Converging lines of evidence from preclinical and human research have resulted in the empirically driven, brain-based conceptual framework of addiction. Animal and human models of addiction have allowed for a sophisticated interrogation of the neurocircuitry that underlies addictive behaviors. Koob and colleagues describe the dynamic allostatic process of the addiction cycle in three stages: (1) binge and intoxication, (2) withdrawal and negative affect, and (3) preoccupation and anticipation stage (9, 10). During the binge and intoxication stages, the reward system is initially hyperactive, specifically the ventral tegmentum and the nucleus accumbens, and following chronic alcohol use, a homeostatic shift to hypoactivation occurs. During withdrawal and negative affect, there is a focus on reduced experiences of reward for conventional stimuli and increases in negative affect. These psychological experiences are coupled with changes in the striatum, extended amygdala, and insula functioning. Finally, the third stage is influenced by stress, increased disinhibition, and leads to preoccupation and anticipation of reward, including craving, which increases relapse risk (11, 12). A core part of this model is the shift from impulsivity fueling early stages of addiction to compulsivity fueling later stages of addiction (including relapse). This co-occurs with a shift from positive reinforcement mechanisms to negative reinforcement mechanisms, which can drive motivated behaviors. At the crossroads of this transition is the SN (13).

The SN is a multifunctional, intrinsically connected, large-scale neural circuit implicated in several psychiatric conditions, such as addiction. Specifically, the SN is associated with the detection of salient changes in the environment, both interoceptive and external, and signals the need for cognitive control (14). Critical cortical nodes of the SN include the anterior insula (AIns) and the dorsal anterior cingulate cortex (dACC) (14–16). Additionally, these core nodes functionally connect with subregions of the prefrontal cortex (PFC) inferior parietal lobule (IPL) (14, 16–18) and downstream, subcortical regions of the extended amygdala, ventral striatum, and substantia nigra/ventral tegmental area (19, 20). Although intrinsic connectivity of the SN is most often reported during states of rest in humans, SN function is also interrogated during active tasks involving cognition, action, and emotion (19).

Recent work confirms these SN nodes are paralleled in preclinical models (21). In humans, the AIns, dACC, and dorsolateral PFC (dlPFC) co-activate in response to tasks of cognitive demand, cognitive control, decision-making, and environmental uncertainty. This co-activation has previously been implicated in negative mood states (17, 22–24), and synchronous activation has been shown to increase with task difficulty and stimulus ambiguity. This finding, of task difficulty-dependent, increased activation, suggests that the dACC and AIns both play an integral role in cognition by filtering and integrating internal and external stimuli during a variety of cognitive tasks (25).

The insular cortex is involved in various cognitive and affective processes, such as responding to internal and external emotionally salient stimuli, decision-making, threat recognition, and conscious urges (26). The insula is also heavily implicated in interoception, which involves integrating a wide array of somatic physiological conditions to maintain homeostasis (27, 28). The role of the AIns in the SN includes bottom-up detection of salient stimuli via integration across perceptual modalities (29–33). Specifically, the AIns plays a key role in externally orienting attention and internally orienting self-related cognitions through engagement with default mode and executive networks (14, 34–37).

Conversely, the dACC plays a crucial role in initiation, motivation, and goal-directed behaviors (38–41), with key projections that influence motor responses (42–44) and interactions with other large-scale networks that have a major role in motor/behavioral selection (25). In addition to co-activation with separate functional networks, the dACC also possesses extensive cortico-cortical connections within the PFC, including the dorsolateral prefrontal cortex (dlPFC) and premotor regions, making it critical for learning and behavior (45). Taken together, the fundamental nodes of the SN—the AIns and dACC—are implicated in the processing and synthesis of several complex human experiences, such as cognition, action, and emotion (19). These critical functions are central to the development and maintenance of addiction (10).

Regardless of clinical phenotype, the AIns and dACC are consistently implicated in the development and persistence of multiple psychiatric disorders, such as addictive disorders, suggesting they are critical for psychological well-being and adaptive functioning (46–48). For addiction specifically, the SN may interact and influence incentive salience (49, 50), negative affect (51–55), and executive function (56–60) networks, which are core neurocircuitry underlying AUD (61, 62). The Competing Neurobehavioral Decision System theory, alongside the Impaired Response Inhibition and Salience Attribution models, among others, are established conceptual frameworks of addiction that unite both behavioral and neurobiological systems involved in AUD (63). These models specify that the cortico-striatal circuits involved in processing salient internal or external stimuli, as well as cognitive decision-making, are compromised in AUD. Preclinical literature has identified regions, such as the dACC, insula, and striatum, as targets that are causally linked to alcohol-seeking behaviors (64). In humans, SN abnormalities contribute to difficulties with impulsivity, compulsivity, and executive dysfunction (65, 66), and an increased relapse risk in AUD (4).

