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“Strong evidence” for a treatment evaporates with a closer look: Many psychotherapies are similarly vulnerable.

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“Strong evidence” for a treatment evaporates with a closer look: Many psychotherapies are similarly vulnerable..

By James Coyne PhD

Promoters of Triple P parenting enjoy opportunities that developers and marketers of other “evidence-supported” psychosocial interventions and psychotherapies only dream of. With a previously uncontested designation as strongly supported by evidence, Triple P is being rolled out by municipalities, governmental agencies, charities, and community-based programs worldwide. These efforts generate lots of cash from royalties and license fees, training, workshops, and training materials, in addition to the prestige of being able to claim that an intervention has navigated the treacherous path from RCT to implementation in the community.

With hundreds of articles extolling its virtues, dozens of randomized trials, and consistently positive systematic reviews, the status of the Triple P parenting intervention as evidence supported would seem beyond being unsettled by yet another review. Some of the RCTs are quite small, but there are public health level interventions, including one involving 7000 children from child protective services. Could this be an instance in which it should be declared “no further research necessary”? Granting agencies have decided not to fund further evaluation of interventions on the basis of a much smaller volume of seemingly less unanimous data.

But the weaknesses revealed in a recent systematic review and meta-analysis of the Triple P by Philip Wilson and his Scottish colleagues show how apparently strong evidence can evaporate when it is given a closer look. Other apparently secure “evidence supported” treatments undoubtedly share these weaknesses and the review provides a model of where to look. But when I took careful look, I discovered that Wilson and colleagues glossed over a very important weakness in the body of evidence for Triple P. They noted it, but didn’t dwell on it. So, weakness in the body of evidence for Triple P is much greater than a reader might conclude from Wilson and colleagues’ review.

 Wikipedia describes Triple P as

a multilevel parenting intervention with the main goal of increasing the knowledge, skills, and confidence of parents at the population level and, as a result, reduce the prevalence of mental health, emotional, and behavioral problems in children and adolescents. The program is a universal preventive intervention (all members of the given population participate) with selective interventions specifically tailored for at risk children and parents.

A Triple P website for parents advertises

the international award winning Triple P – Positive Parenting Program®, backed by over 25 years of clinically proven, world wide research, has the answers to your parenting questions and needs. How do we know? Because we’ve listened to and worked with thousands of parents and professionals across the world. We have the knowledge and evidence to prove that Triple P works for many different families, in many different circumstances, with many different problems, in many different places!

The Triple P website for practitioners declares

As an individual practitioner or a practitioner working within an organisation you need to be sure that the programs you implement, the consultations you provide, the courses you undertake and the resources you buy actually work.

Triple P is one of the only evidence-based parenting programs available worldwide, founded on over 30 years of clinical and empirical research.

Disappearing positive evidence

In taking stock of Triple P, Wilson and colleagues applied objective criteria in a way that readily allows independent evaluation of their results.

They identified 33 eligible studies, almost all of them positive in indicating that Triple P has positive effects on child adjustment.

  • Of the 33 studies, most involving media-recruited families so that participants in the trials were self-selected and more motivated than if they are clients referred from community services or involuntarily getting treatment mandated by child protection agencies.
  • 31/ 33 studies compared Triple P interventions with waiting list or no-treatment comparison groups. This suggests that Triple P may be better than doing nothing with these self-referred families, but doesn’t control for simply providing attention, support, and feedback. The better outcomes for families getting Triple P versus getting than wait list or no treatment may reflect families assigned to these control conditions registering the disappointment with not getting what they had sought in answering the media ads.
  • In contrast, the two studies involving an active control group showed no differences between groups.
  • The trials evaluating Triple P typically administered a battery of potential outcomes, and there is no evidence for any trials that particular measures were chosen ahead of time as the primary outcomes. There was considerable inconsistency among studies using the same instruments in decisions about which subscales were reported and emphasized. Not declaring outcomes ahead of time provides a strong temptation for selective reporting of outcomes. Investigators analyze the data, decide what measures puts Triple P in the most favorable light, and declare post hoc those outcomes as primary.
  • Selective reporting of outcomes occurred in the the abstracts of these studies. Only 4/33 abstracts report any negative findings and 32/33 abstracts were judged to give a more favorable picture of the effects of Triple P.
  • Most papers only reported maternal assessments of child behavior and the small number of studies that obtained assessments from fathers did not find positive treatment effects from the father’s perspective. This may simply indicate the detachment and obliviousness of the fathers, but can also point to a bias in the reports of mothers who had made more of an investment in getting treatment.
  • Comparisons of intervention and control groups beyond the duration of the intervention were only possible in five studies. So, positive results may be short-lived.
  • Of the three trials that tested population level effects of Triple P, two were not randomized trials, but had quasi-experimental designs with significant intervention and control group differences at baseline. A third trial reported a reduction in child maltreatment, but examination of results indicate that this was due to an unexplained increased in child maltreatment in the control area, not a decrease in the intervention area.
  • Thirty-two of the 33 eligible studies were authored by Triple-P affiliated personnel, but only two had a conflict of interest statement. Not only is there strong possibility of investigator allegiance exerting an effect on the reported outcome of trials, there are undeclared conflicts of interest.

