Adolescent outbursts related to prefrontal and amygdala sizes

Whittle et al. have done fMRI experiments on adolescents that focused on three key brain regions which are known to represent critical nodes in neural networks supporting affective regulation: the amygdala, anterior cingulate cortex (ACC), and orbitofrontal cortex (OFC). Increased amygdala volume and a relative decrease of left versus right paralimbic ACC volumes were associated with increased duration of aggressive behaviors during parent-child interactions, with the latter association being apparent in males but not females. Decreased relative volume of left vs. right OFC was associated with greater reciprocity of dysphoric behaviors, the association also being specific to males. An absence of mean gender differences in affective behaviors suggests that the neural circuits underlying affective behaviors may differ for male and female adolescents during this age period. Here are some (slightly edited) comments by the authors:

The maturation of the prefrontal cortex and its inhibitory connections with the subcortex are key outcomes of the adolescent neurodevelopment that underlies the development of emotional and behavioral regulatory abilities. The associations of increased amygdala volume and decreased left frontal asymmetries with more negative affective behaviors may represent a delay in brain maturation. Longitudinal research would be needed to examine whether these findings have implications for the development of affective and behavioral dysregulation later in life.

The male specificity of this finding adds to a growing body of evidence that the neural mechanisms underlying affective processing differ between males and females. Males have been found to exhibit structural and functional brain asymmetries to a greater extent than females in a number of prefrontal areas, including the cingulate region. It has been suggested that these asymmetries may render males more vulnerable to certain disorders involving dysfunction of the frontal lobes such as ADHD, autism, and dyslexia. Although males in the present study did not display more aggressive behavior than females, the more pronounced relationship between ACCP asymmetry and aggressive affective behaviors in males suggests that aggressive affect in male adolescents may function as a mechanism by which their brain asymmetry is implicated in their risk for psychopathology.

Here is a useful figure that shows you the locations and variations in the anatomy of the cingulate structures being discussed:

Figure-Example of changes in the location and extent of the limbic (ACCL; highlighted in green) and paralimbic (ACCP; highlighted in blue) anterior cingulate cortices as a function of variations in the cingulate sulcus (CS; green arrow, Upper row) and paracingulate sulcus (PCS; blue arrow, Upper row). A PCS is absent in the left-hand case and present in the right-hand case. The Upper row presents parasagittal slices through an individual's T1-weighted image. The coronal section illustrates the distinction between absent (left-hand side) and present (right-hand side) cases. Notice that the ACCP is buried in the depths of the CS when the PCS is absent and extends over the paracingulate gyrus when the PCS is present. The same principle applies throughout consecutive coronal sections.

Reasoning about our irrational ways

Elizabert Kolbert writes an interesting review in The New Yorker of several books on our irrational economic and political behaviors, the field of behavioral economics. It seems very likely that as politicians and governments become more knowledgeable about the patterns and emotional mechanisms governing our blunders, they will begin to nudge people towards more rational choices. The 'opt out' plans for increasing the numbers of people with health insurance plans or retirement savings are one example of this. Obama's campaign is making very good use of some basic neuro-economics and some of his people are aware of Westin's work (see my July 11 post), as well as Lakoff's (see Jan 31 post). Hillary doesn't seem to have a clue......

Chill out, and your wounds will heal faster.

It is known that anger expression can be associated with increases in cortisol secretion and lowered immune function of the sort seen with other kinds of stress. Gouin et al. at Ohio State Univ. have examined the effect of anger on wound healing by following 98 community volunteers who agreed to receive a standardized blister wound on their non-dominant forearm. They found that wounds of those who expressed little anger or displayed anger in a controlled fashion healed more rapidly than the hotheads. The hotheads exhibited higher cortisol reactivity during the blistering procedure. This enhanced cortisol secretion was in turn related to longer time to heal.

