Galantamine, along with choline, may help make you …

Think Like Einstein
The two hemispheres of Albert Einstein’s brain were unusually
well-interconnected and may have contributed to his genius

By Will Block

For though fair or stormy weather,
We’ll stick together through thick and thin.

— Cole Porter, Through Thick and Thin


You have to learn the rules of the game. And then you have to play better than anyone else.
— Albert Einstein
A provocative study, “The Corpus Callosum of Albert Einstein’s Brain: Another Clue to His High Intelligence,” was recently published in the journal Brain.1 Using recently discovered photographs of the two hemispheres of Albert Einstein’s brain (Figure 1),2 the researchers found that the left and right hemispheres of his brain were substantially better connected to each other and may have contributed to his brilliance.

Inside Einstein’s Brain

One of the study’s researchers, evolutionary anthropologist Dean Falk of Florida State University, proclaimed, “This study, more than any other to date, really gets at the ‘inside’ of Einstein’s brain” Furthermore, she said, “It provides new information that helps make sense of what is known about the surface of Einstein’s brain.”3

Outer surfaces aside, the lead author Weiwei Men (a candidate for a PhD) of East China Normal University’s Physics Department innovated a new technique to conduct the study, which is the first to detail Einstein’s corpus callosum. The corpus callosum is the largest nerve fiber bundle that connects the cortical regions of the cerebral hemispheres in human brains. Containing upwards of 200 million axons, it is essential for the integration of information transferred between the hemispheres. Many studies have indicated that Alzheimer’s disease is associated with corpus callosum atrophy.

Thickness Determines Cross-Hemispheric Communication

Mr. Men’s (he’s working on his Ph.D.) technique measured and color-coded the subdivision thickness of the corpus callosum along its length, where nerves cross from one side of the brain to the other. The thicker the better, indicating an increased number of nerves crossing the corpus callosum and how well “connected” the two sides of the brain are in particular regions. This facilitates different functions depending on where the fibers cross along the length. For example, movement of the hands is represented toward the front and mental arithmetic along the back. “This technique should be of interest to other researchers who study the brain’s all-important internal connectivity,” said Falk.3

Comparisons from the Miracle Year for Einstein

In particular, the new technique permitted registration and comparison of Einstein’s measurements with those of two samples—one of 15 elderly men and one of 52 men Einstein’s age in 1905. During his so-called “miracle year” at 26 years old, Einstein published four articles that contributed substantially to the foundation of modern physics and changed the world’s views about space, time, mass, and energy. Because Einstein was right-handed and died at the age of 76, the first control group consisted of 15 elderly, healthy right-handed males, aged 70 to 80 years (mean: 74.20±2.60 years). All participants were college graduates or beyond college, and non-demented. The second control group consisted of 52 younger, healthy right-handed Caucasian males, aged 24 to 30 years (mean: 26.60±2.19 years).

The Discovery of New Einstein Brain Photographs

In the precedent paper,2 the scientists who analyzed 14 newly discovered photographs of Einstein’s brain found that it had an extraordinary prefrontal cortex, and that inferior portions of the primary somatosensory and motor cortices were greatly expanded in the left hemisphere. Among these 14 images were photographs of the left and right medial surface of Einstein’s brain, on which the corpus callosum was shown with great resolution and accuracy.

Fig. 1. The left and right halves of Einstein’s brain
LEM1312Einstein'sLandRhemis200.jpg
(click on thumbnail for full sized image)
The two photographs of the medial surfaces of Einstein’s cerebral hemispheres (Fig. 1) provide the basis for the present study. To examine whether there are regional callosal differences between the brain of Einstein and those of ordinary people, and to minimize potential differences in corpus callosum morphology due to cause of death, brain atrophy, age, and sex, in vivo magnetic resonance imaging (MRI) data sets from two different age groups were used.


Many studies have indicated that
Alzheimer’s disease is associated with
corpus callosum atrophy.


The research team’s findings show that Einstein had more extensive connections between certain parts of his cerebral hemispheres compared to both younger and older control groups.

