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 * To whom correspondence should be addressed: bechara@usc.edu. 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 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 log...

A network of cortical brain regions including the insula and anterior cingulate cortex (ACC) has been proposed as the critical and sole substrate for interoceptive awareness. Combining lesion and pharmacological approaches in humans, we found the insula and ACC are not critical for awareness of heartbeat sensations. Rather, both somatosensory afferents from the skin and a network including the insula and ACC mediate it. Together these pathways enable the core human experience of the cardiovascular state of the body.

A considerable body of previous research on the prefrontal cortex (PFC) has helped characterize the regional specificity of various cognitive functions, such as cognitive control and decision making. Here we provide definitive findings on this topic, using a neuropsychological approach that takes advantage of a unique dataset accrued over several decades. We applied voxel-based lesionsymptom mapping in 344 individuals with focal lesions (165 involving the PFC) who had been tested on a comprehensive battery of neuropsychological tasks. Two distinct functional-anatomical networks were revealed within the PFC: one associated with cognitive control (response inhibition, conflict monitoring, and switching), which included the dorsolateral prefrontal cortex and anterior cingulate cortex and a second associated with valuebased decision-making, which included the orbitofrontal, ventromedial, and frontopolar cortex. Furthermore, cognitive control tasks shared a common performance factor related to set shifting that was linked to the rostral anterior cingulate cortex. By contrast, regions in the ventral PFC were required for decision-making. These findings provide detailed causal evidence for a remarkable functional-anatomical specificity in the human PFC.T he prefrontal cortex (PFC) is widely regarded as the pinnacle of brain evolution in humans (1). Its functional organization has long been under scientific scrutiny and has often been subsumed under the rubric "executive functions" (1, 2). Although some early theories attributed a unitary "central executive" to the PFC (3), scientific findings of the past decades have suggested that executive processes fractionate into distinct cognitive functions concerned with motivating behavior (valuation) and controlling behavior (cognitive control), which have been proposed to draw on two partially distinct PFC networks (1,(4)(5)(6). Comparative neuroanatomy suggests a functional and anatomical distinction between ventral PFC with strong connections to the limbic system and dorsolateral PFC (dlPFC) with connections to posterior cortical areas in the parietal lobe (7). Cognitive control, which is thought to draw on multiple processes, including task switching, response inhibition, error detection and response conflict, and working memory (2,4,8), has been associated with the dlPFC and the anterior cingulate cortex (ACC), as well as other sectors of the PFC that together may constitute a rostro-caudally organized hierarchy for behavioral control and planning (9-11). In contrast, valuation, reward learning, and decision-making functions have been mainly associated with ventral and medial sectors of the PFC (vmPFC) (10,(12)(13)(14)(15)(16)(17)(18). Overall, then, the broad functions of "cognitive control" and "valuation" appear to draw on partly distinct, but interacting, networks within the PFC to generate adaptive behavior (6,19,20), although this distinction is sometimes framed between various levels of control and motivation (20) or between executive functions (monitoring and task...