Thursday, January 25, 2007
Descubrimiento contra el tabaquismo: daño en la ínsula (región del cerebro) interrumpe adicción a fumar cigarrillos
Damage to the Insula Disrupts Addiction to Cigarette Smoking
Nasir H. Naqvi, David Rudrauf, Hanna Damasio, Antoine Bechara
Science 26 January 2007:
Vol. 315. no. 5811, pp. 531 - 534
Hallazgo contra el tabaquismo
Descubren el origen de la adicción
Una zona del cerebro es responsable de las ansias de fumar
25 de Enero de 2007
WASHINGTON - Científicos estadounidenses descubrieron que un área del cerebro relacionada con la emotividad y sentimientos está vinculada también con la adicción al tabaco, reveló un informe divulgado hoy por la revista Science (26 Enero 2007, Vol. 315) .
Según investigadores de la Universidad del Sur de California y la de Iowa, el descubrimiento puede ayudar al diseño de nuevos tratamientos contra el tabaquismo y otras conductas adictivas.
El descubrimiento ocurrió cuando los científicos advirtieron que una lesión en una estructura cerebral profunda, la ínsula, cortaba de raíz las ansias de nicotina de los pacientes.
"Debido a que es una estructura ligada con las emociones y los sentimientos, el hecho de que una lesión en la ínsula rompa un hábito adquirido, como el del cigarrillo, muestra que existe una estrecha relación entre el hábito y las emociones o los sentimientos", indicó Dana Dornsife, directora del departamento de Ciencias Neurológicas de la Universidad del Sur de California.
La investigación estuvo inspirada por el caso de un paciente que fumaba cuarenta cigarrillos al día, hasta que su ínsula se dañó y dejó el tabaco de inmediato.
"Mi cuerpo se olvidó de las ansias de fumar", explicó el hombre a los científicos.
"Hemos identificado el blanco cerebral para realizar más investigaciones destinadas a hacer frente a esas ansias", indicó Antoine Bechara, director del grupo de científicos.
El estudio incluyó a 69 pacientes que habían sido fumadores antes de sufrir una lesión cerebral. En diecinueve de ellos el daño afectaba a la ínsula.
Trece de estos últimos dejaron de fumar y los científicos admitieron que desconocían por qué los otros seis no.
Smokers Quit After Brain Region Damage
The study provides direct evidence of smoking’s grip on the brain.
It also raises the possibility that other addictive behaviors may have an equally strong hold on neural circuits for pleasure.
The senior authors of the study are Antoine Bechara and Hanna Damasio, both faculty in the year-old Brain and Creativity Institute at USC College, in collaboration with graduate students Nasir Naqvi, who was first author on the study, and David Rudrauf, both from the University of Iowa.
“This is the first study of its kind to use brain lesions to study a drug addiction in humans,” Naqvi said.
In the 1990s, Antonio Damasio proposed the insula, a small island enclosed by the cerebral cortex, as a “platform for feelings and emotion.” The Science study shows that the pleasure of smoking appears to rest on this platform.
“It’s really intriguing to think that disrupting this region breaks the pleasure feelings associated with smoking,” said Damasio, director of the institute and holder of the David Dornsife Chair in Neuroscience at USC.
“It is immediate. It’s not that they smoke less. They don’t smoke, period.”
The finding raises the question of whether damage to the insula also could cause a person to quit other addictive behaviors. Can a brain lesion cure someone of their bad habits?
The answer is not yet known, Bechara said, but he suggested the phenomenon could be “generalizable” regarding alcohol abuse, overeating and other addictions.
The discovery of the insula’s role in addiction opens new directions for therapies, Bechara said, including possible drugs targeted to a region that “no one paid attention to.”
“There is a lot of potential for pharmacological developments,” Bechara said.
Any treatment would need to preserve the beneficial functions of the insula. But Bechara noted that the region appears to be involved specifically in “learned behaviors” rather than the fundamental drives necessary for survival. As a result, it might be possible to target one without disrupting the other.
Hanna Damasio, co-director of the institute and holder of the Dana Dornsife Chair in Neuroscience, also stressed the difference between habitual and instinctive behaviors.