The data show more rapid wound healing in subjects with high anger control.
Measurement of the rate of transepidermal water loss (TEWL) through human skin provides a noninvasive method to monitor changes in the stratum corneum barrier function of the skin. TEWL was measured using a vapor pressure gradient estimation method. TEWL decreased as the barrier was restored; thus, monitoring of TEWL over time allowed objective evaluation of wound healing.

Your amygdala and your blood pressure

I was intrigued by this article, because it shows what I suppose must be going on in my brain as I notice my blood pressure increasing when my stress system ramps up. (Being an introspective retired professor with sufficient time, I am increasingly noticing small changes in my breathing, heart rate, blood pressure, and relative sympathetic versus parasympathetic activation that accompany changes in context.)

In the article Gianaros et al. use the well-know Stroop color-word interference task to generate stress responses in a group of defined college students. They connect stressor processing with the brainstem cardiovascular control mechanisms regulating blood pressure. People with higher stressor-evoked blood pressure reactivity displayed more activation of the amygdala, especially in the dorsal part that contains the central nucleus. Individuals showing greater blood pressure reactivity also had a lower amygdala gray matter volume, which itself predicted greater amygdala activation. In addition, greater stressor- evoked blood pressure reactivity was correlated with stronger functional connectivity between the amygdala and the pons areas in the brainstem, which is critical for blood pressure control, as well the perigenual anterior cingulate cortex.

The data suggest that the amygdala and some of its projection areas play a role in mediating individual differences in autonomic stress responses and hence vulnerability to psychological stressors.

Figure - A. Greater mean arterial blood pressure (MAP) reactivity varied with greater amygdala activation to the incongruent condition. A, Clusters of the left and right amygdala where MAP reactivity varied with activation after covariate control for sex. Parametric maps are projected onto coronal (top) and axial (bottom) sections of a template derived from study participants. B, MAP reactivity (change from a resting baseline) is shown as a function of mean-centered and standardized amygdala BOLD activation values extracted from the peak voxels of the left (L; open circles, dashed line) and right (R; closed circles, solid line) amygdala clusters profiled in A.

Figure - Greater MAP reactivity varied with stronger positive amygdala-pons functional connectivity. A, Statistical parametric maps derived from an ROI regression analysis identifying pons areas where MAP reactivity varied as a function of connectivity with left (top) and right (bottom) amygdala seed regions. B, MAP reactivity is plotted as a function of amygdala-pons connectivity coefficients for the left (L; open circles, dashed line) and right (R; closed circles, solid line) amygdala.

Killer Instincts.

Dan Jones writes a news feature in Nature on neuroscientific and evolutionary perspectives on homicide, mainly carried out by men. Here are some selected chunks:

Men are not just more likely to kill other people than women are, they are also more likely to do so in groups ...Humans are not the only primates to form coalitions that kill members of neighbouring communities. ...five long-term study sites dotted around Africa have seen murderous 'gang violence' in chimpanzees...Wilson and Muller have compared death rates from conflict between groups of chimps in the five long-term study sites with data for inter-group human conflicts in numerous subsistence-farmer and hunter–gatherer societies...Overall, humans and chimpanzees showed comparable levels of violent death from aggression between groups...however, chimps display within group aggression and killing behaviour 200 times more frequently that aboriginal human groups...this prosocial lack of violence looks like a fundamental aspect of human nature — the human ability to generate in-group amity often goes hand in hand with out-group enmity...Choi and Bowles have produced models in which altruism and war co-evolve, promoting conflict between groups and greater harmony within them.

A decline in inter-personal violence (as opposed to inter-group war) can be seen over the shorter timescale and narrower field of modern European history. Eisner has documented a trend of declining homicide rates estimated from historical records left by coroners, royal courts and other official sources spanning Europe from the twelfth century to the modern day. After rising from an average of 32 homicides per 100,000 people per year in the thirteenth and fourteenth centuries to 41 in the fifteenth, the murder rate has steadily dropped in every subsequent century, to 19, 11, 3.2, 2.6 and finally 1.4 in the twentieth century...a few centuries is too short a time for evolution to have shaped human nature much... A part of the answer that is consistent with an evolutionary approach is a long-term reduction in inequalities of life circumstances and prospects.

