CHAPTER ONE: MASHING THE PLEASURE BUTTON
1. It’s fun to go back and read Olds’s original descriptions of brain self-stimulation in rats: J. Olds and P. M. Milner, “Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain,” Journal of Comparative and Physiological Psychology 47 (1954): 419–27. This review, written a few years after the discovery of the pleasure circuit, is also interesting; J. Olds, “Self-stimulation of the brain: its use to study local effects of hunger, sex, and drugs,” Science 127 (1958): 315–24.
2. C. E. Moan and R. G. Heath, “Septal stimulation for the initiation of heterosexual behavior in a homosexual male,” Journal of Behavioral Therapy and Experimental Psychiatry 3 (1972): 23–30. If you want to read about science spinning wildly out of control, you should check out this paper.
3. R. K. Portenoy, J. O. Jarden, J. J. Sidtis, R. B. Lipton, K. M. Foley, and D. A. Rottenberg, “Compulsive thalamic self-stimulation: a case with metabolic, electrophysiologic and behavioral correlates,” Pain 27 (1986): 277–90.
4. There are several dimensions along which to classify neurotransmitters and their receptors. One of these is “fast versus slow.” Both glutamate and GABA, when released from neurons to act on their neighbors, produce very rapid electrical changes: They act within a few thousandths of a second (milliseconds). They do this by binding neurotransmitters that have a pore structure built into them: When the neurotransmitter binds, this causes a subtle change in the shape of the neurotransmitter receptor, opening the pore (called an ion channel) and allowing charged molecules (ions) to flow in or out of the neuron receiving the signal. If the structure of the ion channel allows some ions (like calcium or sodium) to flow, this will increase the probability that the receiving cell will fire a spike. This is what happens with the fast-acting neurotransmitter glutamate, which we call excitatory because it promotes spike firing. However, when the fast-acting neurotransmitter GABA binds its main receptor, this opens an ion channel that allows chloride ions to flow, producing an electrical effect that suppresses spike firing, and so we call it inhibitory. In addition to fast actions of neurotransmitters like glutamate and GABA, there are also neurotransmitters that have much slower actions. These neurotransmitters bind receptors that don’t have ion channels built into them. Rather, they send slow, biochemical signals that affect the electrical behavior of the receiving cell indirectly, often in complex ways that cannot easily be categorized as excitatory or inhibitory. These neurotransmitters, like dopamine and serotonin and norepinephrine, have actions that last from hundreds of milliseconds to tens of seconds.
5. There is a second group of dopamine neurons in a structure adjacent to the VTA called the substantia nigra. These neurons also project to the dorsal striatum, the prefrontal cortex, and the amygdala. They also have a role in pleasure and reward that may be subtly different from the dopamine neurons of the VTA.
6. Drugs that bind to receptors and activate them are called agonists. Drugs that bind to receptors but fail to activate them are called antagonists or blockers. They function to block the activation of these receptors by their natural activators.
7. For a modern analysis of Parkinson’s original report, see P. A. Kempster, B. Hurwitz, and A. J. Lees, “A new look at James Parkinson’s essay on the shaking palsy,” Neurology 69 (2007): 482–85.
8. The biomedical literature is full of reports on Parkinson’s and pathological gambling. Here’s one case history report I adapted: M. Avanzi, E. Uber, and F. Bonfà, “Pathological gambling in two patients on dopamine replacement therapy for Parkinson’s disease,” Neurological Science 25 (2004): 98–101. And here’s a nice review of the recent scientific literature on this topic: V. Voon, T. Thomsen, J. M. Miyasaki, M. de Souza, A. Shafro, S. H. Fox, S. Duff-Canning, A. E. Lang, and M. Zurowski, “Factors associated with dopaminergic drug-related pathological gambling in Parkinson’s disease,” Archives of Neurology 64 (2007): 212–16.
9. Of course, the fundamental neurophysiological question, the issue of qualia, remains unanswered: Why does dopamine release in the VTA target regions feel pleasurable? A useful discussion of the state of the art may be found in a recent collection of essays: Morten L. Kringelbach and Kent C. Berridge, eds., Pleasures of the Brain (Oxford: Oxford University Press, 2010).
CHAPTER TWO: STONED AGAIN
1. Mordecai Cooke, The Seven Sisters of Sleep (London: James Blackwood, 1860).
2. A central tenet of the Stoic philosophy of Marcus Aurelius can be found in this line from volume VIII of the Meditations: “If thou art pained by any external thing, it is not this that disturbs thee, but thy own judgment about it. And it is in thy power to wipe out this judgment now.” (Translated by George Long.)
3. In the sixteenth century and earlier, sulfuric acid was called vitriol, and so the product formed by mixing sulfuric acid with alcohol to create ether was called sweet vitriol, a term that has an undeniable poetic appeal (and would make a great name for a rock band). Different alcohols mixed with sulfuric acid will create different ethers. Ethanol (a 2-carbon alcohol) will form ethyl ether; methanol (1-carbon alcohol, also called wood alcohol) will form methyl ether, and so on. In the Irish ether-drinking epidemic of the nineteenth century, a mixture of methanol and ethanol, called methylated spirits, was used as the starting material for ether production because, unlike pure ethanol, it was not taxed by the British government. When mixed with sulfuric acid, this produced a mixture of methyl and ethyl ethers in an approximate ratio of 1:6.
4. For contemporaneous accounts of ether drinking in Ireland, see H. N. Draper, “On the use of ether as an intoxicant in the north of Ireland,” Medical Press & Circular 9 (1870): 117–18; H. N. Draper, “Ether drinking in the north of Ireland,” Medical Press & Circular 22 (1877): 425–26. Some mostly retrospective reports, written in the waning days of the ether-drinking craze, are E. Hart, “Ether-drinking: its prevalence and results,” British Medical Journal 2 (1890): 885–90; N. Kerr, “Ether inebriety,” Journal of the American Medical Association 17 (1891): 791–94. A brief, modern review of the phenomenon is R. A. Strickland, “Ether drinking in Ireland,” Mayo Clinic Proceedings 71 (1996): 1015.
5. The whole process of handling and drinking ether is extremely dangerous. In 1903, the British Medical Journal reported the following terrible accident in the town of Trosno, near Kaliningrad, in present-day Russia (reprinted in British Medical Journal 326 [2003] 37): “Ether is drunk by farmers on festive occasions, when it appears to be consumed in pailfuls. A farmer celebrating his son’s wedding, in the fullness of his hospitality, got in two pails of ether. During the process of decanting the ether into bottles, a violent explosion took place, by which six children were killed, and one adult was dangerously, and fourteen others more or less severely, injured.”
6. “Ayahuasca” is a word in the Quechua language that has been used to describe this preparation. Quechua is not the original language of any of the peoples of the Amazon basin, who have a number of different names for the drink, including “caapi,” “yagé,” “pildé,” and others. The account of Don Emilio Andrade Gomez is adapted from two papers by Dr. Luis Eduardo Luna: “The healing practices of a Peruvian shaman,” Journal of Ethnopharmacology 11 (1984): 123–33, and “The concept of plants as teachers among four mestizo shamans of Iquitos, northeastern Peru,” Journal of Ethnopharmacology 11 (1984): 135–56.
7. If you’re interested in stoned critters, a good read is Ronald K. Siegel, Intoxication: The Universal Drive for Mind-Altering Substances (Rochester, VT: Park Street Press, 2005).
8. The Amanita mushroom contains both ibotenic acid and muscimol itself in a ratio of about 10:1. Thus when Amanita is eaten, most of the muscimol that enters the brain does not derive from the mushroom directly, but rather from the enzymatic decarboxylation of ibotenic acid in the body. Muscimol and ibotenic acid have very different biochemical effects on neurons. Muscimol activates receptors for the inhibitory neurotransmitter GABA, while ibotenic acid activates receptors for the excitatory neurotransmitter glutamate. However, it’s not clear if this direct action of ibotenic acid on glutamate receptors also contributes to the psychoactive effects produced by the mushroom.