“Because the insula is now recognized as a key structure in processes of emotion and feeling, the fact that insular damage breaks down a learned habit such as smoking, demonstrates a powerful link between habit and emotion or feeling,” she said.
The finding that one small region could be the Achilles’ heel of smoking addiction is especially surprising, given the brain-wide effects of nicotine on the nervous system.
The study considered smokers with damage that did not include the insula, but the likelihood of disrupting the smoking addiction was many times greater when the insula was involved.
Funding for the research came from the National Institute on Drug Abuse and the National Institute of Neurological Disorders and Stroke. The University of Iowa provided access to its extensive database of patients with brain lesions.
The mission of the Brain and Creativity Institute is to study the neurological roots of human emotions, memory and communication and to apply the findings to the solution of problems in the biomedical and sociocultural arenas.
The institute brings together technology and the social sciences in a novel interdisciplinary setting. For more information, go to http://www.usc.edu/schools/college/bci/index.html
Lea el articulo original aqui:
Nasir H. Naqvi, et al.
Damage to the Insula Disrupts Addiction to Cigarette Smoking
Science Vol. 315, 531, (2007)
Damage to the Insula Disrupts Addiction to Cigarette Smoking
Nasir H. Naqvi,1 David Rudrauf,1,2 Hanna Damasio,3,4 Antoine Bechara1,3,4*
A number of brain systems have been implicated in addictive behavior, but none have yet been shown to be necessary for maintaining the addiction to cigarette smoking. We found that smokers with brain damage involving the insula, a region implicated in conscious urges, were more likely than smokers with brain damage not involving the insula to undergo a disruption of smoking addiction, characterized by the ability to quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke. This result suggests that the insula is a critical neural substrate in the addiction to smoking.
Cigarette smoking, the most common preventable cause of morbidity and mortality
in the developed world (1), is an addictive behavior. Despite being aware of negative
consequences, many smokers have difficulty quitting, and even those who quit experience urges to smoke and tend to relapse (2, 3). These phenomena appear to arise from long-term adaptations within specific neural systems. Subcortical
regions, such as the amygdala, the nucleus accumbens, and the mesotelencephalic dopamine system, have been shown in animal models to promote the self-administration of drugs of abuse (4, 5). Functional imaging studies have shown
that exposure to drug-associated cues activates cortical regions such as the anterior cingulate cortex, the orbitofrontal cortex, and the insula (6–13). Among these regions, the insula is of particular interest because of its potential role in
conscious urges. The insula has been proposed to function in conscious emotional feelings through its role in the representation of bodily (interoceptive)
states (14–16). Activity within the insula on both sides of the brain has been shown to correlate with subjective cue-induced drug urges (7, 8, 11). It has also been shown that a high amount of activity in the right insula during a simple decision-making task is associated with relapse to drug use (17). Given its potential role in cognitive and emotional processes that promote drug use, the question arises as to whether
the insula is necessary for maintaining addiction to smoking. We hypothesized that the insula is a critical neural substrate in the addiction to smoking. We predicted, therefore, that damage to the insula would disrupt addiction to smoking.
We identified 19 cigarette smokers who had acquired brain damage that included the insula (18). Six of these patients had right insula damage, and 13 had left insula damage.We also
1Division of Cognitive Neuroscience, Department of Neurology,
University of Iowa Carver College of Medicine, 200
Hawkins Drive, Iowa City, IA 52242, USA. 2Laboratory of
Computational Neuroimaging, Department of Neurology,
University of Iowa Carver College of Medicine, 200 Hawkins
Drive, Iowa City, IA 52242, USA. 3Dornsife Cognitive Neuroscience
Imaging Center, SGM 501, University of Southern
California, Los Angeles, CA 90089, USA. 4Brain and Creativity
Institute, HNB B26, University of Southern California, Los
Angeles, CA 90089, USA.
*To whom correspondence should be addressed. E-mail:
www.sciencemag.org SCIENCE VOL 315 26 JANUARY 2007 531
Fig. 1. Number (N) of
patientswith lesion in each
of the regions identified in
this study, mapped onto a
reference brain. Boundaries
of anatomically defined
regions are drawn
on the brain surface. Regions
names are provided
in the Materials and Methods.