Faith and Healing

Jerome Groopman reviews Anne Harrington's new book "The Cure Within - A History of Mind-Body Medicine" in the NY Times Book review of Jan. 27. Harrington is professor and chair of the History of Science department at Harvard. Here is the final section of that review:

Harrington offers close observations of the interactions between the Harvard cardiologist Herbert Benson (and later the neuroscientist Richard Davidson of the University of Wisconsin) and the Dalai Lama and his Tibetan monks. She admits longing for scientific support for what is, in essence, an “Orientalist” conception, that the “Other” holds wisdom and therapeutic treasures beyond those imaginable to us in the West. Some of Harrington’s wish is fulfilled in the biology of the placebo response. Recent studies show that belief, even in inert treatments, can have profound benefits in relieving pain, likely via release of endorphins and other mediators in the brain. But despite several decades of concerted research in the field of psychoneuroimmunology, to my scrutiny no robust effects of meditation or other relaxation techniques that could combat illnesses like cancer or AIDS have been identified.

Harrington concludes with the questions that her students at Harvard regularly ask: Which mind-body narratives are “true”? Are all the stories we tell ourselves about illness equally valuable? Harrington has already answered these queries in part in the voice of the woman with breast cancer in the Stanford study. Yet, she has still been “haunted” over the years by unusual events, like the case of a man whose tumors seemed to melt “like snowballs on a hot stove” in response to a “worthlesss” cancer treatment that he nonetheless believed in. The physicist Freeman Dyson once noted that, to a scientist, an event like the spontaneous remission of a tumor is viewed as occurring at the asymptote of probability, one in several million, but through the eyes of a believer it becomes not mathematics but a miracle. Harrington shows us that, whatever science reveals about the cause and course of disease, we will continue to tell ourselves stories, and try to use our own metaphors to find meaning in randomness.

Immune system subjugation of the brain

Research on links between brain, behavior, and the immune system is expanding rapidly. It has long been known that depression lowers immunity, and Dantzer et al. offer a review of causality in the opposite direction: release of cytokines by the innate immune system during infection which in the short term triggers sickness behaviors in the long term can cause depression. Here is their abstract and a PDF.

In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

Terror alerts kill more people than terrorists in the US?

I have long held the opinion, reinforced by this article in the NYTimes, that the absurd terror alert system devised by the department of "homeland security" kills more people than the potential terrorist threat, given that "the chances of the average person dying in America at the hands of international terrorists to be comparable to the risk of dying from eating peanuts, being struck by an asteroid or drowning in a toilet." The article describes studies on a cohort of 2,700 people studied before and after the Sept. 11 attack which indicate a correlation (which is not a cause) between expressed anxiety over a terrorist attack and subsequent cardiovascular ailments.

Antidepressant effects of exercise - a mechanism

Here is an interesting bit from Hunsberger et al. in Nature Medicine, which suggests that a nerve growth factor pathway might be a target for antidepressant drug development (exercise might do the same thing, but depressed people usually aren't that keen on working out):

Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.

Repressed Memory - A recent cultural invention?

