Commentary on Abdolahi <i>et al</i>. (2015): Isolating the role of the insula in drug cravings

If people with addictions experience brain injury, could this render them less susceptible to withdrawal symptoms? Abdolahi et al. show that damage to the insula (via stroke) has this precise effect. Understanding the psychological functions of the insula will be key in translating this knowledge to effective interventions for smoking. Cognitive neuroscience models of addiction have typically fallen into two broad camps. Some models 1 characterize a brain reward system as an ‘accelerator’, with dysfunction of this system causing persistent engagement in risky appetitive behaviours such as drug-taking. Other models emphasize impairments in the ability of the prefrontal cortex to act as a ‘brake’ on maladaptive responses 2. Some theories combine an overactive accelerator with a faulty brake 3. A seminal observation in neurological patients published in 2007 indicated that these various accounts might all be missing a trick. In patients who had recovered physically from strokes or tumours and who were smokers at the time of their brain injury, if the lesion involved the insula they were more likely to have subsequently quit smoking compared to the cases with damage elsewhere in the brain 4. Anecdotally, the insula cases described no longer experiencing the same urge to smoke. Because the insula was not recognized (at the time) as being a key hub for either executive control or reward processing, was this a new clue for understanding the brain basis of craving? Only a handful of studies in the intervening years have sought to replicate Naqvi et al. (e.g. 5), highlighting in itself the limited contact between the disciplines of neurology and addictions science. The new study by Abdolahi et al. 6 represents the strongest experiment to date, improving upon earlier studies by (i) using a larger sample (156 patients, including 38 with insula damage), (ii) measuring smoking behaviour prospectively rather than retrospectively and (iii) formally assessing nicotine withdrawal symptoms. The insula group scored reliably lower on seven of the eight subscales on the Wisconsin Smoking Withdrawal Scale, including ‘craving’, ‘anxiety’ and ‘anger’. As lesion studies cannot ‘randomize’ cases to the experimental condition, it is important to control for clinical variables that differ between groups, which in this case included prior intention to quit and concurrent damage to mesolimbic structures, both of which were greater in the insula group. Why would damage to the insula have this peculiar effect? The dominant account of insula function recognizes this region as sensory cortex for interoceptive signals about the current state of the body 7. Further, neural activity in anterior insula is seen to correlate with the conscious awareness of physiological states. In drug users, interoceptive stimuli (such as inhaled smoke acting on the airway) become powerfully associated with the hedonic effects of drugs. In smokers, damage to the insula may thereby render conditioned stimuli less effective in driving the physiological states that come to be recognized as cravings 8. In this manner, a recent extension to the accelerator–brake model includes the insula as a third system, acting as a gate between deliberative decision-making and impulsive responding 9. Data from other areas of the addictions field help to substantiate these ideas. Patients with insula damage were less sensitive to two classic psychological distortions that maintain gambling behaviour—the effects of near-misses and the gambler's fallacy 10. These biases are also associated with physiological changes at the level of the body, and neuroimaging data support the ensuing hypothesis that pathological gamblers show hyper-recruitment of the insula 11. However, an impressive series of experiments in stimulant users using neuroimaging in combination with interoceptive challenges has indicated that we should not expect the insula signature to be one of simple under- or overactivity: both age and emotional valence (aversive ‘air hunger’ versus pleasant ‘soft touch’) were seen to moderate network changes centred on the insula 12, 13. Returning to the specific case of nicotine dependence, we note that the withdrawal syndrome involves multiple components, including not only the subjective symptoms (e.g. irritability, appetite) assessed by Abdolahi et al., but also physical signs (e.g. sweating, stomach cramps). A straightforward prediction from the interoceptive account would be that patients with insula damage continue to experience physical withdrawal but that their brain injury has disrupted the subjective experience of those bodily signals. Conversely, if the insula dynamically represents the memory for drug–cue associations, then insula lesions may attenuate all facets of withdrawal. As research on this mysterious brain region gains momentum in cognitive neuroscience, complementary hypotheses that emphasize other addiction-relevant constructs such as salience detection 14 and decision uncertainty 15 may provide further ways of understanding this intriguing effect. Delving into the specific mechanisms mediated by the insula during smoking has a great clinical significance in terms of potential development of novel treatments for smoking cessation by directly manipulating the insula by invasive procedures, such as deep brain stimulation, or non-invasive procedures, such as transcranial magnetic stimulation 16. L.C. is the Director of the Centre for Gambling Research at UBC, which is supported by funding from the British Columbia Lottery Corporation and the Province of BC government. L.C. has consulted for Cambridge Cognition Ltd. L.C. has received no personal payments from the gambling industry or any bodies substantially funded by the gambling industry.

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