Regions not assigned
a color contained no lesions.
(Top) All patients.
The horizontal line marks
the transverse section of
the brain shown in the top
row. The vertical line
marks the coronal section
shown in the bottom row.
(Middle) Patients with
lesions that involved the
insula. (Bottom) Patients
with lesions that did not
involve the insula.
Fig. 2. Patients who
quit smoking after lesion
onset and patients who
underwent a disruption
of smoking addiction after
lesion onset. (A) Tree
diagram showing the behavioral
patients. (B) Pie charts
illustrating the proportion
of patients in each anatomical
group who fell
into each of the behavioral
categories. The colors
correspond to the behavioral
in (A). These actual proportions
are shown in the
Materials and Methods.
The proportion of patients
with a disruption of smoking addiction was higher among both left insula–lesioned patients and right insula–
lesioned patients compared with among noninsula-lesioned patients.
identified a group of 50 cigarette smokers who had acquired damage that did not include the insula. All of these patients had been smoking more than five cigarettes per day for more than 2 years at the time of lesion onset. The groups were matched with respect to several characteristics, including the number of cigarettes they were smoking at lesion onset, the total number of years they had been smoking at lesion onset, and the etiology of their brain damage (Fig. 1 and table S1). First, we performed a logistic regression analysis in which the dependent variable was whether or not patients quit smoking some time after lesion onset (i.e., whether or not they were smoking at the time of the study). The independent variable of interest was the extent of damage in the insula on a given side. An estimate of the total extent of the lesion was entered as a nuisance covariable (Materials and Methods). We found that the likelihood of quitting smoking after a lesion in either the right or the left insula was not significantly higher than the likelihood of quitting after a noninsula lesion
(odds ratio = 2.94, c2 = 2.74, and P = 0.10). When we examined the right and left insulae separately, we found that the likelihood of quitting smoking was not significantly higher after a right insula lesion than after a noninsula lesion (odds ratio = 2.53, c2 = 2.98, and P = 0.08), nor was it significantly higher after a left insula lesion compared with after a noninsula lesion (odds ratio = 1.44, c2=1.12, and P=0.29) (Fig. 2 and table S3). One explanation of this null finding is that, whereas the insula-lesioned patients may have quit smoking due to a disruption of
smoking addiction, the noninsula-lesioned patients may have quit smoking at a similar rate because they were concerned about the negative consequences of smoking. Simply determining whether the patients were smoking at the time of
the study did not address this distinction.
To more specifically assess a disruption of smoking addiction, we asked all of the patients who quit smoking after lesion onset a set of questions aimed at their recollection of the experience of quitting. Patients were classified as having had a disruption of smoking addiction if they fulfilled all four of the following criteria:
(i) reporting quitting smoking less than 1 day after lesion onset, (ii) reporting that they did not start smoking again after they quit, (iii) rating the difficulty of quitting as less than three on a scale of one to seven, and (iv) reporting feeling no urges to smoke since quitting. According to these criteria, 16 of the patients who quit smoking after lesion onset were classified as having a disruption of smoking addiction. The 16 quitters who failed to meet all four of these criteria, along with all 37 nonquitters, were considered to have no disruption of smoking addiction (Fig. 2). We performed a logistic regression in which the dependent variable was whether or not patients
underwent a disruption of smoking addiction after lesion onset as defined by the above
26 JANUARY 2007 VOL 315 SCIENCE www.sciencemag.org 532
criteria. As before, the independent variable of interest was the extent of damage to the insula on a given side, whereas the estimate of the total extent of the lesion was entered as a nuisance covariable. We found that the likelihood of having a disruption of smoking addiction after a lesion in either the right or the left insula was
significantly higher than the likelihood of having a disruption of smoking addiction after a noninsula lesion (odds ratio = 22.05, c2 = 16.64, and P = 0.0005). When we examined the right and left insulae separately, we found that the likelihood
of having a disruption of smoking addiction was significantly higher after a right
insula lesion than after a noninsula lesion (odds ratio = 10.87, c2 = 12.90, and P = 0.0003) and was also significantly higher after a left insula lesion compared with after a noninsula lesion (odds ratio = 3.61, c2 = 10.33, and P = 0.001)
(Fig. 2 and table S3). Although it appears that effects may be somewhat larger with right insula lesions compared with left insula lesions, the sample sizes were too small to confirm this statistically. We then conducted a similar logistic regression
that included only the patients in our sample who quit smoking after lesion onset (thus, we were not required to assume that patients who continued to smoke after lesion onset had an intact smoking addiction).We found that five of five of the patients who quit smoking after a right insula lesion and seven of eight of the