9. You can’t imagine how much self-control it has taken not to insert an elaborate joke about “getting pissed” into the narrative here.
10 Siegel, Intoxication, p. vii.
11. Griffith Edwards, Matters of Substance: Drugs—and Why Everyone’s a User (New York: Thomas Dunne/St. Martin’s Press, 2005), xix.
12. Acetylcholine is a neurotransmitter that acts on two classes of neurotransmitter receptor. Muscarinic acetylcholine receptors are slow-acting, G-protein-linked receptors, while nicotinic receptors (which are, of course, the ones that are activated by nicotine) are fast-acting because they have an ion channel built into their structure. The synthesis of nicotine by the tobacco plant is part of an ongoing evolutionary story of chemical warfare. Insects also use acetylcholine as a neurotransmitter, and many insects that eat tobacco plants are paralyzed from the ingestion of nicotine. Other insects have evolved behaviors or biological strategies to shield the insect nervous system from nicotine action. (The former include only eating the parts of the plant that have low nicotine levels; the latter include the development of enzymes to rapidly break down nicotine in the insect’s body and special cellular sheaths to block nicotine from getting to the neurons.)
13. Ethanol (the common form of alcohol found in alcoholic beverages) has many actions in the brain, and it’s not entirely clear which of these are central to alcoholic intoxication. Within the VTA reward circuit, ethanol has direct actions on GABA-A receptors and other ion channels that underlie the production of the spike. There is also reason to believe that ethanol has other pychoactive functions that are entirely independent of dopamine: Dopamine-blocking drugs (or clever genetic engineering tricks in mice to interfere with dopamine receptors) fail to block either ethanol intoxication or ethanol self-administration.
14. The addiction potential of cannabis is an ongoing debate. The best evidence to date is that it does carry some risk of addiction, perhaps similar to that for alcohol. Cannabis addiction research has been hampered by the fact that the active ingredient, THC, as well as synthetic THC-like molecules, are oily and sticky. This makes them hard to inject into the brains of rats or mice, so we have relatively little data from animal models.
15. It is common to speak of coca leaf “chewing” among some people of the Andes, but this is really a misnomer. The traditional mode of use is to mix the coca leaves with wood ashes to render them more alkaline, a process that aids in extraction of the cocaine. Then a wad of treated leaves is packed between the cheek and gum, where, without active chewing, it can deliver a low, steady dose of cocaine for an hour or two.
16. While tobacco smoking has profound health consequences for the smoker, it involves minimal direct social disruption. For example, unlike heroin addicts, nicotine addicts rarely abandon their children. However, while on a road trip in 1989 I did see a pissed-off mother at a Nebraska truck stop attempt to discipline her rowdy toddlers by blowing cigarette smoke in their faces.
17. The development of the cigarette has played an enormous role in the worldwide spread of nicotine addiction. At the beginning of the nineteenth century, about 60 percent of all tobacco was consumed in the form of snuff (inhaled powdered tobacco), with most of the remainder smoked in pipes or chewed. Cigarettes were hand-rolled creations for most of the nineteenth century, but in 1875 the Allen & Ginter tobacco company offered a prize of $75,000 for a machine to rapidly roll cigarettes. The challenge was taken up by James Bonsack of Roanoke, Virginia, who in 1880 filed a patent for a machine that could roll twelve thousand cigarettes per hour. By 1900 the cigarette had driven snuff to a mere 1 percent of market share and had become the dominant nicotine-dosing device.
18. Thirty years after their initial publication, Lømo and Bliss each wrote brief memoirs about the early days of LTP: T. Lømo, “The discovery of long-term potentiation,” Philosophical Transactions of the Royal Society of London, Series B 358 (2003): 617–20; T.V.P. Bliss, “A journey from neocortex to hippocampus,” Philosophical Transactions of the Royal Society of London, Series B 358 (2003): 621–23.
19. S. Schenk, A. Valadez, C. M. Worley, C. McNamara, “Blockade of the acquisition of cocaine self-administration by the NMDA antagonist MK-801 (dizocilpine),” Behavioral Pharmacology 4 (1993): 652–59.
20. A good review of the literature on long-term changes in the reward circuitry is J. A. Kauer and R. C. Malenka, “Synaptic plasticity and addiction,” Nature Reviews Neuroscience 8 (2007): 844–58.
21. If you enjoy tales of famous historical figures engaging in drugs, drink, and other debauchery, I recommend Paul Martin’s book Sex, Drugs and Chocolate (London: Fourth Estate, 2009).
22. Other complex behavioral traits with a similar degree of heritability (approximately 50 percent), such as childhood shyness or so-called general intelligence, have also not been linked to single genes, and likely reflect polygenic effects.
23. A study conducted by Michael Nader and coworkers at Wake Forest University School of Medicine showed that when cynomolgus monkeys were housed individually, brain scans reveled that they all had similar levels of D2 dopamine receptors in the striatum. However, when twenty of these monkeys were placed together in social housing, species-typical dominance relationships developed. When the social hierarchy was established, the monkeys were rescanned: The dominant monkeys showed a 22 percent increase in D2 receptors, with no significant change in the subordinate monkeys. Later, in a Skinner box, the subordinate monkeys self-administered significantly more cocaine. While development of a social hierarchy isn’t a good analog of human talk therapy, the more general point is illustrated: Social experience can drive changes in the function of the pleasure circuit and in addictive behavior. D. Morgan, K. A. Grant, H. D. Gage, R. H. Mach, J. R. Kaplan, O. Prioleau, S. H. Nader, N. Buchheimer, R. L. Ehrenkaufer, and M. A. Nader, “Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration,” Nature Neuroscience 5 (2002): 169–74.
CHAPTER THREE: FEED ME
1. The head/heart duality is a well-known cultural phenomenon. In everyday speech we use “heart” as a shorthand to refer to our emotional state or our faith and “head” to refer to cognition or reason. Should I follow my head or my heart? Both “head” and “heart,” while they are literally the names of body parts, are commonly used to stand for nonbodily phenomena, for mental processes. But what body part do we use when we want to refer explicitly to our corporeal self? Why the humble “ass,” of course! Consider the seminal gangsta rappers Niggaz with Attitude, who in their classic track “Straight Outta Compton” rhyme: “Niggaz start to mumble / They wanna rumble / Mix ’em and cook ’em in a pot like gumbo / Goin’ off on a motherfucker like that / With a gat that’s pointed at yo ass.” Do the guys in NWA mean to say that a gun is literally pointed downward, at your tuchus? Of course not. We understand that in this context “ass” means “corporeal self.”
2. The hypothalamus is an interesting part of the brain because it has both neural and endocrine functions. It sends signals in both the conventional neural manner, through spikes that propagate down axons and trigger neurotransmitter release in other brain regions, and in an endocrine fashion, by secreting hormones into the bloodstream. These hormones are distributed throughout the body and so can have wide-ranging effects.
3. The gene that is disrupted in the db mouse strain is a bit complicated. Through a process known as mRNA splicing, this one gene actually gives rise to several gene products. They are all members of a family called cytokine receptors. Only one particular splice form, called ObRb, can transduce signals from leptin. While the other products of the db gene are distributed widely in the body, the ObRb splice form is strongly enriched in the feeding centers of the hypothalamus, the VTA, and a few other brain regions. For a good review of the leptin and leptin receptor field, see: J. M. Friedman, “Leptin at 14 years of age: an ongoing story,” American Journal of Clinical Nutrition 89 (2009): 973S–79S.
4. The terms “obese” and “morbidly obese” sound vague and pejorative, but they actually have very particular meanings. Physicians define obesity as a body mass index (BMI) greater than 30 and morbid obesity as a BMI greater than 40. To give you an idea of how this plays out, someone who is five feet nine inches tall would be considered obese at 204 pounds and morbidly obese at 270 pounds.