The dominance of small, underpowered for quality studies

Wilson and colleagues noted a number of times in their review that many of the trials are small, but they do not dwell on how many, how small, or with what implications. My colleagues have adopted the lower limit of 35 participants in the smallest group for inclusion of trials in meta-analyses. The rationale is that any trial that is smaller than this does not have a 50% probability of detecting a moderate sized effect, even if it is present. Small trials are subject to publication bias in that if results are not claimed to be statistically significant, they will not to get published because the trial was insufficiently powered to obtain a significant effect. On the other hand, when significant results are obtained, they are greeted with great enthusiasm precisely because the trials are so small. Small trials, when combined with flexible rules for deciding when to stop a trial (often based on a peek at the data), failure to specify primary outcomes ahead of time, and flexible rules for analyses, can usually be made to appear to yield positive findings, but that will not be replicated. Small studies are vulnerable to outliers and sampling error and randomization does not necessarily equalize group differences they can prove crucial in determining results. Combining published small trials  in a meta-analysis does not address these problems, because of publication bias and because of all or many of the trials sharing methodological problems.

What happens when we apply the exclusion criterion to Triple P trials of <35 participants in the smallest group? Looking at table 2 in Wilson and colleagues’ review, we see that 20/23 of the individual papers included in the meta-analyses are excluded. Many of the trials quite small, with eight trials having less than 20 participants (9 -18) in the smallest group. Such trials should be statistically quite unlikely to detect even a moderate sized effect, and that so many nonetheless get significant findings attests to a publication bias. Think of it: with such small cell sizes, arbitrary addition or subtraction of a single participant can alter results. Figure 2 in the review provides the forest plot of effect sizes for two of the key outcome measures reported in Triple P trials. Small trials account for the outlier strongest finding, but also the weakest finding, underscoring sampling error. Meta-analyses attempt to control for the influence of small trials by introducing weights, but this strategy fails when the bulk of the trials are small. Again examining figure 2, we see that even with the weights, small trials still add up to over 83% of the contribution to the overall effect size. Of the three trials that are not underpowered, two have nonsignificant effects entered into the meta-analysis. The confidence intervals for the one moderate size trial that is positive barely excludes zero (.06).

Wilson and colleagues pointed to serious deficiencies in the body of evidence supporting the efficacy of Triple P parenting programs, but once we exclude underpowered trials, there is little evidence left.

Are Triple P parenting programs ready for widespread dissemination and implementation?

Rollouts of the kind that Triple P is now undergoing are expensive and consume resources that will not be available for alternatives. Yet, critical examination of the available evidence suggests little basis for assuming that Triple P parenting programs will have benefits commensurate with their cost.

In contrast to the self-referring families stayed in randomized trials, the families in the community are likely to be more socially disadvantaged, often single parent, and often coming to treatment only because of pressure and even mandated attendance. Convenience samples of self-referred participants are acceptable in the early stages of evaluation of an intervention, but ultimately the most compelling evidence must come from participants more representative of the population who will be treated in the community.

Would other evidence supported interventions survive this kind of scrutiny?