patients who quit smoking after a left insula lesion met the criteria for having a disruption of smoking addiction, compared to 4 of 19 of the patients who quit smoking after a noninsula lesion (right insula–lesioned patients versus
noninsula-lesioned patients: odds ratio = 6.55, c2 = 7.76, and P = 0.005; left insula–lesioned patients versus noninsula-lesioned patients: odds ratio = 7.19, c2 = 10.06, and P = 0.002). Putting the right and left sides together, 12 of 13 patients
who quit smoking after a lesion in the insula did so with a disruption of smoking addiction. Relative to noninsula-lesioned patients, this translates
into an odds ratio of 136.49 as estimated by the logistic regression (c2 = 15.48 and P = 0.00008) (Fig. 2 and table S3). In our sample, the patients with insula lesions
tended also to have damage in adjacent areas (Fig. 1). This raises the question of whether the observed effects were necessarily due to insula damage or whether they required damage in one or more areas adjacent to the insula. To address
this issue, we performed a region-by-region logistic regression analysis that estimated, for each region of the brain that we sampled, the likelihood of having a disruption of smoking addiction after a lesion that included the region
compared to a lesion that did not include the region. This analysis included all of the patients in the sample. We found that the only regions in which lesions were significantly associated with an increased likelihood of having a disruption of
smoking addiction were the right and left insulae (Fig. 3). On the left side, there were nearsignificant effects in regions adjacent to the insula, such as the putamen. We cannot rule out the possibility that some of these regions independently
or cumulatively play a role in smoking addiction. For example, evidence from
animal studies suggests that the dorsal striatum, which includes the putamen, is involved in learning and expression of drug-use habits (4).
However, for most of these regions the patients with lesions who had a disruption of smoking
Fig. 3. Whole-brain region-by-region logistic regression analysis. The color of each region corresponds to a c2 statistic given the sign of regression coefficient obtained from the logistic regression analysis. The only regions that were assigned a color were those for which the number of patients was sufficient to detect a statistically significant effect (Materials and Methods). Regions for which there was a statistically significant association between a lesion and a disruption of smoking addiction (P <>
addiction also had damage in the insula (table S4), suggesting that apparent effects of lesions in these regions were due to a bystander effect.We did find four patients who had a disruption of smoking addiction after suffering from brain damage that did not involve the insula. When we examined their lesions, we found that each of
them had damage in a unique set of regions (table S5). This raises the possibility that certain patients may undergo a disruption of smoking addiction as a general effect of suffering from a brain injury. The results indicate that smokers who acquire
insula damage are very likely to quit smoking easily and immediately and to remain
abstinent. In addition, smokers with insula damage are very likely to no longer experience conscious urges to smoke after quitting. These findings are consistent with previous functional imaging evidence showing that activity in the insula is correlated with subjective drug urges (7, 8, 11). Additionally, the results provide
evidence that subjective urges are an important factor in maintaining smoking addiction. However, urges may not be the only factor that promotes smoking. Recent theories of addiction propose that usual drug use in addicted individuals is driven primarily by automatic or implicit motivational processes, such as habits (4) and
incentive salience wanting (19). Conscious urges come into play when there is an impediment to drug use, such as an attempt to quit or to resist relapse (20). The present results are consistent with this view. However, it remains to be
seen whether insula damage spares the automatic tendency to smoke. It also remains to be seen whether patients with insula damage still obtain pleasure from smoking, because pleasure and urge may be dissociable facets of smoking
reward (19). Our sample included a number of patients with damage to the orbitofrontal cortex (Fig. 1), a region that, like the insula, has been implicated
by functional imaging studies to play a role in conscious drug urges (6, 8, 9, 11–13).We found no association between lesions in the orbitofrontal
cortex and a disruption of smoking addiction (Fig. 3 and table S4). One explanation of this result is that smokers who acquire orbitofrontal damage experience a reduction in conscious urges but continue to smoke because their
automatic tendency to smoke is still intact. At the same time, these patients may have a low likelihood of attempting to quit smoking after suffering from a brain injury, because the orbitofrontal region is critical for decisions that override the automatic tendency to obtain immediate rewards in order to avoid future negative
consequences (21, 22). Insula-lesioned patients, in contrast, may not have such severe decisionmaking deficits and thus may be likely to attempt
to quit smoking after suffering from a brain injury. The results of this study suggest that the insula is a critical neural substrate for the urge to
www.sciencemag.org SCIENCE VOL 315 26 JANUARY 2007 533
smoke, although they do not in themselves indicate
why the insula, a region known to play a
role in the representation of the bodily states
(16), would play such an important role in urge.