5. I. S. Farooqi, S. A. Jebb, G. Langmack, E. Lawrence, C. H. Cheetham, A. M. Prentice, I. A. Hughes, M. A. McCamish, and S. O’Rahilly, “Effects of recombinant leptin therapy in a child with congenital leptin deficiency,” New England Journal of Medicine 341 (1999): 879–84; K. Baicy, E. D. London, J. Monterosso, M. L. Wong, T. Delibasi, A. Sharma, and J. Licinio, “Leptin replacement alters brain response to food cues in genetically leptin-deficient adults,” Proceedings of the National Academy of Sciences of the USA 104 (2007): 18276–79.
6. In truth, what we know about the feeding circuit is even more complicated than the stripped-down version I’ve presented here. For example, NPY isn’t the only appetite-stimulating transmitter in the arcuate nucleus (there’s another called AGRP), and POMC isn’t the only appetite-suppressing transmitter (there’s another called CART). Likewise, the lateral hypothalamus doesn’t just secrete orexin to stimulate appetite (it also uses another hormone called MCH), and the paraventricular nucleus doesn’t only secrete CRH to suppress appetite (it also uses TRH and oxytocin).
7. J. D. Hommel, R. Trinko, R. M. Sears, D. Georgescu, Z. W. Liu, X. B. Gao, J. J. Thurmon, M. Marinelli, and R. J. DiLeone, “Leptin receptor signaling in midbrain dopamine neurons regulates feeding,” Neuron 51 (2006): 801–10.
8. I. S. Farooqi, E. Bullmore, J. Keogh, J. Gillard, S. O’Rahilly, and P. C. Fletcher, “Leptin regulates striatal regions and human eating behavior,” Science 317 (2007): 1355.
9. B. M. Geiger, G. G. Behr, L. E. Frank, A. D. Caldera-Siu, M. C. Beinfeld, E. G. Kokkotou, and E. N. Pothos, “Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats,” FASEB Journal 22 (2008): 2740–46.
10. A useful review on the parallels between food addiction and drug addiction is N. D. Volkow and R. A. Wise, “How can drug addiction help us understand obesity?” Nature Neuroscience 8 (2005): 555–60.
11. E. Stice, S. Spoor, C. Bohon, and D. M. Small, “Relation between obesity and blunted striatal response to food is moderated by Taq IA A1 allele,” Science 322 (2008): 449–52.
12. Eric Stice, interview on National Public Radio, October 16, 2008.
13. While there has been a significant increase in the average weight of citizens in the United States (and many other affluent countries) in recent years, one should be cautious of statistics that tout “an x-fold increase in obesity.” It’s not that they have the numbers wrong—it’s just that the definition of obesity is an arbitrary threshold. If your body mass index (BMI) is 29.9, you’re not obese, but if it’s 30.1, you are. So small increases in average weight can push a lot of people over the line, artificially amplifying the trend.
14. There are several indications that people whose ancestors were regularly subjected to cycles of famine have a greater propensity to become obese when allowed access to unlimited calories. A discussion of this and related issues may be found in Michael L. Power and Jay Schulkin, The Evolution of Obesity (Baltimore: Johns Hopkins University Press, 2009).
15. For an excellent discussion of how corporate test kitchens strive to create craveable foods see Dr. David A. Kessler’s book The End of Overeating (New York: Rodale, 2009). Dr. Kessler, a former commissioner of the U.S. Food and Drug Administration, has coined the term “conditioned hypereating” to refer to the repeated, compulsive overeating triggered by “hyperpalatable” foods loaded with fat, salt, and sugar.
16. There are at least six different receptors for the neurotransmitter NPY. However, only two, called NPY1 and NPY5, appear to be involved in stimulation of appetite. Blockers of NPY1 and NPY5 are under investigation as anti-obesity drugs, but it is possible that they might ultimately fail due to side effects on other brain and spinal cord systems in which NPY acts. These include the regulation of blood pressure, pain perception, and insulin secretion.
17. There are different ways in which drugs can produce side effects. One is if the drug is not specific to its molecular target—for example, if rimonabant has effects on neurotransmitter receptors other than CB1. So far, that doesn’t seem to be what’s happening. The problem with rimonabant is probably more fundamental: It’s targeting CB1 specifically, but CB1 is involved in multiple brain systems, including appetite, mood, and nausea. There is one line of hope, however. Rimonabant is a class of CB1-blocker called an inverse agonist. That means it blocks the action of the CB1 receptor in the resting state as well as blocking its action when stimulated by endocannabinoid molecules (or THC in a cannabis smoker). It’s possible that other CB1-blocking drugs that are neutral antagonists may have fewer side effects because they do not block the signaling of CB1 in the resting state. If you’re interested in the pharmacological details of CB1-acting anti-obesity drugs and the prospects for their further development, you may wish to read the following: D. R. Janero and A. Markiyannis, “Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis,” Expert Opinion on Emerging Drugs 14 (2009): 43–65.
18. While application of leptin alone has had little success in treating obesity, there are some early indications that combination therapy using leptin together with the pancreatic hormone amylin can be useful. In one study, long-term leptin/amylin combination therapy produced a mean weight loss of about 13 percent in obese subjects. This might work because amylin somehow restores leptin responsiveness to the neurons of the hypothalamus.
19. The social rank in small groups of female macaques is not typically enforced by physical violence. Harassment and the threat of physical aggression are sufficient, kind of like middle school. This study is a fascinating read: M. E. Wilson, J. Fisher, A. Fischer, V. Lee, R. B. Harris, and T. J. Bartness, “Quantifying food intake in socially housed monkeys: social status effects on caloric consumption,” Physiology & Behavior 94 (2008): 586–94.
20. D. Saal, Y. Dong, A. Bonci, and R. C. Malenka, “Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons,” Neuron 37 (2003): 577–82.
21. J. Hahn, F. W. Hopf, and A. Bonci, “Chronic cocaine enhances corticotropin-releasing factor-dependent potentiation of excitatory transmission in ventral tegmental area dopamine neurons,” Journal of Neuroscience 29 (2009): 6535–44.
22. P. M. Johnson and P. J. Kenny, “Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats,” Nature Neuroscience 13 (2010): 635–41. For a useful summary and critique of Johnson and Kenny’s paper see D. H. Epstein and Y. Shaham, “Cheesecake-eating rats and the question of food addiction,” Nature Neuroscience 13 (2010): 529–31.
CHAPTER FOUR: YOUR SEXY BRAIN
1. Orangutans appear to be the runners-up in the long-childhood competition, leaving their mothers at six to eight years of age. However, orangutan dads are solitary creatures and are totally out of the picture in terms of child-rearing.
2. The list of masturbating animals goes on and on: Vampire bats self-stimulate with their feet, walruses with their flippers, kangaroos with their front paws, and savanna baboons with their tails. Let’s face it, for both males and females, nature is a huge wank-fest.
3. I refuse to make the obligatory “blowjob” joke here. Science writing is very serious business. And returning to this serious business, a central evolutionary question arises: Why would animals engage in sexual behaviors that don’t, at least directly, result in offspring? This question has been addressed in a clearly written recent review article: N. W. Bailey and M. Zuk, “Same-sex sexual behavior and evolution,” Trends in Ecology and Evolution 24 (2009): 439–46. Bailey and Zuk examine the scientific literature and propose a set of potential explanations of same-sex sexual behavior (which are not mutually exclusive). These include adaptive explanations, such as social glue (in which this behavior reduces tensions, forms alliances, and promotes social cohesion), practice (in which immature individuals learn courtship or mating skills), and kin selection (in which individuals that engage in same-sex sexual behavior provide resources to their siblings or their siblings’ offspring: the doting aunt or uncle effect). Possible nonadaptive explanations include mistaken identity (in which individuals cannot reliably distinguish males from females) and hypersexuality (in which same-sex sexual behavior arises as a by-product when selection acts on a separate but related trait, such as high sexual drive or high sexual responsiveness).