Triple P parenting interventions have the apparent support of a large literature that is unmatched in size by most treatments claiming to be evidence supported. In a number of articles and blog posts, I have shown that other treatments claimed to be evidence supported often have only weak evidence. Similar to Triple P, other treatments are largely evaluated by investigators who have vested financial and professional interests in demonstrating their efficacy, in studies that are underpowered, and with a high risk of bias, notably in the failure to specify which of many outcomes that are assessed are primary. Similar to Triple P, psychotherapies routinely get labeled as having strong evidence based solely on studies that involve comparisons with no treatment or waitlist controls. Effect sizes exaggerate the advantage over these therapies over patient simply getting nonspecific, structured opportunities for attention, support, and feedback under conditions of positive expectations. And, finally, similar to what Wilson and colleagues found for Triple P, there often large gaps between the way findings are depicted in abstracts for reports of RCTs and what can be learned from the results sections of the actual articles.

In a recent blog post, I also showed that American Psychological Association Division 12 Clinical Psychology had designated Acceptance and Commitment Therapy (ACT) as having strong evidence for efficacy n hospitalized psychotic patients, only to have that designation removed when I demonstrated that the basis for this judgment was two null flawed and small trials. Was that shocking or even surprising? Stay tuned.

In coming blog posts, I will demonstrate problems with claims of other treatments being evidence-based, but hopefully this blog provides readers with tools to investigate for themselves.


Written by huehueteotl

November 26, 2012 at 11:42 pm

Smoking And Heroine Have Surprisingly Similar Affect On Brain’s Reward System

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“That was good!” “Do it again.” This is what the rat brain says when researchers use nicotine, as well as ‘hard drugs’ such as heroin with it in the laboratory. New research indicates that the effects of nicotine and opiates on the brain’s reward system are equally strong in a key pleasure-sensing areas of the brain — the nucleus accumbens.“Testing rat brain tissue, we found remarkable overlap between the effects of nicotine and opiates on dopamine signaling within the brain’s reward centers,” says Daniel McGehee, Associate Professor in Anesthesia & Critical Care at the University of Chicago Medical Center.

McGehee and colleagues are exploring the control of dopamine, a key neurotransmitter in reward and addiction. Dopamine is released in areas such as the nucleus accumbens by naturally rewarding experiences such as food, sex, some drugs, and the neutral stimuli or ‘cues’ that become associated with them.

Nicotine and opiates are very different drugs, but the endpoint, with respect to the control of dopamine signaling, is almost identical. “There is a specific part of the nucleus accumbens where opiates have been shown to affect behavior, and when we tested nicotine in that area, the effects on dopamine are almost identical,” says McGehee.

This research is important to scientists because it demonstrates overlap in the way the two drugs work, complementing previous studies that showed overlapping effects on physiology of the ventral tegmenal area, another key part of the brain’s reward circuitry. The hope is that this study will help identify new methods for treating addiction — and not just for one drug type.

“It also demonstrates the seriousness of tobacco addiction, equating its grip on the individual to that of heroin. It reinforces the fact that these addictions are very physiological in nature and that breaking away from the habit is certainly more than just mind over matter,” says McGehee. This is certainly a preposterous conclusion from rat brain experiments. Clinical evidence with humans proves at least, that quitting cigarettes is ways more often successful than quitting heroin.

J Neurosci. 2008 Feb 13;28(7):1672-81.
Presynaptic opioid and nicotinic receptor modulation of dopamine overflow in the nucleus accumbens.

Committee on Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.

Behaviorally relevant stimuli prompt midbrain dopamine (DA) neurons to switch from tonic to burst firing patterns. Similar shifts to burst activity are thought to contribute to the addictive effects of opiates and nicotine. The nucleus accumbens DA overflow produced by these drugs is a key element in their pathological effects. Using electrochemical techniques in brain slices, we explored the effects of opioids on single-spike and burst stimuli-evoked DA overflow in the dorsal and ventral striatum. In specific subregions of the nucleus accumbens, mu-opioids inhibit DA overflow elicited with single-spike stimuli while leaving that produced by burst stimuli unaffected. This is similar to published effects of nicotinic receptor blockade or desensitization, and is mediated by opioid receptor-induced inhibition of cholinergic interneurons. Whereas delta-opioids have similar effects, kappa-opioids inhibit evoked DA overflow throughout the striatum in a manner that is not overcome with high-frequency stimuli. These observations reveal remarkable mechanistic overlap between the effects of nicotine and opiates within the dopamine reward pathway.

