The Insula: A Brain Stimulation Target for the Treatment of Addiction

May combine two claims.

The H-coil is able to reach deeper brain areas such as the insula, though it is less focal.

“whereas the H-coil is able to reach deeper brain areas (Zangen et al., 2005), such as the insula, though it is less focal.”

• cites Zangen et al., 2005Not checked yet

  Not checked in the free run.

May combine two claims.

There are only a handful of approved treatments for SUDs, with limited efficacy as demonstrated by high long-term relapse rates.

“Despite the enormous efforts to find an effective treatment, there are only a handful of approved treatments for these disorders, with limited efficacy as demonstrated by high long-term relapse rates”

• cites O’Brien, 2008Not checked yet

  Not checked in the free run.

• cites Chiamulera et al., 2017Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Low-frequency TMS (usually 1 Hz) is generally shown to inhibit cortical excitability, whereas high-frequency TMS (5-20 Hz) is shown to enhance cortical excitability.

“low-frequency TMS (usually 1 Hz) is generally shown to inhibit cortical excitability, whereas high-frequency TMS (5–20 Hz) is shown to enhance cortical excitability”

• cites Gorelick et al., 2014 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A mounting body of research supports brain stimulation's efficacy and safety in manipulating underlying neuronal processes and reducing addictive behaviors.

“This has fueled a mounting body of research supporting brain stimulation’s efficacy and safety in manipulating underlying neuronal processes and reducing addictive behaviors”

• cites Coles et al., 2018Not checked yet

  Not checked in the free run.

• cites Hanlon et al., 2018bNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Anodal tDCS usually results in cortical excitability, whereas cathodal stimulation usually results in cortical inhibition.

“Anodal stimulation usually results in cortical excitability, whereas cathodal stimulation usually results in cortical inhibition”

• cites Nitsche et al., 2008Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

TMS treatment is usually well tolerated and presents no serious side effects; the most common side effects reported are transient headaches and local pain.

“Treatment is usually well tolerated and presents no serious side effects. The most common side effects reported are transient headaches and local pain.”

• cites Rossi et al., 2009 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

TMS is a non-invasive brain stimulation technique used to alter magnetic fields to generate electrical currents in a targeted brain area.

“TMS is a non-invasive brain stimulation technique used to alter magnetic fields to generate electrical currents in a targeted brain area”

• cites Barker et al., 1985Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

tDCS is a non-invasive brain stimulation technique that emits a weak current (usually 1-2 mA) via two or more electrodes in direct contact with the scalp.

“Transcranial direct current stimulation is another non-invasive brain stimulation technique. However, unlike TMS, tDCS emits a weak current (usually 1–2 mA) via two or more electrodes in direct contact with the scalp”

• cites Priori et al., 1998Not checked yet

  Not checked in the free run.

• cites Nitsche and Paulus, 2000Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

SUDs are chronic relapsing brain disorders characterized by seeking a drug where use becomes compulsive or difficult to control, despite harmful consequences.

“Substance use disorders (SUDs) are chronic relapsing brain disorders, characterized by seeking a drug where use becomes compulsive or difficult to control, despite harmful consequences”

• cites American Psychiatric Association, 2013Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

More serious side effects of TMS, most notably seizures, are extremely rare and are unlikely when the proper safety guidelines are followed.

“More serious side effects, most notably seizures, are extremely rare and are unlikely when the proper safety guidelines are followed”

• cites Rossi et al., 2009 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

tDCS does not directly result in neuron firing as it does not produce action potentials; rather, it produces a subthreshold change in neuronal membrane potentials.

“tDCS does not directly result in neuron firing as it does not produce action potentials. Rather, it produces a subthreshold change in neuronal membrane potentials”

• cites Purpura and McMurtry, 1965Not checked yet

  Not checked in the free run.

• cites Nitsche et al., 2008Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

tDCS is not able to reach deep brain areas; however, secondary activations are possible.

“This brain stimulation technique is not able to reach deep brain areas; however, secondary activations are possible”

Probably not a substantial claim: may not pass S3 (load-bearing).

To produce aftereffects of 1 h or more with tDCS, there needs to be stimulation for at least 9 min.

“It has been shown that to produce aftereffects of 1 h or more, there needs to be stimulation for at least 9 min”

• cites Nitsche and Paulus, 2001Not checked yet

  Not checked in the free run.

May combine two claims.

The risk of adverse events is much higher with DBS than with other techniques; it requires surgery and hardware failure can still occur.

“Although DBS has the capacity to target deeper areas in the brain that might be needed for addiction-related treatments, it should be noted that the risk of adverse events is much higher with this technique.”

• cites Breit et al., 2004Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The insula is composed of three distinct subregions known as the granular, dysgranular, and agranular.