4. The story of the male penguin couple and the female chick they hatched has been made into a lovely children’s book, And Tango Makes Three, by Justin Richardson and Peter Parnell, illustrated by Henry Cole (New York: Simon & Schuster, 2005). There is also a notable example of long-term female pair-bonding in a wild population. Laysan albatrosses are large seabirds that have established breeding colonies in the Hawaiian Islands. It has recently emerged that about one-third of the breeding pairs in the Oahu colony are two-female situations. These pairs stay together for several years and engage in mutual grooming and copulation. Each typically mates with a male and lays a single egg. But one of these is rolled out of the nest, leaving the other, which hatches to yield the chick the female couple will raise together. To read all about it, see L. C. Young, B. J. Zaun, and E. A. VanderWerf, “Successful same-sex pairing in Laysan albatross,” Biology Letters 4 (2008): 323–25.
5. C. W. Moeliker, “The first case of homosexual necrophilia in the mallard Anas platyrhynchos (Aves:Anatidae),” DEINSEA 8 (2001): 243–47.
6. Of course, just because the idea of romantic love exists in a culture, that doesn’t mean that it is the main driver of mate selection. There are many cultures where the idea of romantic love is prevalent but is rarely allowed to flourish, as this would subvert existing (male-dominated) religious and social power structures.
7. Psychologists have devised a fifteen-point standardized test called the Passionate Love Scale, or PLS, to quantify these feelings. It contains statements like “I want _________ physically, emotionally, mentally,” “Sometimes I can’t control my thoughts; they are obsessively on _________,” and “I sense my body responding when _________ touches me.” The subjects are asked to rank these statements on a nine-point scale from “not true at all” to “definitely true.” You can take the test yourself at http://www.prenhall.com/divisions/hss/app/social/chap10_1.html.
8. From the point of the view of the brain scanner, falling in love is not unlike getting high on heroin, cocaine, or amphetamines (thereby validating the premise of a large number of pop songs). Interestingly, lover’s-face viewing activated mostly the pleasure circuit on the right side of the brain, while euphoric drugs work on both sides. An unexpected region of activation by love stimuli was the cerebellar deep nuclei, which are involved mostly in the control of motion and motor learning. The work of Brown and coworkers has been reported in A. Aron, H. Fisher, D. J. Mashek, G. Strong, H. Li, and L. L. Brown, “Reward, motivation, and emotion systems associated with early-stage intense romantic love,” Journal of Neurophysiology 94 (2005): 327–37. This work built upon an earlier study: A. Bartels and S. Zeki, “The neural basis of romantic love,” Neuroreport 11 (2000): 3829–34. Here I have combined the results of the two studies, which are mostly in agreement.
9. At the time of this writing, these results had not yet been published, but had been communicated informally by Dr. Brown in an online interview at the American Physiological Society. Please see http://www.the-aps.org/press/releases/09/4.htm.
10. This design, in which subjects are prescreened to respond similarly to sexual images, has both advantages and disadvantages. One advantage is that this design controls for average differences in arousal to visual stimuli between men and women. The downside is that the population of women is not entirely representative: It is biased toward those women who are more like men in terms of their response to explicit sexual images. Another issue: On average, are men and women thinking similar thoughts when viewing couple-sex images? Might women be imagining participation to a greater degree? The paper is an interesting read: S. Hamann, R. A. Herman, C. L. Nolan, and K. Wallen, “Men and women differ in amygdala response to visual sexual stimuli,” Nature Neuroscience 7 (2004): 411–16.
11. Presumably the sports controls were designed to avoid homoerotic content: no images of beefy football players patting each other on the ass. A. Safron, B. Barch, J. M. Bailey, D. R. Gitelman, T. B. Parrish, and P. J. Reber, “Neural correlates of sexual arousal in homosexual and heterosexual men,” Behavioral Neuroscience 121 (2007): 237–48.
12. The study using the photos of genitals as stimuli was J. Ponseti, H. A. Bosinski, S. Wolff, M. Peller, O. Jansen, H. M. Mehdorn, C. Büchel, and H. R. Siebner, “A functional endophenotype for sexual orientation in humans,” NeuroImage 33 (2006): 825–33.
13. To my knowledge, this was the first study that combined brain scanning with a measure of genital status. See B. A. Arnow, J. E. Desmond, L. L. Banner, G. H. Glover, A. Solomon, M. L. Polan, T. F. Lue, and S. W. Atlas, “Brain activation and sexual arousal in healthy, heterosexual males,” Brain 125 (2002): 1014–23.
14. Here I’m combining the results of three different studies: M. L. Chivers, G. Rieger, E. Latty, and J. M. Bailey, “A sex difference in the specificity of sexual arousal,” Psychological Science 15 (2004): 736–44; M. L. Chivers and J. M. Bailey, “A sex difference in features that elicit genital response,” Biological Psychology 70 (2005): 115–20; M. L. Chivers, M. C. Seto, and R. Blanchard, “Gender and sexual orientation differences in sexual response to sexual activities versus gender of actors in sexual films,” Journal of Personality and Social Psychology 93 (2007): 1108–21. If you’re like me, you’re probably wondering about the particular content of the videos used in these studies. This is not merely prurient interest. One could imagine that responses to female-female cunnilingus might be different from those to female-female vaginal penetration, for example. Here’s the exact description from Chivers et al. (2007):
The experimental stimuli consisted of 18 film clips that were 90 seconds and that were presented with sound, representing nine stimulus categories: control (landscapes accompanied by relaxing music), nonhuman sexual activity (bonobos or Pan paniscus mating), female nonsexual activity (nude exercise), female masturbation, female-female intercourse (cunnilingus and vaginal penetration with a strap-on dildo), male nonsexual activity (nude exercise), male masturbation, male-male intercourse (fellatio and anal intercourse), and female-male copulation (cunnilingus and penile-vaginal intercourse). Participants saw two exemplars of each stimulus category. All of these clips were excerpted from commercially available films.
15. In this study, sexual orientation was assessed by self-report using the Kinsey sexual attraction scale, which uses questions about past sexual behavior to classify respondents along a continuous scale from completely homosexual (score 6) to completely heterosexual (score 0), with gradations in between. The study was G. Rieger, M. L. Chivers, and J. M. Bailey, “Sexual arousal patterns of bisexual men,” Psychological Science 16 (2005): 579–84.
16. R. J. Levin and W. van Berlo, “Sexual arousal and orgasm in subjects who experience forced or non-consensual sexual stimulation—a review,” Journal of Clinical Forensic Medicine 11 (2004): 82–88. The conclusion of this review is that neither vaginal lubrication nor orgasm during rape should be taken as an indication of either a woman’s feelings of arousal or her consent.
17. This study has important implications for the development of drugs to treat low sex drive in women: The genital vascular response appears to function normally, and so the relevant drug targets are more likely to be in the brain than in the genitals. E. Laan, E. M. van Driel, and R. H. van Lunsen, “Genital responsiveness in healthy women with and without sexual arousal disorder,” Journal of Sexual Medicine 5 (2008): 1424–35.
18. In one study, women with complete spinal cord lesions achieved orgasm through vaginal/cervical stimulation while in a brain scanner. The pattern of brain activation indicates that the signals from genital stimulation were conveyed to the brain via the vagus nerve, which exits through the brain stem and is therefore not affected by spinal cord damage. B. R. Komisaruk and B. Whipple, “Functional MRI of the brain during orgasm in women,” Annual Review of Sex Research 16 (2005): 62–86.
19. As someone who has always enjoyed accounts of alien abduction, I can’t tell you how much satisfaction I’m getting by typing the words “rectal probe.” For an insightful analysis of the alien abduction phenomenon, I highly recommend Susan A. Clancy, Abducted: How People Come to Believe They Were Kidnapped by Aliens (Cambridge: Harvard University Press, 2005).