Written by huehueteotl

February 19, 2008 at 3:51 pm

Amygdala And Learning Fear

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Very young rat brains process memories of fear differently than more mature ones, new research indicates. The work significantly advances scientific understanding of when and how fear is stored and unlearned, and introduces new thinking on the implications of fear experience early in life.

“This important paper raises questions that are the ‘tip of the iceberg’ related to the very complex series of events that occur as we learn to fear something. In the real world, we become fearful, extinguish that fear, reacquire it at another time, and then conquer it yet again,” says John Krystal, MD, of Yale University and director of the clinical neuroscience division of the VA National Center for Post-Traumatic Stress Disorder. “Typically, we think about long-term, negative impact of fear learning, such as lifelong problems with anxiety. But this work highlights an avenue for adapting to early stresses that apparently can occur only early in life: to erase a learned fear from memory.” Krystal was not affiliated with the research.

Study co-authors Jee Hyun Kim and Rick Richardson, PhD, of the University of New South Wales in Sydney, homed in on the amygdala, using anesthesia to temporarily inactivate it and therefore isolate its role. The amygdala is critical for emotional learning and plays a central role in dulling the memory of a fear.

Kim and Richardson trained rats that were 16 and 23 days old–the human equivalent of children and budding adolescents–to associate a specific sound with a mild shock to the foot. After subsequent training, when the sound was not followed by a shock, the animals’ fearful reaction to hearing the sound faded. Technically, this is known as “extinction,” and depended on the function of the amygdala.

In a second round of training, the researchers reintroduced the fear and tried to re-extinguish it. This time around, they found, only the older rats were able to do so without the amygdala.

The researchers concluded that the age at which the initial extinction training occurred was critical to whether or not the rats’ fear faded the second time independently of the amygdala. The authors suggest that in the very young, it is primarily the amygdala that extinguishes fearful memories, but that mechanisms independent of the amygdala develop later.

This raises the possibility that fears unlearned at an early enough age are, in fact, erased. As brains develop, however, and related structures near the amygdala mature, these structures take on a greater role. Thus, fear in adolescence and later in life may not be erased, but instead be, for example, inhibited by a process of overlaying neutral memories on top of the initial fear reaction. The initial memory could still exist and be called on again.

“Extinction in the young brain might forever erase early traumatic learning–but accepting this hypothesis will have to wait for more research,” says Mark Bouton, PhD, of the University of Vermont, who did not participate in the esearch. “What might change as the brain develops is where and how fear learning and extinction are stored and how they can be retrieved.”

J Neurosci. 2008 Feb 6;28(6):1282-90.
The effect of temporary amygdala inactivation on extinction and reextinction of fear in the developing rat: unlearning as a potential mechanism for extinction early in development.

School of Psychology, The University of New South Wales, Sydney 2052, Australia.

It is well accepted that fear extinction does not cause erasure of the original conditioned stimulus (CS)-unconditioned stimulus association in the adult rat because the extinguished fear often returns (e.g., renewal and reinstatement). Furthermore, extinction is NMDA and GABA dependent, showing that extinction involves new inhibitory learning. We have recently observed each of these extinction-related phenomena in 24-d-old but not in 17-d-old rats. These results suggest that different neural processes mediate extinction early in development. However, the neural processes underlying extinction in the developing rat are unknown. Therefore, the present study investigated amygdala involvement in extinction and reextinction during development. In experiment 1, temporary inactivation of the amygdala (using bupivacaine, a sodium channel modulator) during extinction training impaired extinction of conditioned fear in 17- and 24-d-old rats. In experiment 2, 17- and 24-d-old rats were conditioned, extinguished, and then reconditioned to the same CS. After reconditioning, the CS was reextinguished; at this time, some rats at each age had their amygdala temporarily inactivated. Reextinction was amygdala independent in 24-d-old rats, as previously shown in adult rats. However, reextinction was still amygdala dependent in 17-d-old rats. In Experiment 3, the age at conditioning, reconditioning, reextinction, and test was held constant, but the age of initial extinction varied across groups; reextinction was found to be amygdala independent if initial extinction occurred at 24 d of age but amygdala dependent if it occurred at 17 d of age. Consistent with previous findings, these results show that there are fundamental differences in the neural mechanisms of fear extinction across development.

Written by huehueteotl

February 19, 2008 at 11:32 am

Beauty Bias: People Love The Their Liking

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Physical attractiveness is important in choosing whom to date. Good looking people are not only popular targets for romantic pursuits, they themselves also tend to flock together with more attractive others. Does this mean then that more attractive versus less attractive people wear a different pair of lens when evaluating others’ attractiveness?

