Putting On Einstein's Thinking Cap 

by Will Block 

A recent study of Albert Einstein's brain has provided what may be one explanation for his extraordinary genius. Published in the British medical journal The Lancet, the study showed that the parietal lobes of Einstein's brain were 15% larger than normal (see Figure 1). In addition, the right- and left-hemisphere fissures that separate the parietal lobes were missing.1 Because current theories of intelligence assign certain functions to the parietal lobes - specifically, traits involving visual-spatial cognition, mathematical ideation, and imagery of movement - the researchers believe that their findings may help explain Einstein's genius.

The parietal lobes constitute an area of the brain where significant declines in acetylcholine activity occur with the onslaught of Alzheimer's disease.2 In the brain and throughout the central nervous system, acetylcholine is one of the most important neurotransmitters, conducting messages from neuron to neuron and facilitating memory. While its decline is closely connected to Alzheimer's, it is also age-related. Eventually, if we live long enough, most of us will fall victims to Alzheimer's. Einstein might have been an exception - in part, not because he was so smart, but because he kept on exercising his brain, a practice that is believed to confer some protection even in mere mortals like us. But then, he may have had more acetylcholine than most of us.

Einstein's Brain Probably Had More Acetylcholine
A study published in 1985, written by Marion Diamond and co-authored with her husband, Arnold B. Scheibel (see Figure 2), a UCLA professor of neurobiology and psychiatry, found an intriguingly compatible conclusion to that of the Lancet paper upon examining Einstein's brain.3 Diamond et al found an unusually high ratio of glial to neuron cells in the parietal region of Einstein's brain, the same area that was found to be larger in the Lancet study. Unlike neurons, glial cells can reproduce themselves. In culture, glial cells synthesize acetylcholine.4 One type of glial cell, oligodendrocytes, the myelin-producing cells of the central nervous system, are known to be powerful expressers of acetylcholine receptors.5 Because acetylcholine is thought to act as a trophic factor in developing oligodendrocytes, regulating their growth and development in the central nervous system, it is plausible to conclude that Einstein had an abundance of acetylcholine.6

Figure 2.
Research partners Diamond and Scheibel choose to exercise their brains by learning new things instead of surrendering to retirement.

Alzheimer's disease is characterized by the gradual loss of performance of routine tasks, communication skills, time and space orientation, cognitive abilities, and abstract thinking.7 Since abstract thinking was an area in which Einstein excelled (to put it mildly), right up to the end of his 76 years of life,8 acetylcholine abundance is quite plausible, indeed.

Einstein's Missing Cap
In addition to its enlarged parietal lobes, Einstein's brain did not have an operculum, a fissure (or natural division) that widens into a caplike structure and normally separates the inferior from the posterior parietal lobes on each side of the brain (see Figure 1). This rare anatomy may have resulted in greater and more varied neuronal connectivity in this region of Einstein's brain. The variations in neuronal connections could have provided a functional advantage, enhancing his intelligence. It is metaphorically appropriate that Einstein's brain did not have the usual "cap," thus giving rise to his soaring flights of imagination.

The Lancet study showed that the parietal lobes of Einstein's brain were 15% larger than normal.  

In conclusion, the researchers were able to say that the anatomical features of Einstein's parietal lobes are probably related to his genius. It also stands to reason that, if his parietal lobes were larger (and he had increased numbers of glial cells), he also had increased amounts of acetylcholine. But aside from enlarging one's cerebral anatomy (for which this researcher is not aware of any evidence), are there any prospects for improving one's own intelligence or fortifying the brain's capabilities in terms of visual, spatial, mathematical, and imagery memory functions?

More Acetylcholine May Enhance Intelligence
Studies have shown that when brain levels of acetylcholine are increased, Einstein-like visual, spatial, mathematical, and imagery cognitive traits tend to improve. Until about ten years ago, these traits could be elevated principally by increasing the intake of choline,9 choline agonists such as DMAE (dimethylaminoethanol),10 or choline donors such as citicoline.11 But starting in the late 1980s, interest has developed in an extract from a Chinese plant called chien tseng ta (Huperzia serrata). Called huperzine A (HupA), this extract represents a whole new look at what may well be the most potent approach to age-related cognitive decline, and it may also be of benefit in helping to prevent Alzheimer's disease.