20. All this makes you wonder what’s going on in the mind of the subject. Either she’s got to be deep into a faraway fantasy to block out all the unsexy medical stuff, or she’s volunteered for this study precisely because she is excited by the rectal probe, the intravenous lines, and the other medical and scientific trappings.
21. Results from several studies are being combined in this account: J. R. Georgiadis, R. Kortekaas, R. Kuipers, A. Nieuwenburg, J. Pruim, A. A. Reinders, and G. Holstege, “Regional cerebral blood flow changes associated with clitorally induced orgasm in healthy women,” European Journal of Neuroscience 24 (2006): 3305–16; J. R. Georgiadis, A. A. Reinders, A. M. Paans, R. Renken, and R. Kortekaas, “Men versus women on sexual brain function: prominent differences during tactile genital stimulation, but not during orgasm,” Human Brain Mapping 30 (2009): 3089–101; J. R. Georgiadis, A. A. Reinders, F. H. Van der Graaf, A. M. Paans, and R. Kortekaas, “Brain activation during human male ejaculation revisited,” Neuroreport 18 (2007): 553–57.
22. Interestingly, all of the various groups of judges were equally clueless. Women were no better than men, gynecologists were no better than psychologists, etc. See E. B. Vance and N. N. Wagner, “Written descriptions of orgasm: a study of sex differences,” Archives of Sexual Behavior 5 (1976): 87–98.
23. Another class of popular drugs that suppress orgasm are the SSRI antidepressants. Indeed, activation of serotonin receptors, particularly the 5HT-2 subtype, has a powerful orgasm-suppressing and libido-dampening effect (an observation that has led to off-label prescribing of SSRIs for premature ejaculation). Conversely, drugs that have the opposite action, reducing serotonin release or blocking 5HT-2 receptors, stimulate libido and orgasm. How activation of 5-HT2 receptors leads to attenuated orgasm and libido is not entirely clear. One hypothesis has been that serotonin exerts a chronic dampening effect on sexual function through attenuation of dopamine release. However, this is just a hypothesis—it’s not even clear that all of the sexual side effects of SSRIs are due to their actions on serotonin levels. It has been suggested that vaginal dryness and dysfunction of penile erection that can result from SSRIs may result from a side effect on a different neurotransmitter acting in the genital tissues, called nitric oxide. One strategy that some psychiatrists are using to mitigate the sexual side effects of SSRIs is to combine them with the dopamine-boosting drug bupropion (sold as Wellbutrin and Zyban). Another is to combine SSRIs with a 5HT2-receptor-blocking drug called trazodone. This still allows serotonin to act on other types of serotonin receptors to relieve depression. To read more on this topic, see S. H. Kennedy and S. Rizvi, “Sexual dysfunction, depression, and the impact of antidepressants,” Journal of Clinical Psychopharmacology 29 (2009): 157–64. If you just can’t get enough information about orgasm, you may also want to read this book: Barry R. Komisaruk, Carlos Beyer-Flores, and Beverly Whipple, The Science of Orgasm (Baltimore: Johns Hopkins University Press, 2006).
24. There’s a clearheaded and compassionate examination of sex addiction in Benoit Denizet-Lewis’s America Anonymous: Eight Addicts in Search of a Life (New York: Simon & Schuster, 2009). This book follows a range of recovering addicts of different backgrounds, ages, and circumstances as they struggle with their addictions to sex, drugs, alcohol, and shoplifting.
25. T. Baumgartner, M. Heinrichs, A. Vonlanthen, U. Fischbacher, and E. Fehr, “Oxytocin shapes the neural circuitry of trust and trust adaptation in humans,” Neuron 58 (2008): 639–50; M. Kosfeld, M. Heinrichs, P. J. Zak, U. Fischbacher, and E. Fehr, “Oxytocin increases trust in humans,” Nature 435 (2005): 673–76; G. Domes, M. Heinrichs, A. Michel, C. Berger, and S. C. Herpertz, “Oxytocin improves ‘mind-reading’ in humans,” Biological Psychiatry 61 (2007): 731–33.
26. For an interesting review of this field and a discussion of the prospects of certain neurohormone therapies for various personality disorders, see M. Heinrichs, B. von Dawans, and G. Domes, “Oxytocin, vasopressin, and human social behavior,” Frontiers in Neuroendocrinology 30 (2009): 548–57.
27. M. M. Lim, Z. Wang, D. E. Olazábal, X. Ren, E. F. Terwilliger, and L. J. Young, “Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene,” Nature 429 (2004): 754–57; M. M. Lim and L. J. Young, “Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole,” Neuroscience 125 (2004): 35–45.
28. B. J. Aragona, Y. Liu, Y. J. Yu, J. T. Curtis, J. M. Detwiler, T. R. Insel, and Z. Wang, “Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds,” Nature Neuroscience 9 (2005): 133–39; J. T. Curtis, Y. Liu, B. J. Aragona, and Z. Wang, “Dopamine and monogamy,” Brain Research 1126 (2006): 76–90.
29. Oxytocin may have a social behavior role in males as well: Both male and female mice in which the oxytocin gene has been deleted do not appear to form social memories of other mice they have encountered previously (they sniff their butts just as assiduously as they would a newly introduced mouse). For a review of oxytocin and pair-bond formation see H. E. Ross and L. J. Young, “Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior,” Frontiers in Neuroendocrinology 30 (2009): 543–47.
CHAPTER FIVE: GAMBLING AND OTHER MODERN COMPULSIONS
1. Susan Cheever, Desire: Where Sex Meets Addiction (New York: Simon & Schuster, 2008), 14–15. Cheever’s book is a terrific read, artfully blending stories from her life with information gleaned from interviews with addiction experts ranging from biologists to psychotherapists.
2. The overall rate of gambling addiction has been assessed in many surveys in countries including the United Kingdom, Italy, New Zealand, Sweden, Switzerland, Canada, and the United States. These are complicated by the usual problems involving truthful and complete responses. In addition, some gambling researchers use the term “problem gambling” to refer to a less severe form and “pathological gambling” for a more severe form. Nonetheless, it seems that about 1 to 2 percent of the population in these affluent countries are gambling addicts. A useful meta-analysis of surveys of compulsive gambling is S. Stucki and M. Rihs-Middel, “Prevalence of adult problem and pathological gambling between 2000 and 2005: an update,” Journal of Gambling Studies 23 (2007): 245–57. A recent telephone survey of fourteen-to twenty-one-year-olds in the United States yielded a compulsive gambling rate of about 2 percent, similar to that seen in adults: J. W. Welte, G. M. Barnes, M. O. Tidwell, and J. H. Hoffman, “The prevalence of problem gambling among U.S. adolescents and young adults: results from a national survey,” Journal of Gambling Studies 24 (2008): 119–33.
3. Bill Lee, Born to Lose: Memoirs of a Compulsive Gambler (Center City, Minn.: Hazelden, 2005).
4. Ibid., 71.
5. Ibid., 145.
6. Two reviews that discuss the genetics of compulsive gambling are N. M. Petry, “Gambling and substance-use disorders: current status and future directions,” American Journal on Addictions 16 (2007): 1–9; D. S. Lobo and J. L. Kennedy, “The genetics of gambling and behavioral addictions,” CNS Spectrums 11 (2006): 931–39.
7. Genetic variants that attenuate serotonin signaling have also been implicated in compulsive gambling and ADHD. These include the genes involved in serotonin synthesis (the enzyme tryptophan hydroxylase), serotonin transport, and the enzymatic breakdown of serotonin and other transmitters (monoamine oxidase type A).
8. R. M. Stewart and R. I. Brown, “An outcome study of Gamblers Anonymous,” British Journal of Psychiatry 152 (1988): 284–88.
9. O. Kausch, “Suicide attempts among veterans seeking treatment for pathological gambling,” Journal of Clinical Psychiatry 64 (2003): 1031–38.