Columbia University marketing professor, Leonard Lee, and colleagues, George Loewenstein (Carnegie Mellon University), Dan Ariely (MIT) and James Hong and Jim Young (, decided to test this theory in the realm of an online dating site. The site allows members to rate others on their level of physical attractiveness.

Lee and colleagues analyzed two data sets from — one containing members’ dating requests, and the other containing the attractiveness ratings of other members. Both data sets also included ratings of members’ own attractiveness as rated by other members.

The results, which will be published in an upcoming issue of Psychological Science, a journal of the Association for Psychological Science, are revealing. Consistent with previous research, people with similar levels of physical attractiveness indeed tend to date each other, with more attractive people being more particular about the physical attractiveness of their potential dates.

Furthermore, people prefer to date others who are moderately more attractive than them.

Compared to females, males are more influenced by how physically attractive their potential dates are, but less affected by how attractive they themselves are, when deciding whom to date. Also, regardless of how attractive people themselves are, they seem to judge others’ attractiveness in similar ways, supporting the notion that we have largely universal, culturally independent standards of beauty (e.g. symmetric faces).

These results indicate that people’s own attractiveness does not affect their judgment of others’ attractiveness. People of different physical attractiveness levels might instead vary the importance they place on different desirable qualities in their dates.

Lee and colleagues conducted a follow-up speed-dating study in which more attractive people placed more weight on physical attractiveness in selecting their dates, while less attractive people placed more weight on other qualities (e.g. sense of humor). Much like the famous line from Crosby, Stills, Nash, and Young, people find a way to love the ones they can be with.


If I’m Not Hot, are You Hot or Not?
Physical Attractiveness Evaluations and Dating Preferences as a Function of Own Attractiveness

Columbia Business School
Carnegie Mellon University – Department of Social and Decision Sciences
Massachusetts Institute of Technology (MIT) – Sloan School of Management

November 1, 2007
Prior research has established that people’s own physical attractiveness affects their selection of romantic partners. The current work provides further support for this effect and also examines a different yet related question: when less attractive people accept less attractive dates, do they persuade themselves that those they choose to date are more physically attractive than others perceive them to be? Our analysis of data from the popular website suggests that this is not the case: less attractive people do not delude themselves into thinking that their dates are more physically attractive than others perceive them to be.

see also:

Beauty is in the ‘we’ of the beholder: Greater agreement on facial attractiveness among close relations

Written by huehueteotl

February 15, 2008 at 1:25 pm

Even Momentary Sadness Increases Spending

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How you are feeling has an impact on your routine economic transactions, whether you’re aware of this effect or not. In a new study that links contemporary science with the classic philosophy of William James, a research team finds that people feeling sad and self-focused spend more money to acquire the same commodities than those in a neutral emotional state.

The new study follows up on earlier research that established a connection between sadness and buying. Researchers Cynthia Cryder (Carnegie Mellon University), Jennifer Lerner (Harvard University), James J. Gross (Stanford University), and Ronald E. Dahl (University of Pittsburgh) have now discovered that heightened self-focus drives the connection — a finding that expands understanding of consumer behavior and, more broadly, the impact of emotions on decision-making.

In the experiment, participants viewed either a sad video clip or one devoid of human emotion. Afterward, participants could purchase an ordinary commodity, such as a water bottle, at various prices. Participants randomly assigned to the sad condition offered almost 300% more money to buy the product than “neutral” participants. Notably, participants in the sadness condition typically insist, incorrectly, that the emotional content of the film clip did not carry over to affect their spending.

Self-focus helps to explain the spending differences between the two groups. Among participants “primed” to feel sad, those who were highly self-focused paid more than those low in self-focus. Notably, sadness tends to increase self-focus, making the increased spending prompted by sadness difficult to avoid.

Why might a combination of sadness and self-focus lead people to spend more money? First, sadness and self-focus cause one to devalue both one’s sense of self and one’s current possessions. Second, this devaluation increases a person’s willingness to pay more for new material goods, presumably to enhance sense of self.