A clue may be provided by the account of one
patient in our sample who quit smoking immediately
after he suffered a stroke that damaged
his left insula. He stated that he quit
because his “body forgot the urge to smoke”
(23). His experience suggests that the insula
plays a role in the feeling that smoking is a
bodily need. Indeed, much of the pleasure and
satiety that is obtained from smoking is derived
from its bodily effects, in particular its impact on
the airway (24, 25). In addition, nicotine withdrawal
is associated with changes in autonomic
and endocrine function (26, 27), which may
contribute to its unpleasantness. Current evidence
suggests that the insula plays a role in
conscious feelings by anticipating the bodily
effects of emotional events (14, 15). The insula
may therefore function in the conscious urge to
smoke by anticipating pleasure from the airway
effects of smoking and/or relief from the aversive
autonomic effects of nicotine withdrawal.
Thus, damage to the insula could lead a smoker
to feel that his or her body has “forgotten” the
urge to smoke.
An important question pertains to whether
insula lesions cause a disruption of motivated
behaviors other than smoking. In a follow-up
survey, we found that none of the patients with
insula damage who had a disruption of smoking
addiction admitted to any reductions in their
pleasure from eating, their desire to eat, or their
intake of food. This does not preclude the possibility
that these patients had some impairment
of taste perception (28, 29) or had deficits in
othermotivated behaviors thatwe did not assess.
One possibility is that motivated behaviors that
are fundamental to survival, such as eating, are
supported by redundant neural mechanisms that
are difficult to disrupt with a lesion in a single
brain region. A related possibility is that the insula
is critical for behaviors whose bodily effects
become pleasurable through learning; although
the bodily effects of eating are inherently pleasurable,
the bodily effects of smoking are initially
aversive and become pleasurable as
addiction develops (25). It would be interesting
to see how insula damage affects other learned
Our findings suggest that therapies that modulate
the function of the insula will be useful in
helping smokers quit. For example, sensory
replacements for smoking, such as denicotinized
cigarettes and irritant inhalers, are highly effective
in reducing urges and promoting abstinence
(30, 31). Such therapies may work by engaging
sensory representations of the airway within the
insula, thereby satisfying the “bodily need” to
smoke. Future pharmacologic therapies may
target neurotransmitter receptors that are expressed
within the insula. In addition, the efficacy
of various smoking cessation therapies may be
monitored by measuring activity within the
insula with functional brain imaging. Lastly, the
findings of this study demonstrate that conscious
feelings, such as urges, are an important component
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32. The authors thank A. Damasio, T. Grabowski, D. Tranel, and
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S. Mehta for expert advice on the logistic regression
analyses. This research was supported by National Institute
on Drug Abuse grants F30 DA016847 (N.H.N.) and R21
DA16708 (A.B.) and National Institute of Neurological
Disorders and Stroke grant P01 NS019632 (A.B. and H.D.).
Supporting Online Material
Materials and Methods
Figs. S1 and S2
Tables S1 to S5
4 October 2006; accepted 15 December 2006
Materials and Methods
Figs. S1 and S2
Tables S1 to S5
4 October 2006; accepted 15 December 2006
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