Volume 2, Issue 2 
2nd Quarter, 2007


Neuronanotechnology to Cure Criminality and Mental Illness

Nancy Woolf, Ph.D.

Page 3 of 4

"I propose that these multiple tubulin isotypes in brain enable a semi-periodic distribution of these rarer tubulins such that there can be varied information storage."

Where there’s too much orderliness, this interferes with the potential for diverse information. In other words, you need some chaos or randomness for there to be specific information.

If there is only the most prevalent type of tubulin, the Beta-1, the microtubule structure is too orderly for there it to represent many different examples of specific information;  that’s the idea. Another idea is that when these different MAPs are de-phosphorylated, the microtubule acts as a universal cable—transmitting nearly any information. However, when these MAPs are phosphorylated and the contour is exposed, then only specific information that matches this contour can be amplified.

Based on what is known about microtubules, one would expect that information can flow longitudinally down the microtubule, as well as transversely, from one microtubule to its adjacent neighbor.

Now, I want to spend some time talking about bipolar disorder and then I’ll get back to how the microtubules might be involved in this disorder.

First, some very basic facts: Bipolar disorder is an effective disorder, in other words, it’s a mood disorder. It afflicts as much as four percent of the population. It’s characterized by dramatic changes in moods, shifts from depression to mania, hypo-mania or mixed states to periods of normal mood. Bipolar disorder has been shown to involve changes in the cingulate cortex, orbitofrontal cortex [1], hippocampus [2], and amygdala [3].

"There are a number of studies that suggest there are deficiencies or problems with both tubulin and the MAP2 in bipolar disorder."



Image # 6 - Bipolar Disorder

The drugs that are used to treat bipolar disorder are collectively called mood stabilizers because they treat both the depression, as well as the mania (they normalize mood by bringing up depressed mood and decreasing mania).



Image # 7 - Mood Stabilizers

All of the known mood stabilizers that include lithium, valproate, and carbamazepine, inhibit a protein kinase called GSK-3, which primarily acts on microtubule-associated proteins, both the MAP2 I’ve been talking about and another one that’s called tau protein. GSK-3 acts to phosphorylate MAP2 and tau [4] (protein). By this mechanism mood stabilizers alter microtubule dynamics, and they may indeed exert their therapeutic effects by this means.

Interestingly, when you look at meta-analyses of genetic studies on bipolar disorder, you find that many of the different gene loci that have been implicated as showing possible insertions, deletions, or polymorphisms overlap with loci that code and transcribe the various tubulin isotypes, for example, the Beta-2, Beta-2 A, B, and C, the Beta-3, and the Beta-6 tubulin. There is also overlap with some other tubulin-related proteins. 

"[W]hen a person’s thoughts speed up during mania and slowdown during depression, we may be able to model this as altered MAP2 binding dynamics as dictated by tubulin isotypes."



Images # 8 - Tubulin

We know some things about what triggers a manic or depressive episode (bipolar disorder is also called manic depressive illness). We know that these episodes are frequently triggered by stress. It’s conceivable that there’s increased polymerization and de-polymerization of microtubules with stress, and that this exacerbates problems with microtubules transmitting and amplifying information.

After a stressful catalyst, thoughts either speed up or slow down. We might expect this to occur because of increased orderliness due to a lack of rarer isotypes of tubulin.

And too much orderliness would be expected to lead to either too much or too little binding of MAP2s to the microtubules. That’s going to affect the dynamics of the microtubule’s housekeeping functions, information processing, and presumably interfere with mental activities.

So what’s proposed is a novel treatment for bipolar disorder. This is necessary because certain individuals don’t respond to mood stabilizers. So that’s a group of people who need attention. In fact, many people don’t respond to one mood stabilizer so multiple mood stabilizers are often prescribed. The problem with this approach is some mood stabilizers counteract others. Clinicians have to increase levels of one mood stabilizer to counter its metabolism or breakdown by another mood stabilizer.



Image # 9 - Treatment

Also, bipolar disorder affects a large number of the population, around 12 million Americans, and it has serious social consequences. Bipolar disorder is often found along with substance abuse or criminality and we’ll talk about that a little more because this raises important socio-biological issues and ethical concerns.

Criminality is a problem found especially in those bipolar patients that also have a serious substance abuse problem--either alcohol abuse or drug abuse.

"Quoting one study, 53 percent of female and 79 percent of male rapid-cycling bipolar patients who had co-morbid substance abuse issues, reported having been charged with a crime. And this is far higher than in the general population."



Image # 10 - Substance Abuse

An old rule of thumb proposed by Lionel Penrose [5] is that at any given time in any society, there’s going to be an inverse relationship between the number of patients housed in mental institutions and the number of prison inmates. In other words, people who are having extreme difficulties, such as those with bipolar disorder and co-morbid substance abuse, are at risk of either going to a mental institution or going to a prison. So, it’s in the best interest of society to pay attention to these issues and to use nanotechnology, if it’s effective, at treating this disorder.

As it turns out, transcranial magnetic stimulation (TMS), which stimulates electromagnetic currents in cortical neurons, is a promising treatment for affective disorder, but since there’s no clear-cut theoretical mechanism for why it works, this limits our ability to make the technique any better.



Image # 11 - Electromagnetic

Redefining TMS and other electromagnetic treatments in terms of how they affect electromagnetic currents in microtubules and how they might reorganize the structure of microtubule matrices to correct abnormal transmission and amplification patterns by microtubules could afford significant improvements to techniques such as TMS.

Now, this depends on microtubules being sensitive to electromagnetic energy, but it turns out they are. Second harmonic, generation microscopy shows that microtubules are one of a very small number of proteins that do respond to laser excitation in the near infrared range. Also, individual microtubules respond to near infrared waves by growing towards the source. So, there are two different indicators that microtubules respond to electromagnetic energy.

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Footnotes


[1] Orbitofrontal cortex - (OFC) is a region of association cortex of the human brain involved in cognitive processes such as decision making. This region is named based upon its location within the frontal lobes, resting above the orbits of the eyes.

http://en.wikipedia.org/wiki/Orbitofrontal_cortex
March 6, 2007 5:03 PM EST

[2] Hippocampus – The complex, internally convolutes structure that forms the medial margin of the cortical mantle of the cerebral hemisphere, borders the choroid fissure of the lateral ventricle, is composed of two gyri with their white matter, and forms part of the limbic system.

Stedman, The American Heritage Medical dic·tion·ar·y, Boston, New York: Houghton Mifflin Company, 2004: 368.

[3] Amygdalae – 1. an almond-shaped mass of gray mater in the front part of the temporal lobe of the cerebrum. Also called amygdaloid nucleus. 2. The cerebellar tinsil. 3. Any of the lymphatic onsils.

Stedman, The American Heritage Medical dic·tion·ar·y, Boston, New York: Houghton Mifflin Company, 2004: 38.

[4] Tau (protein) – microtubule-associated proteins that are abundant in neurons and in the central nervous system and are less common elsewhere.They were discovered in 1975 in Marc Kirschner's laboratory at Princeton University
[Weingarten et al., 1975].

http://en.wikipedia.org/wiki/Tau_%28protein%29
March 27, 2007 10:03AM EST

[5] Lionel Sharples Penrose - (11 June 1898 - 12 May 1972) a British psychiatrist, medical geneticist, mathematician and chess theorist, who carried out pioneering work on the genetics of mental retardation.http://en.wikipedia.org/wiki/Lionel_Penrose
March 9, 2007 2:45PM EST

 

 

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