Literary references to depression, hallucinations, anxiety, and dementia can be found throughout history. A fascinating article in Harvard Magazine by Ashley Pettus describes the research of Harrison Pope, who reasoned that if dissociative amnesia were an innate capability of the brain it also should appear in ancient texts. An extensive search, and a $1000 reward, was able to find no reference earlier than Nina, an opera by Dalayrac and Marsollier performed in Paris in 1786. The absence of dissociative amnesia in works prior to 1800 suggests that the phenomenon is not a natural neurological function, but rather a “culture-bound” syndrome rooted in the nineteenth century. From the article:

What, then, accounts for “repressed memory’s” appearance in the nineteenth century and its endurance today? Pope and his colleagues hope to answer these questions in the future. “Clearly the rise of Romanticism, at the end of the Enlightenment, created fertile soil for the idea that the mind could expunge a trauma from consciousness,” Pope says. He notes that other pseudo-neurological symptoms (such as the female “swoon”) emerged during this era, but faded relatively quickly. He suspects that two major factors helped solidify “repressed memory” in the twentieth-century imagination: psychoanalysis (with its theories of the unconscious) and Hollywood. “Film is a perfect medium for the idea of repressed memory,” he says. “Think of the ‘flashback,’ in which a whole childhood trauma is suddenly recalled. It’s an ideal dramatic device.”

Brief exposure to media violence alters cortical networks regulating reactive aggression.

This article from Kelly et al. in PLoS One biology is worth a look...here are some clips:

Media depictions of violence, although often claimed to induce viewer aggression, have not been shown to affect the cortical networks that regulate behavior...Using functional magnetic resonance imaging (fMRI), we found that repeated exposure to violent media, but not to other equally arousing media, led to both diminished response in right lateral orbitofrontal cortex (right ltOFC) and a decrease in right ltOFC-amygdala interaction. Reduced function in this network has been previously associated with decreased control over a variety of behaviors, including reactive aggression. Indeed, we found reduced right ltOFC responses to be characteristic of those subjects that reported greater tendencies toward reactive aggression. Furthermore, the violence-induced reduction in right ltOFC response coincided with increased throughput to behavior planning regions...These novel findings establish that even short-term exposure to violent media can result in diminished responsiveness of a network associated with behaviors such as reactive aggression.

Drug enhancement of athletic performance - with no drugs!

Given the gnashing of teeth in the sports world over role models outed for their drug use, this bit from an Italian group is fascinating. It turns out that after only a few administrations of a pain killer (morphine), a placebo or sham injection on the day of the athletic event has the same effect as taking the real drug! Does this count as illegal drug use before an athletic performance? Here is the abstract from Benedetti et al.:

The neurobiological investigation of the placebo effect has shown that placebos can activate the endogenous opioid systems in some conditions. So far, the impact of this finding has been within the context of the clinical setting. Here we present an experiment that simulates a sport competition, a situation in which opioids are considered to be illegal drugs. After repeated administrations of morphine in the precompetition training phase, its replacement with a placebo on the day of competition induced an opioid-mediated increase of pain endurance and physical performance, although no illegal drug was administered. The placebo analgesic responses were obtained after two morphine administrations that were separated as long as 1 week from each other. These long time intervals indicate that the pharmacological conditioning procedure has long-lasting effects and that opioid-mediated placebo responses may have practical implications and applications. For example, in the context of the present sport simulation, athletes can be preconditioned with morphine and then a placebo can be given just before competition, thus avoiding administration of the illegal drug on the competition day. However, these morphine-like effects of placebos raise the important question whether opioid-mediated placebo responses are ethically acceptable in sport competitions or whether they have to be considered a doping procedure in all respects.

This is Your Brain on Politics

Marco Iacoboni, whose work I have mentioned before, has together with several collaborators performed brain imaging experiments on 20 swing voters who indicate willingness to vote for a candidate from either party in the Nov. 2008 presidential elections. They summarize their findings in an Op-Ed piece in the Nov. 11 New York Times. There is a slide show you might like to watch. While insiders in the imaging business go apoplectic over simplistic interpretations of averaged data taken from a small number of subjects using ambiguous protocols with dubious controls, some correlations do emerge that "make sense." (See these comments on the article as 'junk science'.) For example: anterior cingulate (conflict resolution) associates with Hillary Clinton; or amygdala (anxiety) and insula (disgust) correlates with viewing the words "Democrat" or "Republican" but not "independent". One bit I found interesting: "Barack Obama and John McCain have work to do. The scans taken while subjects viewed the first set of photos and the videos of Mr. McCain and Mr. Obama indicated a notable lack of any powerful reactions, positive or negative."