The first study to suggest the AIns may have a critical role in the addiction cycle was by Naqvi et al. (67), showing that structural damage to the insula disrupted cigarette consumption. Following a right or left insula lesion, individuals demonstrated rapid and extended smoking cessation, had fewer conscious smoking urges during abstinence (67), and were five times more likely to quit smoking compared with people with no insula lesion (68). Structural damage to the insula has also been shown to decrease the occurrence and severity of nicotine withdrawal symptoms (69), and smoking cessation difficulty (68). Taken together, these fundamental lesion studies highlight the role of the insula in withdrawal and relapse.

Dysfunction of the dACC has also been intensively described as having a role in psychiatric conditions, such as the development and maintenance of AUD. For example, prior studies have demonstrated that reduced dACC activation and compromised connectivity of the SN nodes are associated with greater decision-making latency in AUD (70, 71). Similarly, in individuals who reported binge drinking, acute alcohol consumption caused blunted functional connectivity between the bilateral AIns and the ACC (72). Several groups have demonstrated that such neurobiological abnormalities of the SN are related to the inability to restrain subjective urges (71) and evaluate emotionally salient stimuli (72) in AUD, further supporting that dysregulation of the SN in AUD (63), across resting state, social and emotional processing, and inhibitory control tasks, such as specific reductions in blood flow (73). Acute alcohol consumption significantly attenuates bilateral anterior insula activation to emotional face cues relative to neutral faces and is exacerbated by the level of response to alcohol, which increases the risk for AUD development (74, 75). SN dysfunction, such as structural and metabolic abnormalities (4, 5, 76) and reduced functional connectivity among nodes of the SN, is also predictive of future relapse in AUD (77, 78).

Similar evidence also points to the insula and the dACC playing major roles in reactivity to alcohol cues. A systematic review of over 100 task-related imaging studies by Zilverstand et al. revealed hyper-activation and hyper-connectivity during substance cue exposure, but blunted activation and reduced connectivity during all other tasks, such as cognitive control, non-substance reward, and social/emotional tasks (63). Other cue reactivity studies have found that neural activation in the insular cortex and the ventral striatum can be used to differentiate between heavy and light alcohol drinkers, with heavy drinkers having a higher activation in those regions in response to alcohol cues (79). This differentiation of neural activation between levels of alcohol use may also provide insights into who is at the highest risk of relapse (26). For example, Kohno and colleagues reported that individuals who did not complete AUD treatment showed increased resting-state connectivity between the striatum and the insula, demonstrating that SN dysfunction could be predictive of future drinking (77).

In summary, evidence suggests that insula and dACC activation and connectivity to other key nodes of the SN and how they relate to the neurocircuitry of addiction are highly relevant to the development and maintenance of AUD. One approach to improving treatment outcomes for these individuals may be to directly target SN function through novel therapeutic techniques that have demonstrated efficacy in other psychiatric conditions.

As described above, the SN nodes are likely promising brain-based targets for therapeutic intervention, particularly by utilizing unique forms of TMS as tools to modulate deeper brain structures. However, one of the constraints of TMS is that current technology cannot reach the insula or dACC without also delivering a strong electric field to the superficial cortical areas between the TMS coil and the deeper brain target (as shown in Figure 1). To move the field forward, it is important to think creatively about non-invasive brain stimulation options that may allow us to selectively activate core SN nodes without simultaneously activating off-target cortical regions.

There are several complementary non-invasive approaches that may be useful for the field to consider as it evaluates the SN as a fruitful target for AUD treatment. One possibility is to use temporally interfering electric fields non-invasively applied at multiple cortical locations simultaneously. Grossman and colleagues recently demonstrated that by exploiting the inherent sensitivity of neural populations to varying frequencies, it is possible to selectively stimulate the mouse hippocampus. It remains unclear if this would yield similar results in humans.

Finally, while our focus has been on deep TMS (dTMS) potential, it is also possible to modulate these brain regions through a targeted cortical area with strong afferent projections to the cingulate or insula. This “cortical window” approach relies on the known ability of TMS to modulate areas monosynaptically connected to the area targeted by the electric field. This simple principle is evident by the basic generation of a motor evoked potential in the hand following stimulation of the primary motor cortex (a 2-synapse network). For example, active TMS applied to the frontal pole can change functional connectivity with the insula and cingulate cortex, when compared with sham TMS (96, 97). These are just a few considerations that the field may find fruitful when searching for a strategy to non-invasively modulate the SN nodes.