Notably, the “misery is not miserly” effect may be even more dramatic in real life, as the low-intensity sadness evoked in the experiment likely underestimates the power of intense sadness on spending behavior. The effect could extend to domains beyond purchasing decisions, causing people to engage in increased stock trading, for example, or even to seek new relationships– without conscious awareness that they are being driven by their emotions.

The study is an early step toward uncovering the hidden impact of different, fluctuating, and what would otherwise seem irrelevant emotions on our day-to-day decisions.

The article, that is available at several websites, will be published in the June 2008 edition of Psychological Science and will be presented at the Society for Social and Personality Psychology’s Annual Meeting on Feb. 9.:

Carnegie Mellon:

Lerner Lab:

Cryder, C. E., Lerner, J. S., Gross, J. J., & Dahl, R. E. (in press).
Misery is not miserly: Sad and self-focused individuals spend more.
Psychological Science
Misery is not miserly: sadness increases the amount of money decision makers give up to acquire a commodity (Lerner, Small, & Loewenstein, 2004). The present research investigated when and why the “misery-is-not-miserly” effect occurs. Drawing on William James’s (1890) concept of the material self, we tested a model specifying relationships among sadness, selffocus, and the amount of money decision makers spend. Consistent with our Jamesian hypothesis, results revealed that self-focus both moderates and mediates the effect of sadness on spending. Results were consistent across males and females. Because the study used real
commodities and real money, results hold implications for everyday decisions. They also hold implications for theoretical development. Economic theories of spending may benefit from incorporating psychological theories – specifically theories of emotion and the self.

Written by huehueteotl

February 9, 2008 at 3:39 pm

Drug-seeking Circuitry In Rat Brains Identified

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In experiments with rats, researchers have identified the change in brain circuitry that drives development of a compulsion to seek drugs, even when that compulsion is self-destructive. The researchers demonstrated the function of the circuitry by selectively switching off drug-seeking in the animals. They said their findings show the key role of the brain region, known as the striatum, which is a region activated by reward.

The researchers drew on previous studies indicating that when drug-seeking transforms from a goal-directed behavior to a compulsion, control over that behavior shifts from the ventral to dorsal region of the striatum. In their experiments, the researchers first trained rats to press a lever to obtain cocaine, which also activated a signal light. The researchers manipulated the schedule of cocaine-receiving and lever-pressing so that it would induce compulsive lever-pressing in the rats to obtain cocaine.

The researchers found that when they used surgery and drugs to sever the functional connection between the two striatal regions, the result was decreased drug-seeking behavior in rats, compared with rats in which the disconnection was not made.

In a second set of experiments, the researchers showed that the “disconnected” rats did not show reduced ability to acquire such training responses. Both normal and disconnected rats could learn to pull a chain to receive a sugar-water reward so long as the activity was continuously reinforced.

The researchers concluded that “The results of the present study demonstrate that intrastriatal connectivity is a key aspect of the functional organization of the striatum and also a critically important component of the complex neural mechanisms involved in the development of drug addiction.”

Neuron. 2008 Feb 7;57(3):432-41.
Cocaine Seeking Habits Depend upon Dopamine-Dependent Serial Connectivity Linking the Ventral with the Dorsal Striatum.
Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge CB2 3EB, UK.

A neuroanatomical principle of striatal organization has been established through which ventral domains, including the nucleus accumbens, exert control over dorsal striatal processes mediated by so-called “spiraling,” striato-nigro-striatal, circuitry. We have investigated the functional significance of this circuitry in the control over a cocaine-seeking habit by using an intrastriatal disconnection procedure that combined a selective, unilateral lesion of the nucleus accumbens core and infusion of a dopamine receptor antagonist into the contralateral dorsolateral striatum, thereby disrupting striato-midbrain-striatal serial connectivity bilaterally. We show that this disconnection selectively decreased drug-seeking behavior in rats extensively trained under a second-order schedule of cocaine reinforcement. These data thereby define the importance of interactions between ventral and dorsal domains of the striatum, mediated by dopaminergic transmission, in the neural mechanisms underlying the development and performance of cocaine-seeking habits that are a key characteristic of drug addiction.

 see also

Subconscious Signals Can Trigger Drug Craving


Written by huehueteotl

February 8, 2008 at 4:20 pm

Subconscious Signals Can Trigger Drug Craving

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Using a brain imaging technology called functional magnetic resonance imaging (fMRI), scientists have discovered that cocaine-related images trigger the emotional centers of the brains of patients addicted to drugs — even when the subjects are unaware they’ve seen anything.
Cocaine patients were shown photos such as these. The 24 randomly-presented 33 msec targets in each of four categories (cocaine, sexual, aversive and neutral, interspersed with grey-screen nulls) were immediately followed by a 467 msec neutral “masking” stimulus”. Under these conditions, the 33 msec stimuli can escape conscious detection. (Credit: Childress AR, Ehrman RN, Wang Z, Li Y, Sciortino N, et al.)

