Connectome (51 page)

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stroke of insight:
Other times, it's the available tools of measurement that motivate the hypothesis. For example, Galton hypothesized that intelligence was related to head size mainly because he was able to measure head size, not because this was a great hypothesis.

 

13. Changing

 

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Der Freischütz:
This literally means “The Freeshooter,” but it's typically translated as “The Marksman.”

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suffering of millions of people: Bosch and Rosich 2008.
Bosch and Rosich 2008.

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inspired by Weber's popular opera:
Strebhardt and Ullrich 2008. Ehrlich also invented the idea of receptor molecules.

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last-ditch measure:
The current practice of psychosurgery and the history of the “frontal lobotomy,” which earned the Portuguese physician Egas Moniz a Nobel Prize in 1949, are described in Mashour, Walker, and Martuza 2005. While lobotomy could reduce the symptoms of psychosis, it also mentally crippled the patients. It became apparent that the side effects were worse than the disease. Because of psychosurgery's abuses, many regard the prize to Moniz as an embarrassment to the Nobel committee. However, some historians argue that psychosurgery was justifiable in an age before antipsychotic drugs, when the only alternative was confinement in a mental institution. Much of the infamy of the procedure was due to American physician Walter Freeman, who developed a version of the procedure that he called the “transorbital leucotomy.” In his gruesome technique—nicknamed the “ice pick lobotomy”—a mallet was used to drive a sharp instrument resembling an ice pick past the eye through the eye socket into the brain. Moving the tip back and forth destroyed tissue in the frontal lobe. Freeman's innovation made the procedure so quick and easy that non-surgeons and even non-physicians could perform it.

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surplus or deficiency of neurotransmitter:
Schildkraut 1965.

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effects of fluoxetine on the four R's:
Hajszan, MacLusky, and Leranth 2005 found an increase in dendritic spine density, a sign of synapse creation. Wang et al. 2008 demonstrated increased dendritic growth of newborn neurons. The extensive literature on neuron creation in the hippocampus and its role in depression is reviewed in Sahay and Hen 2008.

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specifically target connectomes:
Other treatments for brain disorders involve manipulating neural activity. In electroconvulsive therapy (ECT), shocks administered through scalp electrodes induce epileptic seizures. ECT is far from a magic bullet, as the seizures spread unselectively over the brain, yet for some unknown reason ECT can alleviate symptoms of depression and other mental disorders. Better-targeted electrical stimulation can be performed using electrodes that are surgically implanted inside the brain. Symptoms of Parkinson's disease, for example, can be relieved by stimulating parts of the basal ganglia. Some researchers are developing even more precise therapies based on optogenetics, the optical stimulation of activity in a single neuron type that has been genetically altered to be sensitive to light. Like altering neurotransmitter levels, manipulating neural activity may sound completely different from promoting connectome change, but it's not. For example, the seizures of ECT may change the connectome through Hebbian plasticity, and it's quite possible that such changes are responsible for its therapeutic effects (and for side effects like amnesia).

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supplemented by training regimens:
It's intuitively plausible that combining drugs and “talk therapy” might be more effective than either alone. Evidence supporting this idea for the treatment of depression is presented by Keller et al. 2000.

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alive but damaged:
Lipton 1999.

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“gene therapy” for Parkinson's:
Yamada, Mizuno, and Mochizuki 2005; Mochizuki 2009.

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degeneration in neurons:
Some researchers report that neurons “die backwards” in many diseases. In other words, degeneration affects the synapses and tips of axons first, and then moves backward along the axon toward the cell body. The collapse of the axon in turn might trigger the neuron to initiate the suicidal mechanisms of programmed cell death. See Coleman 2005; Conforti, Adalbert, and Coleman et al. 2007.

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connections are lost:
Selkoe 2002.

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before the first onset:
Baum and Walker 1995.

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such as lizards:
Lledo, Alonso, and Grubb 2006.

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fingertips grow back:
Illingworth 1974.

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Injury naturally activates:
Carmichael 2006.

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divert them from:
Zhang, Zhang, and Chopp 2005.

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survive in recipients' brains:
Mendez et al. 2008.

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whether the transplants actually:
Olanow et al. 2003.

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“reprogrammed” to divide:
This is known as a patient-derived induced pluripotent stem cell (iPSC).

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skin cells of Parkinson's:
Soldner et al. 2009.

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Whether created naturally:
Zhang, Zhang, and Chopp 2005; Buss 2006; Lledo 2006.

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added by transplantation:
Brundin 2000.

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molecules that promote plasticity:
Murphy and Corbett 2009.

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grow new axonal branches:
Carmichael 2006.

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natural molecular processes:
Carmichael 2006. Reweighting might also be important for recovery from stroke, by unmasking previously nonfunctional pathways through strengthening of their synapses. Another type of change can unmask pathways, which should perhaps be included in reweighting. This is a change in the threshold for producing a spike. (In the weighted voting model, the threshold specifies the margin between “yes” and “no” votes required from presynaptic “advisors” for a neuron to fire an action potential.) Lowering thresholds can unmask pathways by making neurons more excitable, that is, less choosy about when to spike. This could be especially important for recovery from stroke, because the death of neurons reduces the number of advisors for the surviving neurons. They may receive less “yes” votes, so they will not spike unless their thresholds are lowered.

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effect on learning and memory:
Nehlig 2010.

