert uses by government and other organisations.

But these tools of transformation are not likely to remain limited to deep pocketed groups and individuals. Garage biohackers are not as uncommon as you might think, and are performing a similar service for bio-hacking as the garage techno-hackers performed for microcomputers in the early days. And it is also extremely likely that persons involved in expensive and large scale research into bio-transformation technologies will set off on their own as they discover the ability to profit from their technical knowledge and skills.

Cross-posted at Al Fin