A team of researchers at the University of Pennsylvania, led by Dr. Anna Rose Childress and Dr. Charles O’Brien, showed cocaine patients photos of drug-related cues like crack pipes and chunks of cocaine. The images flashed by in just 33 milliseconds — so quickly that the patients were not consciously aware of seeing them. Nonetheless, the unseen images stimulated activity in the limbic system, a brain network involved in emotion and reward, which has been implicated in drug-seeking and craving.

“This is the first evidence that cues outside one’s awareness can trigger rapid activation of the circuits driving drug-seeking behavior,” said NIDA director Dr. Nora Volkow. “Patients often can’t pinpoint when or why they start craving drugs. Understanding how the brain initiates that overwhelming desire for drugs is essential to treating addiction.”

To verify that the patterns of brain activity triggered by the subconscious cues reflected the patients’ feelings about drugs, Childress and her colleagues gave the patients a different test two days later, allowing them to look longer at the drug images. The patients who demonstrated the strongest brain response to unseen cues in the fMRI experiment also felt the strongest positive association with visible drug cues. Childress notes, “It’s striking that the way people feel about these drug-related images is accurately predicted by how strongly their brains respond within just 33 milliseconds.”

Childress and her colleagues also found that the regions of the brain activated by drug images overlapped substantially with those activated by sexual images. This finding supports the scientific consensus that addictive drugs usurp brain regions that recognize natural rewards needed for survival, like food and sex.

According to Childress, these results could improve drug treatment strategies. “We have a brain hard-wired to appreciate rewards, and cocaine and other drugs of abuse latch onto this system. We are looking at the potential for new medications that reduce the brain’s sensitivity to these conditioned drug cues and would give patients a fighting chance to manage their urges.”

PLoS ONE 3(1): e1506. doi:10.1371/journal.pone.0001506

Prelude to Passion: Limbic Activation by “UnseenDrug and Sexual Cues

Anna Rose Childress, Ronald N. Ehrman, Ze Wang, Yin Li, Nathan Sciortino, Jonathan Hakun, William Jens, Jesse Suh, John Listerud, Kathleen Marquez, Teresa Franklin, Daniel Langleben, John Detre, Charles P. O’Brien



The human brain responds to recognizable signals for sex and for rewarding drugs of abuse by activation of limbic reward circuitry. Does the brain respond in similar way to such reward signals even when they are “unseen”, i.e., presented in a way that prevents their conscious recognition? Can the brain response to “unseen” reward cues predict the future affective response to recognizable versions of such cues, revealing a link between affective/motivational processes inside and outside awareness?

Methodology/Principal Findings

We exploited the fast temporal resolution of event-related functional magnetic resonance imaging (fMRI) to test the brain response to “unseen” (backward-masked) cocaine, sexual, aversive and neutral cues of 33 milliseconds duration in male cocaine patients (n = 22). Two days after scanning, the affective valence for visible versions of each cue type was determined using an affective bias (priming) task. We demonstrate, for the first time, limbic brain activation by “unseen” drug and sexual cues of only 33 msec duration. Importantly, increased activity in an large interconnected ventral pallidum/amygdala cluster to the “unseen” cocaine cues strongly predicted future positive affect to visible versions of the same cues in subsequent off-magnet testing, pointing both to the functional significance of the rapid brain response, and to shared brain substrates for appetitive motivation within and outside awareness.


These findings represent the first evidence that brain reward circuitry responds to drug and sexual cues presented outside awareness. The results underscore the sensitivity of the brain to “unseen” reward signals and may represent the brain’s primordial signature for desire. The limbic brain response to reward cues outside awareness may represent a potential vulnerability in disorders (e.g., the addictions) for whom poorly-controlled appetitive motivation is a central feature.

Written by huehueteotl

February 6, 2008 at 9:37 am