“It is also composed of three distinct subregions known as the granular, dysgranular, and agranular”

• cites Paxinos and Watson, 1986Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

DBS is mainly used for movement disorders such as Parkinson's disease; it has been approved by the U.S. FDA for treatment-resistant obsessive-compulsive disorder.

“Currently, DBS is mainly used for movement disorders such as Parkinson’s disease (Kringelbach et al., 2007); however, it has been approved by the U.S. FDA for treatment-resistant obsessive-compulsive disorder.”

• cites Kringelbach et al., 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

CRF plays a role in the motivation to consume drugs in human subjects with substance dependence and distress during withdrawal and stress-induced relapse.

“Corticotropin-releasing factor (CRF) plays a role in the motivation to consume drugs in human subjects with substance dependence and distress during withdrawal and stress-induced relapse”

• cites Contoreggi et al., 2003Not checked yet

  Not checked in the free run.

May combine two claims.

Dopaminergic innervation of the insular cortex was found to play an important role in the conditioning of the aversive aspects of opiate withdrawal and the active avoidance of withdrawal.

“The importance of visceral perception in addiction was first noted in the late 1980s, as dopaminergic innervation of the insular cortex was found to play an important role in the conditioning of the aversive aspects of opiate withdrawal (Zito et al., 1988) and the active avoidance of withdrawal.”

• cites Zito et al., 1988Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

tDCS outcomes are subject to inter-individual variability, possibly due to a number of factors including anatomical brain differences.

“tDCS outcomes have also been shown to be subject to inter-individual variability, possibly due to a number of factors (Wiethoff et al., 2014), one of them being anatomical brain differences”

• cites Wiethoff et al., 2014Not checked yet

  Not checked in the free run.

• cites Kim et al., 2014Not checked yet

  Not checked in the free run.

May combine two claims.

The aIC sends projections to the caudate-putamen, nucleus accumbens, and extended amygdala while having reciprocal connections with the basolateral amygdala and the prelimbic cortex.

“The anterior insular cortex (aIC) sends projections to the caudate-putamen, nucleus accumbens (NAcc), and extended amygdala (McGeorge and Faull, 1989; Wright and Groenewegen, 1996; Shi and Cassell, 1998b; McDonald et al., 1999) while having reciprocal connections with the basolateral amygdala (BLA) and the prelimbic cortex”

• cites McGeorge and Faull, 1989Not checked yet

  Not checked in the free run.

• cites Wright and Groenewegen, 1996 sourceNot checked yet

  Not checked in the free run.

• cites Shi and Cassell, 1998bNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In general, the aIC has greater connectivity with the frontal lobe, and the pIC has greater connectivity with the parietal lobe.

“In general, the aIC has greater connectivity with the frontal lobe, and the pIC has greater connectivity with the parietal lobe”

• cites Gasquoine, 2014Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The aIC receives inputs from the medial subdivision of the mediodorsal thalamic nucleus and other various medial thalamic nuclei involved in motivational/affective aspects of nocioception.

“The aIC receives inputs from the medial subdivision of the mediodorsal thalamic nucleus and other various medial thalamic nuclei involved in motivational/affective aspects of nocioception”

• cites Krettek and Price, 1977Not checked yet

  Not checked in the free run.

• cites Van der Werf et al., 2002Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

DBS is an invasive brain stimulation technique that requires neurosurgical implantation of bipolar electrodes attached to a permanently implanted pulse generator.

“Deep brain stimulation is an invasive brain stimulation technique that requires neurosurgical implantation of bipolar electrodes attached to a permanently implanted pulse generator”

• cites Greenberg and Rezai, 2014Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The insula is commonly divided into anterior and posterior parts, based on cytoarchitectonic and functional connectivity.

“It is commonly divided into anterior and posterior parts, based on the cytoarchitectonic and functional connectivity”

• cites Mesulam and Mufson, 1982Not checked yet

  Not checked in the free run.

• cites Deen et al., 2011 sourceNot checked yet

  Not checked in the free run.

• cites Kelly et al., 2012Not checked yet

  Not checked in the free run.

May combine two claims.

The entire granular subregion has notably high dopamine utilization, with the aIC having high density D1-subtype receptors surrounding dopaminergic terminals from the VTA and substantia nigra.

“The entire granular subregion has notably high dopamine utilization (Gaspar et al., 1989) with the aIC having high density D1-subtype receptors surrounding dopaminergic terminals from the VTA and substantia nigra.”

• cites Gaspar et al., 1989 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

tDCS side effects are typically mild, such as tingling sensation and light itching under the electrode, and usually dissipate after stimulation; tDCS is well tolerated and presents no serious side effects.