Slide 2
Photos of Hillary Clinton elicited increased activity in the anterior cingulate cortex, a part of the brain that processes conflicting impulses, in swing voters who reported having an unfavorable opinion of her.

Society for Neuroscience meeting: news from the front lines

You might like to check out the Society for Neuroscience website, which offers very accessible information for general public, press, and educators. The site contains links to these topics from the recent annual meeting:

* Antidepressant Drugs, Exercise, Young Age, Even Food Intake, Frequency, and Type, Affect Generation of New Brain Cells

* Research Sheds Light on Brain Differences in Adolescents, Understanding their Impulsive, Risk-Taking Behavior

* Training, Sensory Substitution, Thought-Reading Computers, Sleep, and Molecular Imaging Advance Stroke Research

* Thoughts, Not Arms and Hands, Can Operate Machines: New Devices May Soon Improve Lives or Physically Handicapped

* New Research Explores Dietary Effects on Amyloid in Search for Ways To Prevent, Treat Alzheimer's Disease

* New Studies Find Potential Biomarker for PTSD, Make Gains in Understanding Disorder and Why it is Difficult To Treat

Susceptibility and Resistance to Social Defeat: Molecular Correlates

The research highlights section of the Nov. 1 issue of Nature points to an interesting article from Nester's group on a strain of mice susceptible to social stress. A description excerpted from a review by Hymen:

...mice are exposed to 10 bouts of social defeat in which c57bl/6 test mice are forced to intrude into space occupied by mice of a larger and more aggressive strain, leading to subordination of the test mice. Following this repeated stress, a subset of mice develop significant avoidance of social contact with mice of the same strain and exhibit other signs that are reminiscent of symptoms of human depression, including weight loss and loss of hedonic (pleasure) responses to sucrose. A strength of the social defeat stress model is that, at least in this mouse strain, the stressor convincingly separates the mice into two groups, a group that the authors designate “Susceptible,” which develop social avoidance, and a group described as “Unsusceptible,” which continue to interact with other mice at the same rate as never stressed controls. The model has other strengths. Repeated social defeat would appear to be a good model for some adverse human experience. Moreover, the traits that emerge in susceptible mice reverse only with chronic antidepressant treatment, which mirrors the requirements for treatment of depression and anxiety disorders with these drugs in humans.

Figure 1. Neural Circuits Regulating Responses to Social Defeat

The mesolimbic dopamine pathway comprises a projection from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc) and to other forebrain structure, such as the amygdala and prefrontal cortex (PFC). These dopamine projections, which act as the neural substrates of the rewarding properties of food, mating behaviors, and addictive drugs, are now shown by Krishnan et al. (2007) to mediate the response of mice to social defeat. In mice susceptible to social defeat, expression of brain-derived neurotrophic factor (BDNF) increases in the VTA. The NAc is the recipient of increased BDNF release and shows enhanced downstream signaling via the BDNF receptor.

Less SAD with more sun and serotonin

Welberg offers a summary and review of work by Willeit et al. on the role of serotonin, and a serotonin transporter, in seasonal affective disorder. Here is an portion of the review:

Short, dark winter days put most of us in a gloomy mood, but in people with seasonal affective disorder (SAD), they can cause severe clinical depression. Fortunately, this depression can be treated with bright-light therapy (BLT), and it disappears altogether in summer. Willeit et al. now show that these changes in mood are associated with alterations in the efficiency of the serotonin (5-hydroxytryptamine) transporter (5-HTT) in the patients' blood platelets.

One theory of depression posits that impaired functioning of monoamine neurotransmitters, such as serotonin, causes the disorder, but it is unknown how this impairment might arise. Serotonin levels in the synapse are controlled by the 5-HTT, and Willeit and colleagues therefore investigated whether alterations in 5-HTT functioning might underlie depression in SAD.