10. In recent years there has been a slew of general-interest books examining the psychology and neurobiology of human decision-making, what has come to be called neuroeconomics. These include Dan Ariely, Predictably Irrational: The Hidden Forces That Shape Our Decisions (New York: HarperCollins, 2008), and Jonah Lehrer, How We Decide (New York: Houghton Mifflin, 2009). While pleasure circuits in the brain are central to decision-making, I’m going to resist the temptation to go much deeper into this material, given the extensive coverage it has already received. If you’ve enjoyed one or more of these neuroeconomics books and want to delve more deeply into some of the neurobiology and computational theory underlying this topic, I highly recommend Read Montague, Why Choose This Book? How We Make Decisions (New York: Dutton, 2006).
11. In these experiments, recordings were made from both dopamine neurons in the VTA and dopamine neurons in a nearby region called the substantia nigra. The visual signals used by these experimenters were not red, green, and blue lights. They were actually unique geometric patterns. I’ve just used colors for ease of description. The original, now classic papers are J. R. Hollerman and W. Schultz, “Dopamine neurons report an error in the temporal prediction of reward during learning,” Nature Neuroscience 1 (1998): 304–9; C. D. Fiorillo, P. N. Tobler, and W. Schultz, “Discrete coding of reward probability and uncertainty by dopamine neurons,” Science 299 (2003): 1898–902. A more recent and comprehensive review of this topic is W. Schultz, “Multiple dopamine functions at different time courses,” Annual Review of Neuroscience 30 (2007): 259–88.
12. The paper discussed here is H. C. Breiter, I. Aharon, D. Kahneman, A. Dale, and P. Shizgal, “Functional imaging of neural responses to expectancy and experience of monetary gains and losses,” Neuron 30 (2001): 619–39. A similar study is B. Knutson, C. M. Adams, G. W. Fong, and D. Hommer, “Anticipation of increasing monetary reward selectively recruits nucleus accumbens,” Journal of Neuroscience 21 (2001): RC159 (1–5). When comparing the human brain scanner results with microelectrode recordings in monkeys, it should be cautioned that these measures are related but not equivalent. The microelectrode records the spiking activity of individual dopamine neurons in the VTA. The brain scanner is measuring slower changes in blood oxygenation that indirectly indicate the activity of large groups of neurons of many different types in an entire brain region. Microelectrodes have about two thousand times better temporal resolution and about one hundred times better spatial resolution than the brain scanners used in these studies.
13. B. A. Mellers, A. Schwartz, K. Ho, and I. Ritov, “Decision affect theory: emotional reactions to the outcomes of risky option,” Psychological Science 8 (1997): 423–29.
14. J. I. Kassinove and M. L. Schare, “Effects of the ‘near miss’ and the ‘big win’ on persistence at slot machine gambling,” Psychology of Addictive Behaviors 15 (2001): 155–58.
15. K. A. Harrigan, “Slot machine structural characteristics: creating near misses using high award symbol ratios,” International Journal of Mental Health and Addiction 6 (2008): 353–68. This study examines a 1989 ruling in which a video slot machine manufacturer was found in violation of Nevada Gaming Commission regulations by programming its terminals to display near misses on the payline in excess of chance levels. Video slot machines also display one row of symbols above and another below the payline, and interestingly, the ruling allowed the continuation of the “virtual reel mapping” technique that employs a different kind of near miss using these rows adjacent to the payline. For example, the payline might display a cherry, a gold bar, and an apple, but the row above the payline would show three plums. This alternate type of near miss also promotes continued gambling.
16. A classic paper relied upon fieldwork conducted at late-night craps games held by off-duty taxi drivers in St. Louis in the 1960s: J. M. Henslin, “Craps and magic,” American Journal of Sociology 73 (1967): 316–30.
17. L. Clark, A. J. Lawrence, F. Astley-Jones, and N. Gray, “Gambling near-misses enhance motivation to gamble and recruit win-related brain circuitry,” Neuron 61 (2009): 481–90.
18. The subjects in this study were all men (and almost all of them were tobacco smokers): J. Reuter, T. Raedler, M. Rose, I. Hand, J. Gläscher, and C. Büchel, “Pathological gambling is linked to reduced activation of the mesolimbic reward system,” Nature Neuroscience 8 (2005): 147–48.
19. F. Hoeft, C. L. Watson, S. R. Kesler, K. E. Bettinger, and A. L. Reiss, “Gender differences in the mesocorticolimbic system during computer game-play,” Journal of Psychiatric Research 42 (2008): 253–58.
20. M. J. Koepp, R. N. Gunn, A. D. Lawrence, V. J. Cunningham, A. Dagher, T. Jones, D. J. Brooks, C. J. Bench, and P. M. Grasby, “Evidence for striatal dopamine release during a video game,” Nature 393 (1998): 266–68.
21. You can see an “Internet Addiction Test,” developed by Dr. Kimberly Young, at http://www.netaddiction.com/resources/internet_addiction_test.htm. It has questions like “How often do you lose sleep to late-night log-ins?” There is a large literature in which surveys and interviews are used to assess presumed addiction to video games and various aspects of Internet use. Here is an early example: M. D. Griffiths and N. Hunt, “Dependence on computer games by adolescents,” Psychological Reports 82 (1998): 475–80. Unfortunately, much of this work is a mess. I must agree with the authors of a recent meta-analysis: S. Byun, C. Ruffini, J. E. Mills, A. C. Douglas, M. Niang, S. Stepchenkova, S. K. Lee, J. Loutfi, J. K. Lee, M. Atallah, and M. Blanton, “Internet addiction: metasynthesis of 1996–2006 quantitative research,” CyberPsychology & Behavior 12 (2009): 203–7. On page 203 they write, “The analysis showed that previous studies have utilized inconsistent criteria to define Internet addicts, applied recruiting methods that may cause serious sampling bias and examined data using primarily exploratory rather than confirmatory data analysis techniques.”
22. Vaughn Bell, writing on the Mind Hacks website, bemoaned an overly simple model of dopamine and pleasure. In so doing, he coined the splendid phrase “four dopamen of the neurocalypse”: “My other pet hate is when something pleasurable is described as having the same effect on the brain as one of the four dopamen of the neurocalypse: ‘drugs,’ ‘sex,’ ‘gambling’ and ‘chocolate.’ Almost any one is used to explain the effect of the others, and if you’re really lucky, all four will be invoked to make for an exciting-sounding but often scientifically empty article.” http://www.mindhacks.com/blog/2008/02/push_my_brain_button/. This quotation is reproduced here according to the terms of the Creative Commons Attribution License, version 2. 0.
CHAPTER SIX: VIRTUOUS PLEASURES (AND A LITTLE PAIN)
1. Jeff Tweedy interview by Jason Crock, http://pitchfork.com/features/interviews/6602-wilco/, posted May 7, 2007.
2. There is a large number of survey-based studies of exercise addiction. One example is V. V. MacLaren and L. A. Best, “Symptoms of exercise dependence and physical activity in students,” Perceptual and Motor Skills 105 (2007): 1257–64. Not surprisingly, there is also a high rate of exercise addiction among people with body-image-based eating disorders, such as anorexia and bulimia.
3. There is a large body of literature on long-term effects of exercise on the brain and on mental function. A nice recent review that also discusses potential neural synergies between exercise and certain aspects of diet is H. van Praag, “Exercise and the brain: something to chew on,” Trends in Neuroscience 32 (2009): 283–90.
4. S. Brené, A. Bjørnebekk, E. Åberg, A. A. Mathé, L. Olson, and M. Werme, “Running is rewarding and antidepressive,” Physiology & Behavior 92 (2007): 136–40; K. F. Koltyn, “Analgesia following exercise,” Sports Medicine 29 (2000): 85–98.