Albert Einstein was the greatest physicist in the 20th century. His extraordinary intelligence has long intrigued both scientists and the general public. Despite 20+ papers that focused mainly on the histological and morphological features of Einstein’s brain after his death, the substrates of Einstein’s genius are still a mystery.

The External Examination of Einstein’s Brain

One of the most interesting of the papers about Einstein’s brain written in the past was a paper published in 1999.4 (See “Putting On Einstein’s Thinking Cap,” in the August 1999 issue of Life Enhancement.) Appearing in the British medical journal The Lancet, this study showed that the parietal lobes of Einstein’s brain were 15% larger than normal (Figure 2). 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.

Alzheimer’s Disease and the Parietal Lobe

The parietal lobes constitute an area of the brain where significant declines in acetylcholine activity occur with the onslaught of Alzheimer's disease.5 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 merely 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 such as us. But then, he may have had more of a particular neurotransmitter than most of us.

Einstein’s Brain Probably Had More Acetylcholine

Fig. 2. The absence of the parietal operculum from Einstein’s brain may have allowed a part of his brain to grow wider than normal.
LEM1312brains200.gif
(click on thumbnail for full sized image)
A study published in 1985, found an intriguingly compatible conclusion to that of the 1999 paper.6 Upon examining Einstein’s brain, the 1985 researchers 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’s 1999 study. Unlike neurons, glial cells can reproduce themselves. In culture, glial cells synthesize acetylcholine.7 One type of glial cell, oligodendrocytes, the myelin-producing cells of the central nervous system, are known to be powerful expressers of acetylcholine receptors.8 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.9


It is possible to increase acetylcholine
by supplementing with choline and
the precursor vitamin B5 .
That may not create an Einstein, but
it could help us to preserve some of
our Einstein-like qualities, as
galantamine may be able to do.


Missing Fissures in Einstein’s Parietal Lobes

In addition, the clefts that separate the parietal lobes on both the left and right halves of the brain (aka, the Sylvian fissures) were missing. 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. We now know that it is possible to increase acetylcholine by supplementing with choline and the precursor vitamin B5. That may not create an Einstein, but it could help us to preserve some of our Einstein-like qualities.

Alzheimer’s and Corpus Callosum Deterioration

Diffusion tensor imaging (DTI) demonstrates the decline of fractional anisotropy (FA) as a marker of fiber tract integrity in Alzheimer’s disease. Anisotropy is the property of being directionally dependent, as opposed to isotropy, which implies identical properties in all directions. FA is a scalar value between zero and one that describes the directional independence. A value of zero means that diffusion is isotropic, i.e. it is unrestricted in all directions. So a decline in FA is desirable.

In a recent study,10 researchers aimed to assess white matter* changes in Alzheimer’s and healthy elderly control subjects and to evaluate the effects of treatment with the cholinesterase inhibitor galantamine on white matter in Alzheimer’s patients. The corpus callosum is the largest white matter structure in the brain, consisting of 200–250 million contralateral axonal projections.


* White matter is one of the two components of the central nervous system and consists mostly of glial cells and myelinated axons that transmit signals from one region of the cerebrum to another and between the cerebrum and lower brain centers.


A Case of Brain Theft?

The doctor who performed the autopsy on Einstein’s body just after he died was a Princeton pathologist named Thomas Harvey, M.D. As is customary during autopsies, Harvey removed the brain for examination … but he never replaced it! Harvey instead placed it in a jar of formaldehyde and took it home! He did this despite the possibility of loss of his job and reputation.

For 40 years, he sent bits of Albert Einstein’s brain to leading neuroscientists for them to study, believing that the theft of Einstein’s brain was his scientific duty! What is left of the brain now resides back at Princeton where it started. Harvey tried to return it to Albert Einstein’s daughter at one point, but she didn’t want it, so he gave it back to the university.

