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...

A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n=10); from a larger study on prescription opioid dependent patients (n=133)] and matched healthy individuals (n=10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function.

Investigating the relationship between brain structure and function is a central endeavor for neuroscience research. Yet, the mechanisms shaping this relationship largely remain to be elucidated and are highly debated. In particular, the existence and relative contributions of anatomical constraints and dynamical physiological mechanisms of different types remain to be established. We addressed this issue by systematically comparing functional connectivity (FC) from resting-state functional magnetic resonance imaging data with simulations from increasingly complex computational models, and by manipulating anatomical connectivity obtained from fiber tractography based on diffusion-weighted imaging. We hypothesized that FC reflects the interplay of at least three types of components: (i) a backbone of anatomical connectivity, (ii) a stationary dynamical regime directly driven by the underlying anatomy, and (iii) other stationary and non-stationary dynamics not directly related to the anatomy. We showed that anatomical connectivity alone accounts for up to 15% of FC variance; that there is a stationary regime accounting for up to an additional 20% of variance and that this regime can be associated to a stationary FC; that a simple stationary model of FC better explains FC than more complex models; and that there is a large remaining variance (around 65%), which must contain the non-stationarities of FC evidenced in the literature. We also show that homotopic connections across cerebral hemispheres, which are typically improperly estimated, play a strong role in shaping all aspects of FC, notably indirect connections and the topographic organization of brain networks.

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General intelligence (g) captures the performance variance shared across cognitive tasks and correlates with real-world success. Yet it remains debated whether g reflects the combined performance of brain systems involved in these tasks or draws on specialized systems mediating their interactions. Here we investigated the neural substrates of g in 241 patients with focal brain damage using voxel-based lesion-symptom mapping. A hierarchical factor analysis across multiple cognitive tasks was used to derive a robust measure of g. Statistically significant associations were found between g and damage to a remarkably circumscribed albeit distributed network in frontal and parietal cortex, critically including white matter association tracts and frontopolar cortex. We suggest that general intelligence draws on connections between regions that integrate verbal, visuospatial, working memory, and executive processes.lesion patients | voxel-based lesion-symptom mapping | Wechsler Adult Intelligence Scale | white matter