The Diamond study found an unusually high ratio of glial cells to neurons in the parietal region of Einstein's brain. In culture, glial cells synthesize acetylcholine.

Huperzine A: China's Rich Offering
Throughout its long history, China has accumulated a rich body of empirical knowledge regarding the use of medicinal plants for the treatment of various diseases. The problem is that, until recently, very little of the science had been translated into English, let alone adopted into our Western way of thinking. Although the flow is still just a trickle, chemical studies on Chinese medicinal plants are providing a valuable material base for the discovery and development of new drugs of natural origin. The source of HupA is a plant that has been used for treating contusions, strains, hematuria (blood in the urine), and swelling in Chinese folk medicine. From it, the herbal extract HupA was isolated only a decade ago.

HupA is used for treating patients with myasthenia gravis and Alzheimer's disease in China. It is a potent, yet reversible, inhibitor of acetylcholinesterase (AChE), an enzyme that breaks down acetylcholine (ACh). When this occurs too quickly or when too much is broken down (as in the aging process), cognitive functions suffer. This is especially true in Alzheimer's patients, in whom ACh levels are significantly diminished.

Together the two studies make plausible the case that Einstein's brain had more acetylcholine. 

Mechanism of Action
An estimated 100,000 people in China have been treated with HupA, reports Alan Kozikowski, PhD, professor of pharmacy at Georgetown University's Institute of Cognitive and Computational Sciences in Washington, DC. The toxicity is very low, and complaints have been minor. Dr Kozikowski is the researcher who first isolated HupA in 1991. Just two years ago, at the Weizmann Institute of Sciences in Israel, he and his colleagues worked out the 3-dimensional structure of the complex that forms when HupA binds to AChE by sliding smoothly into the latter's "active site." This binding deactivates the AChE and prevents it from breaking down the ACh.12 According to one of the researchers, Professor Joel Sussman, "It is as if this natural substance were ingeniously designed to fit into the exact spot where it will do the most good."

As a reversible acetylcholinesterase inhibitor, HupA prevents the breakdown of the acetylcholine produced naturally in the body. In normal interneuronal housekeeping, AChE plays a vital role by removing excess ACh. However, in the brains of Alzheimer's patients, biopsies and postmortem studies show a substantial loss of cholinergic neurons - those using the neurotransmitter ACh.13 Unfortunately, whatever ACh is produced in the brains of these patients is quickly broken down by AChE, and the shortage of this neurotransmitter appears to contribute to patients' memory loss and other cognitive defects.

Huperzine A is a potent reversible inhibitor of acetylcholinesterase (AChE), and an important psychotherapeutic agent for improving cognitive function in Alzheimer's patients through the enhancement of central cholinergic tone.  

HupA remains in the body longer than other AChE inhibitors, making it more effective; it also has fewer side effects. Its superior inhibition of AChE helps make ACh available for attention, concentration, long- and short-term memory, and learning. HupA also helps to make ACh available for visual, spatial, mathematical, and imagery cognition.

Double-Blind Placebo-Controlled Studies
Pharmacological studies indicate that HupA, which can readily cross the blood-brain barrier, is able to conserve ACh in the brain through its powerful and reversible anticholinesterase activity.14 When lab animals that have received HupA are given maze tests, the results demonstrate that HupA improves learning and retrieval (recall) processes and facilitates memory retention.

An estimated 100,000 people in China have been treated with huperzine A. 

Recently, purified HupA isolated from the plant Huperzia serrata has undergone double-blind, placebo-controlled clinical trials in China with patients suffering from various memory disorders, including Alzheimer's. Significant effects were noted in these patients, in terms of both life quality and memory retrieval.15 In one study, 50 Alzheimer's patients were given 100 mcg of HupA twice a day for 8 weeks. Compared with controls, the results showed that 58% of the subjects treated with HupA improved in all measured memory, cognitive, and behavioral functions.

Increased ACh Levels
In another study, HupA increased ACh levels by as much as 220% above baseline in the brains of rats.16 It also increased noradrenaline and dopamine levels by 121% and 129%, respectively. It took only 60 minutes to reach peak AChE inhibition at the highest dose (300 mcg/kg), and ACh elevation lasted at least 6 hours. Serotonin levels did not change.