Enrolled were 28 Alzheimer’s patients and 11 healthy elderly controls. Alzheimer’s patients were randomly assigned to 6-month double-blind galantamine treatment or placebo, with a 6-month open-label extension phase. DTI was performed at baseline, as well as at 6 and 12-month follow-up in Alzheimer’s patients. Galantamine/placebo administration was started at a daily single dose of 8 mg for 4 weeks then increased to 16 mg daily for 4 weeks and continued with 24 mg through the study, including the open-label extension.


The research team’s findings show
that Einstein had more
extensive connections between
certain parts of his cerebral
hemispheres compared to both
younger and older control groups.


The researchers measured FA in regions of interest covering the posterior cingulate and corpus callosum. At 6-month follow-up, the Alzheimer’s group showed significant FA decline in the left posterior cingulate, the upper part of the “limbic lobe.” The posterior cingulate has been shown to communicate with various brain networks simultaneously, including those involving the corpus callosum.

Galantamine Preserved the Corpus Callosum

Of greater significance, FA decline was significantly preserved in the posterior body of the corpus callosum in the Alzheimer’s group with treatment compared to placebo after 6 months. At 12-month follow-up, the Alzheimer’s patients maintained a significant FA decline in the left posterior cingulate. Yet there were no differences in FA decline between initial treatment and placebo groups after the 6-month open-label extension phase. The decline of the first 6 months was reversed. Corpus callosum bidirectionality appeared to diminish.

Possible Masking in the Follow-up Part of the Study

The apparent inability of galantamine to preserve regional FA decline, during the additional 6-month open-label treatment in the corpus callosum was puzzling. Nevertheless, a 3-month follow-up study using functional MRI (fMRI), a technique to measure blood flow in the brain, reported significant treatment effects of galantamine on visual processing in Alzheimer’s disease. In combination, these findings may relate to a functional effect of galantamine on the posterior association cortex that sends interhemispheric connections through the posterior corpus callosum.

At 12-month follow-up, the researchers did not find significant treatment effects of galantamine suggesting that the difference in treatment effects on FA decline after the first 6-month treatment period was not preserved in the 6-months open-label extension phase where all patients received galantamine.

Also at 12-months follow-up, FA decline was observed in left posterior cingulate across the Alzheimer’s and control groups without a significant effect of diagnosis. The FA decrease in this area may explain the cross-sectional finding of age-associated regional anisotropy decline in elderly subjects.

The researchers expected to find greater degree of FA decline over time in Alzheimer’s compared to controls. However, higher variation of longitudinal FA values in the Alzheimer’s patients compared to controls may have masked between-group differences of FA values.


The cholinergic compounds for which
there is the most evidence for
balancing activity between the left and
right hemispheres are galantamine,
centrophenoxine, acetyl-L-carnitine,
and particularly CDP-choline.


Also, the decline of FA in healthy elderly subjects agrees with the findings in a study of elderly subjects which demonstrated widespread decline of FA across different fiber tracts over a 2-year period, supporting the validity of the longitudinal FA changes in the current study.

The 12-month follow-up in the corpus callosum reversals may be due to the shorter follow-up period than the previous longitudinal study on corpus callosum area. The finding may either represent fluctuations of scanner parameters between the two time points or true neurobiological effects. If this increase would only reflect changes in scanner parameters, it would suggest a tendency for an increase in FA values over time in all regions, which were studied. This would indicate that the effects of FA reduction were underestimated across the Alzheimer’s and control groups.

The observed increase in the FA may therefore reflect the net effect from the loss of crossing fiber tracts with age and neurodegeneration. The study was limited to detect a short-term effect of galantamine on fiber tract integrity over 6 months as the main outcome, and in addition, the potentially preserved effects after the 6-month open-label extension phase.

Another limitation was the high number of dropouts in the Alzheimer’s group. Some of these were due to insufficient scan quality resulting from artifacts. This suggests that DTI acquisitions demand a high compliance of the patients that may be limiting for examinations in more advanced stages of the disease.

One could speculate that the effect of treatment may have masked some differences in FA decline between the Alzheimer’s patients and the healthy elderly subjects after 12 months. However, due to the lack of longitudinal FA data on 12-month untreated Alzheimer’s subjects, the researchers presently could not answer this question.