The authors compared people with SAD with healthy volunteers, and assessed 5-HTT functioning in winter, after 4 weeks of BLT and in summer. They did this by measuring 5-HTT-mediated inward and outward transport in blood platelets (which are easily obtainable). In winter, both inward transport rate and outward transport were enhanced in the platelets of SAD patients compared with healthy controls. Importantly, these differences in platelet 5-HTT functioning disappeared after 4 weeks of BLT and were absent in summer. The number of 5-HTTs and their affinity for serotonin did not change with BLT or with the seasons, indicating that the increased 5-HTT inward transport that was found in SAD patients was due to increased efficiency of the transporter.

The authors also assessed the patients' depression levels at the three time points, using a structured interview. They found that post-treatment, both inward transport rate and outward transport correlated with depression scores in SAD patients. Moreover, patients whose depression did not decrease after treatment did not show a change in 5-HTT-mediated outward transport after treatment.

Biology and Health Inequality

PLoS Biology has ventured beyond its usual fare to publish several articles focusing on poverty, human development, and the environment. This article is from Eric Brunner. He points out several studies that demonstrate a direct psychosocial pathway to disease. It's precis: "Intriguing parallels between civil servant and nonhuman primate hierarchies suggest that highly stratified societies foster health inequalities. Determining how social differences translate into chronic disease remains a challenge, but neuroendocrine pathways appear to play a role."

Emotion and Disorders of Emotion

You might want to check out this open access special focus issue of Nature Magazine on emotion and disorders of emotion. The starting editorial introduces the articles. Individual susceptibility to depression and anxiety in response to life stressors may be related to genetic variation, and I would point to the review article by Klaus-Peter Lesch and Turhan Canli. It explores how individual variation in the serotonin transporter gene may interact with personality, emotion regulation and social cognition.

Prospection: simulation of future unique to humans

Gilbert and Wilson offer a concise review of our unique human ability to simulate the future, covering brain regions involved and stereotyped errors that occur (PDF here). (I did a series of posts in June, 2006 abstracting Gilberts book "Stumbling on Happiness." You can use the blog search box to find them by entering the word "stumbling.") Here are some clips:

Prefeelings will be reliable predictors of subsequent hedonic experiences when two conditions are met. As the figure shows, when we are in the present (T₁) attempting to predict our hedonic reaction to an event in the future (H₂), our present hedonic experience (H₁) is influenced by our simulation of the future event (e₁) as well as by contextual factors (₁), such as the events that are occurring in the present, the thoughts we are having in the present, our present bodily states, and so on. We feel better when we imagine going to the theater than to the dentist, but we feel better imagining either event on a sunny day than on a rainy day, or when we are well rather than ill. Similarly, our future hedonic experience (H₂) will be influenced both by our perception of the event (e₂) and by contextual factors (₂). Because our hedonic experiences are influenced both by our mental representation of the event and by contextual factors, our present hedonic experience will be a reliable predictor of our future hedonic experience if and only if (i) our simulation of the event at T₁ exerts the same influence on our hedonic experience at T₁ as our perception of the event at T₂ exerts on our hedonic experience at T₂, and (ii) contextual factors at T₁ exert the same influence on our hedonic experience at T₁ as contextual factors at T₂ exert on our hedonic experience at T₂. In other words, H₁ = H₂ if and only if e₁ = e₂ and ₁ = ₂. Errors in prospection arise from the fact that people use their prefeelings to make hedonic predictions even when one or both of these conditions is not met. These errors are of four kinds.

Simulations are unrepresentative. We naturally imagine our next dental appointment by remembering our last one.... research suggests that people often use unrepresentative memories as a basis for simulation. For example, when people who have missed trains in the past are asked to imagine missing a train in the future, they tend to remember their worst train-missing experience rather than their typical train-missing experience.