As a reversible AChE inhibitor HupA prevents the degradation of endogenous acetylcholine. 

Huperzine Better than Tacrine and Donepezil
Alzheimer's disease remains a diagnosis of exclusion, meaning that it is diagnosed by what it doesn't do as well as what it does do. Until treatment strategies aimed at targeting its underlying cause become available, a cholinergic approach appears to be the most promising treatment for improving cognition in this devastating disease.

When compared with two leading acetylcholinesterase inhibitors, tacrine and donepezil, huperzine A proved superior. Rats given an oral dose of HupA were able to negotiate a maze even after previously receiving a dose of scopolamine, a compound that induces working and reference memory errors.17 HupA fit the criteria for an ideal acetylcholinesterase inhibitor. Unlike the drugs, it is a naturally derived compound. It also proved to be more selective, thus improving working memory significantly better than did the drugs. This suggests that it may be a promising agent for clinical therapy of cognitive impairment in patients with Alzheimer's disease.

HupA also helps make ACh available for the Einstein mental traits of visual-spatial, mathematical and imagery cognition. 

The Neuroprotectant Powers of Huperzine A
Pretreatment with HupA at 500 mcg/kg totally prevented seizures and ensured the survival of guinea pigs for 24 hours after intoxication with a poison.18 The brain tissue was free of any neuronal damage. Comparatively, all animals pretreated with pyridostigmine (another AChE inhibitor) exhibited epileptic activity after intoxication, and five of six animals died. The efficacy of HupA seems to be related to its ability to protect both peripheral and central stores of ACh.

HupA has also been found to be a potent neuroprotective agent under conditions in which the functions of the neurotransmitter glutamate are compromised.19 Under conditions of stress, glutamate induces cell death in cultures from all the brain regions in which AChE operates: the forebrain, hippocampus, cortex, and cerebellum. Pretreatment of these cell cultures with HupA has been shown to reduce cell toxicity and cell death.

Compared with controls, the results showed that 58% of the subjects treated with HupA improved all measured memory, cognitive and behavioral functions. 

In an experiment with rats, the activity of choline acetyltransferase (ChAT) was decreased by drugs, disrupting the rats' spatial working memory processes.20 ChAT is an enzyme that helps produce ACh; its loss of activity is associated with Alzheimer's. HupA significantly improved the induced spatial memory deficit, enabling the rats to resume their disrupted processes.

Cognition Enhancers in Age-Related Cognitive Decline
In the "normal" age-related process of moving from cognitive health to dementia to Alzheimer's disease, deterioration occurs gradually, step by step. But this needn't be so. A review of recently published studies on the effect of cognition enhancers in nondemented subjects demonstrates that cognitive decline can be slowed, stopped, or even reversed. The key to improvement lies in identifying whether cognitive decline is age-extrinsic or age-intrinsic, and supplementing accordingly. In other words, is the underlying factor of a specific cognitive decline pathological or not?21

In elderly people in whom memory impairment, psychomotor performance, or cognitive function resulting from a pathology was determined, the results usually required "big gun" cognitive supplementation. Alternatively, when the determination was age-related declines of memory, etc., then much could often be achieved with less potent supplements.

By tipping your thinking cap to his - remember Einstein was missing his parietal operculum cap - you may find yourself more mindful in the richest sense. 

It is important to grasp that each of us is likely to fall into both categories for different cognitive deficits. The cognition-enhancing properties of widely used substances such as caffeine and vitamins may be adequate for garden-variety problems, but they may prove marginal and disappointing in more advanced conditions.

Cholinergics such as choline and DMAE generally fall into the garden-variety arena, while citicoline and huperzine A generally fall into the more advanced arenas. This is not to say that all four cholinergic supplements do not have crossover values. Suffice it to say that together these cholinergics cover a lot of ground and that their selectivity and specificity may help stave off what would otherwise be an inevitable future of a foreshortened cognitive life.

Had Einstein lived longer than his 76 years, his creativity would have undoubtedly continued. Remember that Einstein's missing parietal operculum cap probably represented better neuronal connectivity, and probably even better cholinergic function. By tipping your thinking cap to choline, choline agonists, choline donors, and acetylcholinesterase inhibitors, you may find yourself more mindful, in the richest sense.


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