Balancing the Hemispheres

In Psychiatry, Third Edition, described by the Journal of Clinical Psychiatry (December 2009) as, “an excellent textbook and a remarkable achievement in collaborative authorship, on par with, if not superior to, other references in this field … to have one single textbook that addresses a vast array of topics with thoroughness and comprehensiveness that this publication does is a magnificent accomplishment and a true gift to the reader. The contributors are all leaders in their respective areas, and the writing is always clear and articulate, regardless of the complexity of the covered subjects … we wholeheartedly recommend this heavy tome of knowledge as well worth its weight.” With 127 chapters and over 400 contributors this book is a truly comprehensive exposition of the specialty of psychiatry. Written by well-known and highly regarded experts from around the world, it takes a patient-centered approach making it an indispensable resource for all those patients with psychiatric disorders.

From with this tome, comes the following, “Patients who, under psychological testing or on EEG, show over-activation of one cerebral hemisphere compared to the other, and who seem to have impaired transfer of information across the corpus callosum (on neurological testing), may do best with one of the racetam pyrrolidomes [such as piracetam and its family], the agents in combination with a cholinergic agent. The cholinergic compounds for which there is the most evidence of efficacy in cognitively impaired populations or in animal models are galantamine, centrophenoxine, acetyl-L-carnitine, and particularly CDP-choline.”11 This could be valuable for those who lack other qualities of an Einstein-like mind!

References

  1. Men W, Falk D, Sun T, Chen W, Li J, Yin D, Zang L, Fan M. The corpus callosum of Albert Einstein’s brain: another clue to his high intelligence? Brain. 2013 Sep 24. [Epub ahead of print]
  2. Falk D, Lepore FE, Noe A. The cerebral cortex of Albert Einstein: a description and preliminary analysis of unpublished photographs. Brain. 2013 Apr;136(Pt 4):1304-27.
  3. Florida State University. Well-connected hemispheres of Einstein’s brain may have sparked brilliance. ScienceDaily. http://www.sciencedaily.com/releases/2013/10/131004104754.htm Published October 4, 2013. Accessed October 18, 2013.
  4. Witelson SF, Kigar DL, Harvey T. The exceptional brain of Albert Einstein. Lancet. 1999;353:2149-53.
  5. Iyo M, Namba H, Fukushi K, Shinotoh H, Nagatsuka S, Suhara T, Sudo Y, Suzuki K, Irie T. Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer's disease. Lancet. 1997 Jun 21;349(9068):1805-9.
  6. Diamond MC, Scheibel AB, Murphy GM Jr, Harvey T. On the brain of a scientist: Albert Einstein. Exp Neurol. 1985 Apr;88(1):198-204.
  7. Wessler I, Reinheimer T, Klapproth H, Schneider FJ, Racke K, Hammer R. Mammalian glial cells in culture synthesize acetylcholine. Naunyn Schmiedebergs Arch Pharmacol. 1997 Nov;356(5):694-7.
  8. Larocca JN, Almazan G. Acetylcholine agonists stimulate mitogen-activated protein kinase in oligodendrocyte progenitors by muscarinic receptors. J Neurosci Res. 1997 Dec 1;50(5):743-54.
  9. Cohen RI, Molina-Holgado E, Almazan G. Carbachol stimulates c-fos expression and proliferation in oligodendrocyte progenitors. Brain Res Mol Brain Res. 1996 Dec 31;43(1-2):193-201.
  10. Likitjaroen Y, Meindl T, Friese U, Wagner M, Buerger K, Hampel H, Teipel SJ. Longitudinal changes of fractional anisotropy in Alzheimer's disease patients treated with galantamine: a 12-month randomized, placebo-controlled, double-blinded study. Eur Arch Psychiatry Clin Neurosci. 2012 Jun;262(4):341-50.
  11. Brown RP, Gerbarg PL, Muskin PR. Complementary and Alternative Treatments, chapter 108. In: Tasman A, Kay J, Lieberman JA, eds. Psychiatry, 3rd ed. London, UK: John Wiley & Sons; 2008:2318-2353.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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