5. H. Boecker, T. Sprenger, M. E. Spilker, G. Henriksen, M. Koppenhoefer, K. J. Wagner, M. Valet, A. Berthele, and T. R. Tolle, “The runner’s high: opioidergic mechanisms in the human brain,” Cerebral Cortex 18 (2008): 2523–31.
6. A. Dietrich and W. F. McDaniel, “Endocannabinoids and exercise,” British Journal of Sports Medicine 38 (2004): 536–41.
7. W. M. Wilson and C. A. Marsden, “Extracellular dopamine in the nucleus accumbens of the rat during treadmill running,” Acta Physiologica Scandanavica 155 (1995): 465–66; I. H. Iversen, “Techniques for establishing schedules with wheel running as reinforcement in rats,” Journal of the Experimental Analysis of Behavior 60 (1993): 219–38.
8. G. J. Wang, N. D. Volkow, J. S. Fowler, D. Franceschi, J. Logan, N. R. Pappas, C. T. Wong, and N. Netusil, “PET studies of the effects of aerobic exercise on human striatal dopamine release,” Journal of Nuclear Medicine 41 (2000): 1352–56.
9. Jeremy Bentham, An Introduction to the Principles of Morals and Legislation (1789; rev. 1823; reprint, Oxford: Clarendon Press, 1907), 1.
10. I know it looks cheesy to cite your own work, but in this case I’m going to do it anyway. For a useful discussion of emotional versus sensory/discriminative pain circuits in the brain see David J. Linden, The Accidental Mind: How Brain Evolution Has Given Us Love, Memory, Dreams, and God (Cambridge, Mass.: Belknap Press of the Harvard University Press, 2007), 100–104.
11. Like a number of other studies we have discussed, this experiment used radioactive raclopride as a tracer, a drug that selectively binds D2-type dopamine receptors. D. J. Scott, M. M. Heitzeg, R. A. Koeppe, C. S. Stohler, and J. K. Zubieta, “Variations in the human pain stress experience mediated by ventral and dorsal basal ganglia dopamine activity,” Journal of Neuroscience 26 (2006): 10789–95.
12. F. Brischoux, S. Chakraborty, D. I. Brierley, and M. A. Ungless, “Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli,” Proceedings of the National Academy of Sciences of the USA 106 (2009): 4894–99.
13. You may recall that this is similar to the previously discussed response of dopamine neurons to the absence of an expected reward in Schultz’s experiments, trials in a well-trained monkey with a green light followed by no syrup droplet (Figure 5.1).
14. Shanida Nataraja, The Blissful Brain: Neuroscience and Proof of the Power of Meditation (London: Gaia, 2008), 18–19. The text in parentheses is my own commentary.
15. This quote is from an interview of Richard Davidson by Bonnie J. Horrigan. It appeared in Explore 1 (2005), 380–388.
16. Dögen Kigen, the twelfth-century patriarch of the Soto Zen school in Japan, outlined the practice of zazen (seated meditation) as follows: “Think of neither good nor evil and judge not right or wrong. Stop the operation of the mind and consciousness; bring to an end all desires, all concepts and judgments. . . . If a thought arises, take note of it and then dismiss it. When you forget all attachments steadfastly, you will naturally become zazen itself.” From the text Fukan Zazengi, quoted in Hee-Jin Kim, Eihei Dogen: Mystical Realist (London: Wisdom Publications, 2004).
17. There is a substantial literature on brain measurements during meditation, most of it performed using the electroencephalograph (EEG), before the advent of brain scanners. A nice review of the literature through 2006 may be found in B. R. Cahn and J. Polich, “Meditation states and traits: EEG, ERP and neuroimaging studies,” Psychological Bulletin 132 (2006): 180–211. Two exemplars from the meditation and brain scanning literature are S. W. Lazar, G. Bush, R. L. Gollub, G. L. Frichione, G. Khalsa, and H. Benson, “Functional brain mapping of the relaxation response and meditation,” NeuroReport 11 (2000): 1581–85; G. Pagnoni, M. Cekic, and Y. Guo, “‘Thinking about not-thinking’: neural correlates of conceptual processing during Zen meditation,” PLoS ONE 3 (2008): e3083.
18. J. A. Brefczynski-Lewis, A. Lutz, H. S. Schaefer, D. B. Levinson, and R. J. Davidson, “Neural correlates of attentional expertise in long-term meditation practitioners,” Proceedings of the National Academy of Sciences of the USA 104 (2007): 11483–88.
19. T. W. Kjaer, C. Bertelsen, P. Piccini, D. Brooks, J. Alving, and H. C. Lou, “Increased dopamine tone during meditation-induced change of consciousness,” Cognitive Brain Research 13 (2002): 255–59.
20. Mario Beauregard and Denyse O’Leary, The Spiritual Brain: A Neuroscientist’s Case for the Existence of the Soul (New York: HarperCollins, 2007). If you would like to read the key paper that underlies this book, it’s M. Beauregard and V. Paquette, “Neural correlates of a mystical experience in Carmelite nuns,” Neuroscience Letters 405 (2006): 186–90. Be forewarned that, in my view, this paper is written in an unclear fashion. The abstract reads, “The brain activity of Carmelite nuns was measured while they were subjectively in a state of union with God.” Nonsense. As the authors reveal in their methods section, the truth is more like “The brain activity of Carmelite nuns was measured while they attempted to recall a long-past experience in which they were subjectively in a state of union with God.” There is likely to be a very big difference between these two conditions.
21. Beauregard and O’Leary, The Spiritual Brain, 276.
22. The paper I discuss is W. T. Harbaugh, U. Mayr, and D. R. Burghart, “Neural responses to taxation and voluntary giving reveal motives for charitable donations,” Science 316 (2007): 1622–25. It built upon earlier work, showing activation of both the VTA and the nucleus accumbens by anonymous charitable giving: J. Moll, F. Krueger, R. Zahn, M. Pardini, R. de Oliveira-Souza, and J. Grafman, “Human fronto-mesolimbic networks guide decisions about charitable donation,” Proceedings of the National Academy of Sciences of the USA 103 (2006): 15623–28. Not surprisingly, these experiments have generated all sorts of political discussion. Writing in the Times Online (UK), Terence Kealey says, “First, it disproves the Left’s belief that only the state will succour the poor…. Secondly, of course, it disproves the Right’s belief that taxes are unpopular.” Oy. http://www.timesonline.co.uk/tol/comment/columnists/guest_contributors/article2204111.ece.
23. I’m not a scholar of philosophy, but it’s worth noting that motivations for prosocial behavior have been a topic of intense interest in this field. Kant, for example, wrote that acts driven by feelings of sympathy were not truly altruistic, and were thereby undeserving of praise, because they made the actor feel good. Brain scanning studies of the brain’s pleasure circuit suggest that this is a very tough standard to meet.
24. K. Izuma, D. N. Saito, and N. Sadato, “Processing of social and monetary rewards in the human striatum,” Neuron 58 (2008): 284–94. These authors used a clever control experiment to address the concern that merely seeing positive words was rewarding. They showed the subjects images in which the terms were applied to a fictitious third party, whose image was presented on the video screen. These positive terms failed to activate the reward circuit. There is also a recurring caveat that should be sounded about the interpretation that monetary and social reward activate the same circuit. Of course, these are low-resolution brain imaging studies, and we don’t yet know that these two forms of reward activate the exact same neurons. It is formally possible that there are two different circuits in the nucleus accumbens for these two different forms of reward and they are separate when analyzed at the level of individual cells.
25. K. Fleissbach, B. Weber, P. Trautner, T. Dohmen, U. Sunde, C. E. Elger, and A. Falk, “Social comparison affects reward-related brain activity in the human ventral striatum,” Science 318 (2007): 1305–8.
26. Exodus 20:17, paraphrased a bit.
27. E. S. Bromberg-Martin and O. Hikosaka, “Midbrain dopamine neurons signal preference for advance information about upcoming rewards,” Neuron 63 (2009): 119–26.