“Side effects from tDCS are typically mild, such as tingling sensation and light itching under the electrode, and usually dissipate after stimulation. Afterward headaches and, occasionally, nausea are reported. In general, tDCS is well tolerated and presents no serious side effects”

• cites Matsumoto and Ugawa, 2016Not checked yet

  Not checked in the free run.

May combine two claims.

Several studies have demonstrated the insula's primary role in sensations of taste and disgust and the integration of a wide variety of visceral sensations from the airways, gut, and cardiovascular systems, indicating the insula is heavily involved in the integration of internal and external stimuli to guide behavior toward or away from said stimuli for the purposes of maintaining homeostasis.

“Since then, several studies have demonstrated the insula’s primary role in sensations of taste and disgust (Ragozzino and Kesner, 1999; Fresquet et al., 2004; Isnard et al., 2004) and the integration of a wide variety of visceral sensations from the airways, gut, and cardiovascular systems”

• cites Ragozzino and Kesner, 1999Not checked yet

  Not checked in the free run.

• cites Fresquet et al., 2004Not checked yet

  Not checked in the free run.

• cites Isnard et al., 2004Not checked yet

  Not checked in the free run.

May combine two claims.

The insular cortex is involved in feelings of anxiety, pain, cognition, mood, threat recognition, and conscious urges.

“The insular cortex is involved in feelings of anxiety, pain, cognition, mood, threat recognition, and conscious urges”

• cites Hardy, 1985Not checked yet

  Not checked in the free run.

• cites Suhara et al., 1992 sourceNot checked yet

  Not checked in the free run.

• cites Craig, 2002 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The exact mechanism of DBS is not completely understood; it seems to elicit multiple mechanisms of action.

“The exact mechanism of DBS is not completely understood, it seems to elicit multiple mechanisms of action”

• cites Herrington et al., 2016 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The insula has a high level of endogenous opioids, high density of μ-subtype opioid receptors, high density of hypocretin subtype-1 receptors, and a high level of nicotinic acetylcholine receptors containing the β2 subunit, the major subtype of nAChR implicated in nicotine reward.

“Furthermore, the insula has a high level of endogenous opioids (Gaspar et al., 1989), high density of µ-subtype opioid receptors (Baumgartner et al., 2006), high density of hypocretin subtype-1 receptors (Hollander et al., 2008), and a high level of nicotinic acetylcholine receptors (nAChRs) containing the β2 subunit”

• cites Gaspar et al., 1989 sourceNot checked yet

  Not checked in the free run.

• cites Baumgartner et al., 2006Not checked yet

  Not checked in the free run.

• cites Hollander et al., 2008Not checked yet

  Not checked in the free run.

May combine two claims.

Individuals with methamphetamine dependence have a reduced emotional response to threatening scenes, empathy for another's pain, and fearful or angry face, all of which correlate with hypoactivation of the insula.

“Interestingly, individuals with methamphetamine dependence have a reduced emotional response to threatening scenes, empathy for another’s pain, and fearful or angry face, all of which correlate with hypoactivation of the insula”

• cites Kim et al., 2011Not checked yet

  Not checked in the free run.

May combine two claims.

The pIC keeps a constant account of the current state of the body; this information is then relayed through the thalamus and dysgranular insular cortex, which appears to integrate salient external stimuli.

“The pIC keeps a constant account of the current state of the body; this information is then relayed through the thalamus and dysgranular insular cortex, which appears to integrate salient external stimuli”

• cites Craig, 2004 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Inactivation of the pGIC, but not the aAgIC, prevents the acquisition of CPP induced by morphine, without producing any effect on general motor and/or spatial learning.

“Finally, inactivation of the pGIC, but not the aAgIC, prevents the acquisition of CPP induced by morphine, without producing any effect on general motor and/or spatial learning”

• cites Li et al., 2013Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The insular cortex is critical for experiencing disgust and recognizing it in others, causing learning and memory of disgust to play a critical evolutionary role in mammals.

“The insular cortex is critical for experiencing disgust and recognizing it in others, causing learning and memory of disgust to play a critical evolutionary role in mammals”

• cites Woolley et al., 2015Not checked yet

  Not checked in the free run.

May combine two claims.

Optogenetic inhibition of aIC glutamatergic input to the NAccCore attenuates aversion-resistant alcohol taking, but not alcohol taking in the absence of aversive stimuli.

“Optogenetic inhibition of aIC glutamatergic input to the NAccCore attenuates aversion-resistant alcohol taking, but not alcohol taking in the absence of aversive stimuli”

• cites Seif et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

Inactivation of the aAgIC or chemogenic silencing of the aIC projections to the nucleus accumbens core produce sensitivity to the interoceptive effects of alcohol.