Simulations are essentialized. When we imagine "going to the theater next week," we don't imagine every detail of the event, but rather, we imagine the essential features that define it. We imagine seeing a stage filled with actors but we do not imagine parking the car, checking our coat, or finding our seat. The problem with omitting inessential features from simulations is that such features can profoundly influence our subsequent hedonic experience... Because simulations omit inessential features, people tend to predict that good events will be better and bad events will be worse than they actually turn out to be. The young couple who simulate the joys of parenthood but fail to simulate the drudgery of diapers are unlikely to have the hedonic experience they imagined.

Simulations are abbreviated. If we imagined each and every moment of the events we were simulating, our simulations would take as long as the events themselves. Simulations are naturally abbreviated and represent just a few, select moments of a future event. The moments they select tend to be the early ones. When people imagine what their lives would be like if they won the lottery or became paraplegic, they are more likely to imagine the first day than the two-hundred-and-ninety-seventh. The problem with imagining only the early moments of an event is that hedonic reactions to events typically dissipate over time, which means that mental simulations tend to the moments that evoke the most intense pleasure or pain.

Simulations are decontextualized. Research shows that people often do not consider the potentially significant differences between contextual factors at T1 and T2 when using their present hedonic state to predict their future hedonic state. For example, hungry people mistakenly expect to like eating spaghetti for breakfast the next day, and sated people mistakenly expect to dislike eating it for dinner the next day. People who have just exercised mistakenly expect to enjoy drinking water the next day more than do people who are about to exercise (53). In both cases, people do not seem to realize that their present hunger and thirst are influencing their hedonic reactions to simulated future consumption. They ignore the fact that the contextual factors that are presently exerting an influence at T1 (i.e., hunger and thirst) will not exert the same influence at T2.

Their conclusion makes a nice summary of how modern and ancient brain systems interact in imagining possible future feelings:

Mental simulation is the means by which the brain discovers what it already knows. When faced with decisions about future events, the cortex generates simulations, briefly tricking subcortical systems into believing that those events are unfolding in the present and then taking note of the feelings these systems produce. The cortex is interested in feelings because they encode the wisdom that our species has acquired over millennia about the adaptive significance of the events we are perceiving. Alas, actually perceiving a bear is a potentially expensive way to learn about its adaptive significance, and thus evolution has provided us with a method for getting this information in advance of the encounter. When we preview the future and prefeel its consequences, we are soliciting advice from our ancestors.

This method is ingenious but imperfect. The cortex attempts to trick the rest of the brain by impersonating a sensory system. It simulates future events to find out what subcortical structures know, but try as it might, the cortex cannot generate simulations that have all the richness and reality of genuine perceptions. Its simulations are deficient because they are based on a small number of memories, they omit large numbers of features, they do not sustain themselves over time, and they lack context. Compared to sensory perceptions, mental simulations are mere cardboard cut-outs of reality. They are convincing enough to elicit brief hedonic reactions from subcortical systems, but because they differ from perceptions in such fundamental ways, the reactions they elicit may differ as well. Although prospection allows us to navigate time in a way that no other animal can, we still see more than we foresaw.

Placebo effect on human opiod pain system

A recent issue of Nature Reviews Neuroscience points to an interesting article by Wagner et al.
(open access).

The mere expectancy of pain relief has been shown to reduce pain in a manner that is reversible by opioid antagonists. Using positron-emission tomography and a mu-opioid-receptor selective radiotracer, Wagner et al. were able to measure the placebo-induced activation of the opioid system in specific brain regions. They found an increase in opioid neurotransmission in regions that have a central role in pain processing, demonstrating that placebo analgesic treatments potentiate the endogenous opioid response to painful stimuli.

Figure - Connectivity analysis of opioid binding potential. (A) 3D rendering of connectivity among regions that show placebo opioid responses.