28. Read Montague’s theory of how ideas can engage the pleasure/reward circuit in the human brain and thereby cause all kinds of things to happen in human behavior and culture is laid out in his Why Choose This Book? How We Make Decisions (New York: Dutton, 2006). Confusingly, this book has been republished in paperback with a different title: Your Brain Is (Almost) Perfect: How We Make Decisions (New York: Plume, 2007).
29. While we are imagining that this association is created by strengthening excitatory synapses that drive the VTA, there are other possibilities as well. Perhaps, for example, there are inhibitory synapses received by VTA dopamine cells that are undergoing LTD. Alternatively, there might be changes in the spike-generating machinery (voltage-sensitive ion channels) of the VTA dopamine neuron that allow it to respond with more spikes to a green-light-driven synaptic input.
CHAPTER SEVEN: THE FUTURE OF PLEASURE
1. Ray Kurzweil, The Singularity Is Near (New York: Viking Penguin, 2005), 163–67.
2. Ray Kurzweil interview in GOOD magazine, http://www.good.is/post/going-down-the-rabbit-hole/, posted April 7, 2009.
3. Kurzweil, The Singularity Is Near, 198–203.
4. Here’s an example from my own lab. We study cellular and molecular processes underlying memory storage in the cerebellum, a part of the brain involved in motor control and motor learning. Together with the labs of our colleagues David Ginty and Paul Worley, we have evidence suggesting that a protein called serum response factor, or SRF, is required for the transition from short-term to long-term memory. If we want to interfere with SRF function to test this hypothesis, we can just look up the sequence of the SRF gene in the mouse genome database and design an RNA probe to block its function. We can then coat the probe on a tiny gold particle and blast it into a mouse neuron using compressed nitrogen gas. Having the mouse genome sequence doesn’t give us a “Eureka!” moment just by looking at the SRF gene sequence, but it is a very useful tool.
5. Kudos to philanthropists Paul G. Allen and Jody Allen Patton, who have provided the initial funding for this project at the Allen Institute for Brain Science. You can see the images at http://www.brain-map.org.
6. M. J. Frank, B. B. Doll, J. Oas-Terpstra, and F. Moreno, “Prefrontal and striatal dopaminergic genes predict individual differences in exploration and exploitation,” Nature Neuroscience 12 (2009): 1062–68; J.-C. Dreher, P. Kohn, B. Kolachana, D. Weinberger, and K. F. Berman, “Variation in dopamine genes influences responsivity of the human reward system,” Proceedings of the National Academy of Sciences of the USA 106 (2009): 617–22.
7. J. V. Becker and V. L. Quinsey, “Assessing suspected child molesters,” Child Abuse & Neglect 17 (1993): 169–74.
8. In this study, the pedophile and nonpedophile populations were matched for age and socioeconomic status: B. Schiffer, T. Krueger, T. Paul, A. de Greiff, M. Forsting, N. Leygraf, M. Schedlowski, and E. Gizewski, “Brain response to visual stimuli in homosexual pedophiles,” Journal of Psychiatry and Neuroscience 33 (2008): 23–33.
9. The effects of drinking alcohol while on Antabuse are similar to the intense flushing reaction experienced by those who harbor a deletion of one or both copies of their alcohol dehydrogenase type 2 gene. This deletion is particularly common among East Asians and Native Americans.
10. F. M. Orson, B. M. Kinsey, R.A.K. Singh, Y. Wu, T. Gardner, and T. R. Kosten, “Substance abuse vaccines,” Annals of the New York Academy of Sciences 1141 (2008): 257–69.
11. The neurotransmitter acetylcholine works by activating two broad classes of receptor on neurons: slow-acting muscarinic receptors and fast-acting nicotinic receptors. Nicotine, of course, activates the latter. Nicotine receptors are assembled in a combinatorial manner from different subunits. Varenicline binds to one specific type of nicotinic receptor complex, called α4β2. It’s neither a pure activator nor a pure blocker of this receptor. Rather, it functions as a “partial agonist,” which means that it binds the receptor but activates it weakly, thereby reducing its activation by acetylcholine or nicotine.
12. For an overview of the near-term prospects for new anti-addiction drugs see G. F. Koob, G. K. Lloyd, and B. J. Mason, “Development of pharmaco-therapies for drug addiction: a Rosetta Stone approach,” Nature Reviews Drug Discovery 8 (2009): 500–515.
13. Glutamate receptors are divided into two large families: the fast-acting ionotropic receptors, which open ion channels to produce rapid electrical signaling (these carry the bulk of information flow in your brain); and the slow-acting metabotropic receptors, which activate or inhibit ion channels or enzymes through an intermediate form of signaling called a G-protein. Metabotropic glutamate receptors generally have actions that last for seconds to tens of seconds, and they are often the trigger for other plastic processes that last much longer still. There are eight major forms of metabotropic receptor in the human brain with different distribution patterns and different electrical and biochemical sequelae.
14. C. Chiamulera, M. P. Epping-Jordan, A. Zocchi, C. Marcon, C. Cottiny, S. Tacconi, M. Corsi, F. Orzi, and F. Conquet, “Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice,” Nature Neuroscience 4 (2001): 873–74.
15. While, at the time of this writing, mGluR5 antagonists are not being evaluated as anti-addiction therapies in clinical trials, these drugs are being assessed for a number of other uses, including reduction of anxiety, pain relief, and control of seizures.
16. E. K. Miller and M. A. Wilson, “All my circuits: using multiple electrodes to understand functioning neural networks,” Neuron 60 (2008): 483–88.
17. M. A. Nicolelis and M. A. Lebedev, “Principles of neural ensemble physiology underlying the operation of brain-machine interfaces,” Nature Reviews Neuroscience 10 (2009): 530–40; N. G. Hatsopoulos and J. P. Donoghue, “The science of neural interface systems,” Annual Review of Neuroscience 32 (2009): 249–66.
18. It turns out that there are a number of ways of introducing fluorescent molecules into neurons in the living mouse brain. One way is to use genetic tricks to make strains of mice that have sequences spliced into their DNA to command the neurons to make fluorescent proteins. Another way is to introduce this DNA by injecting an engineered virus into the brain. The virus infects certain neurons and causes them to produce the fluorescent proteins. Yet another way is to use fluorescent molecules that are not proteins and inject these small molecules directly into the brain where neurons (and sometimes glial cells) can take them up. Two reviews that discuss the use of in vivo multiphoton imaging are O. Garaschuk, R. I. Milos, C. Grienberger, N. Marandi, H. Adelsberger, and A. Konnerth, “Optical monitoring of brain function in vivo: from neurons to networks,” Pflügers Archiv 453 (2006): 385–96; A. Holtmaat, T. Bonhoeffer, D. K. Chow, J. Chuckowree, V. De Paola, S. B. Hofer, M. Hübener, T. Keck, G. Knott, W. C. Lee, R. Mostany, T. D. Mrsic-Flogel, E. Nedivi, C. Portera-Cailliau, K. Svoboda, J. T. Trachtenberg, and L. Wilbrecht, “Long-term, high-resolution imaging in the mouse neocortex through a cranial window,” Nature Protocols 4 (2009): 1128–44.
19. V. Gradinaru, K. R. Thompson, F. Zhang, M. Mogri, K. Kay, M. B. Schneider, and K. Deisseroth, “Targeting and readout strategies for fast optical neural control in vitro and in vivo,” Journal of Neuroscience 27 (2007): 14231–38.
20. This paper is really interesting: D. Nutt, L. A. King, W. Saulsbury, and C. Blakemore, “Development of a rational scale to assess the harm of drugs of potential misuse,” Lancet 369 (2007): 1047–53. It attempts to measure the social and individual harm produced by a number of psychoactive drugs, from alcohol and nicotine to ecstasy and heroin, and then compares that ranking with the penalties for use of those substances in the United Kingdom. The conclusion: In many cases, the penalties do not match up well with the harm.