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deprived of cigarettes:
Newhouse, Potter, and Singh 2004.

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nine out of ten:
Kola and Landis 2004.

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a billion dollars:
Morgan et al. 2011. These estimates are uncertain because such financial information is proprietary. Also, pharmaceutical companies have an interest in overstating their costs, to answer criticisms that they are greedily overcharging for their products.

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swept through the psychiatric hospitals:
The serendipitous history of antipsychotic drugs is reviewed in Shen 1999. The first-generation, or “typical,” drugs were created by varying the molecular structure of chlorpromazine. The second-generation, or “atypical,” drugs have more diverse molecular structures.

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first antidepressant medications:
Lopez-Munoz and Alamo 2009. Iproniazid was the first of the monoamine oxidase inhibitors, and imipramine kicked off the discovery of many tricyclic antidepressants.

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golden age of the 1950s:
Since the 1950s, the only major success story has been fluoxetine, which was discovered by rational means rather than serendipity. From studies of the first antidepressants, scientists had formulated the theory that depression had something to do with the brain system that secretes the neurotransmitter serotonin. In the early 1970s, the company Eli Lilly searched for molecules that acted on the serotonin system but lacked the side effects of the tricyclic antidepressants like imipramine. The search turned up fluoxetine, which was finally approved by the U.S. government in 1987. See Lopez-Munoz and Alamo 2009.

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A drug is an artificial molecule:
The line between artificial and natural is blurred by “biologics.” Vaccines are the classic example, but newer ones are proteins identical or similar to the ones that occur naturally in the body. These can still be viewed as artificial, in the sense that they are synthesized or introduced by non-natural means. Biologics are distinguished from “small molecules,” which contain many fewer atoms and are the classic kind of drug.

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the attrition rate:
Kola and Landis 2004.

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between the first and last stages:
Markou et al. 2008.

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humanized mouse models:
Legrand et al. 2009.

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animal behavior that is analogous:
Nestler and Hyman 2010.

 

14. To Freeze or to Pickle?

 

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probability theory:
The founding of probability theory is recorded in a series of letters between Pascal and another famous mathematician, Pierre de Fermat. See Devlin 2010.

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a searing religious vision:
The two-hour vision took place the evening of November 23, 1654, which has come to be known as Pascal's “night of fire.” We know of it only because Pascal recorded the event on a document that was sewn into his coat, and discovered by a housekeeper after his death. See O'Connell 1997.

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one thousand living members:
According to an Alcor web page, as of July 31, 2011, there are 955 members and 106 cryopreserved “patients.”

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want to live forever:
Some friends tell me that they wouldn't want to be immortal. This position has also been argued by philosophers, notably Charles Hartshorne. I find this ironic, as I saw Hartshorne a few times in my father's office at the University of Texas, and he seemed practically immortal—he rode a bicycle well into his eighties and lived until age 103. But I agree with Camus that suicide is more interesting as a philosophical problem, since immortality doesn't seem like a realistic option anyway.

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apocryphal, alas:
Peck 1998.

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the court sorcerer Xu Fu:
Howland 1996.

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laid the athlete's remains to rest: The Ted Williams story is told in Johnson and Baldyga 2009.
The Ted Williams story is told in Johnson and Baldyga 2009.

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“Miracle of the Sun”:
There are many books on the miracle. Bertone and De Carli 2008 was written by a cardinal and endorsed by the pope. The apparition of the Virgin Mary revealed three secrets to the shepherd children. The Vatican claims to have disclosed all of them to the world, but has been accused of holding back part of the third, “Last Secret of Fatima.”

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believe in miracles:
Pew Forum on Religion 2010.

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270,000 customers:
Markoff 2007.

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According to Clarke's:
Clarke 1973 lays out three laws. The first and second are: (1) When a distinguished but elderly scientist states that something is possible, he is almost certainly right. When he states that something is impossible, he is very probably wrong. (2) The only way of discovering the limits of the possible is to venture a little way past them into the impossible.

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Sonny Graham received a heart:
Dudley 2008.

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Cheryl had been married five times:
Wigmore 2008.

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Sperm survive the best: Woods et al. 2004.
Woods et al. 2004.

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ice inside cells is lethal: Mazur, Rall, and Rigopoulos 1981.
Mazur, Rall, and Rigopoulos 1981.

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still damaging to cells:
I use the term
salty
here for convenience, but in reality other solutes beside salt ions are also important.

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oocytes and embryos:
Woods et al. 2004.

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vitrified kidney:
Fahy et al. 2009.

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Peter Mazur:
Mazur 1988.

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“respirator brain”:
Towbin 1973.

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determination of death:
Laureys 2005; President's Council on Bioethics 2008.

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   “
If the brainstem is dead”:
Laureys 2005.

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vicious cycle continues:
President's Council on Bioethics 2008.

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discarded information:
Conversely, some of the information in the connectome might be irrelevant to personal identity, because it's just random “noise” created as the brain wired itself up during development.

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After mechanical ventilation:
Agarwal, Singh, and Gupta 2006.

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types of damage present:
Rees 1976; Kalimo et al. 1977.

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still intact in the EM images:
However, many are depleted of their vesicles containing neurotransmitter. Recall that the strength of a synapse is related to its size, and one measure of size is the number of vesicles. Therefore, information about synaptic strength—information that can be regarded as part of the connectome—may be difficult to recover.