“Inactivation of the aAgIC (Jaramillo et al., 2016) or chemogenic silencing of the aIC projections to the nucleus accumbens core (NAccCore) (Jaramillo et al., 2017), both produce sensitivity to the interoceptive effects of alcohol.”

• cites Jaramillo et al., 2016Not checked yet

  Not checked in the free run.

• cites Jaramillo et al., 2017Not checked yet

  Not checked in the free run.

May combine two claims.

Lesions of the aAgIC facilitate the escalation of cocaine intake, yet post-escalation lesions still reduce intake.

“In fact, lesions facilitate the escalation of cocaine intake, yet post-escalation lesions still reduce intake”

• cites Rotge et al., 2017Not checked yet

  Not checked in the free run.

May combine two claims.

aAgIC lesions have no effect on the acquisition of cocaine taking, nor does inactivation of the aAgIC affect established cocaine-taking.

“Contrarily, aAgIC lesions have no effect on the acquisition of cocaine taking (Pelloux et al., 2013), nor does inactivation of the aAgIC affect established cocaine-taking”

• cites Pelloux et al., 2013Not checked yet

  Not checked in the free run.

• cites Pietro et al., 2006Not checked yet

  Not checked in the free run.

May combine two claims.

Under nicotine deprivation, the SN switches to DMN, directing attention resources toward internal withdrawal symptoms, while under nicotine administration, the SN switches to ECN, directing attentional resources toward external stimuli and executive functions.

“They showed that under nicotine deprivation, the SN would switch to DMN, hence, direct attention resources toward internal withdrawal symptoms, while under nicotine administration, the SN would switch to ECN, hence direct attentional resources toward external stimuli and executive functions”

• cites Sutherland et al., 2012Not checked yet

  Not checked in the free run.

• cites Lerman et al., 2014Not checked yet

  Not checked in the free run.

• cites Sutherland and Stein, 2018Not checked yet

  Not checked in the free run.

May combine two claims.

The insula's critical thalamic connections allow it to integrate a range of visceral sensations, including inputs from the airways, gut, and cardiovascular systems, all known to be relevant with regard to bodily responses to the performance of addictive behaviors.

“Beyond acting as the primary taste cortex, the insula’s critical thalamic connections allow it to integrate a range of visceral sensations, including inputs from the airways, gut, and cardiovascular systems (Cechetto and Saper, 1987), all known to be relevant with regard to bodily responses to the performance of addictive behaviors”

• cites Cechetto and Saper, 1987Not checked yet

  Not checked in the free run.

• cites Verdejo-Garcia et al., 2007Not checked yet

  Not checked in the free run.

May combine two claims.

Inactivation of the aAgIC attenuates context-induced reinstatement of cocaine seeking without altering locomotor activity; inactivation immediately following re-exposure to drug context has no effect on memory reconsolidation.

“Inactivation of the aAgIC attenuates context-induced reinstatement of cocaine seeking without altering locomotor activity; however, inactivation immediately following re-exposure to drug context has no effect on memory reconsolidation”

• cites Arguello et al., 2017Not checked yet

  Not checked in the free run.

May combine two claims.

Lesion to the insula best predicts smoking cessation, and the probability of quitting smoking is fivefold greater than when there is no damage to the insula.

“Since then, other lesion studies have emerged, indicating that lesion to the insula best predicts smoking cessation and the probability of quitting smoking is five folds greater than when there is not damage to the insula (Suñer-Soler et al., 2012).”

• cites Suñer-Soler et al., 2012 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Inhibition of monoacylglycerol lipase in the pGIC prevents the acquisition of CPA from morphine withdrawal, which was reversed by the blockade of cannabinoid-1 receptors.

“The cannabinoid system has also been implicated, with the inhibition of monoacylglycerol lipase (causing elevation of the endocannabinoid 2-arachidonyl glycerol; 2-AG) in the pGIC preventing the acquisition of CPA from morphine withdrawal, which was reversed by the blockade of cannabinoid-1 receptors”

• cites Wills et al., 2016 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The presentation of morphine-induced CPP is abolished by lesions to the pIC or the inhibition of nitric oxide in the pIC.

“The presentation of morphine-induced CPP is also abolished by lesions to the pIC (Sun et al., 2018) or the inhibition of nitric oxide in the pIC”

• cites Sun et al., 2018Not checked yet

  Not checked in the free run.

• cites Ma et al., 2014Not checked yet

  Not checked in the free run.

May combine two claims.

Smokers with insular damage experience less frequent and severe withdrawal symptoms of nicotine and less smoking urges.

“It has also been shown that smokers with insular damage experience less frequent and severe withdrawal symptoms of nicotine (Abdolahi et al., 2015b) and less smoking urges (Abdolahi et al., 2017).”

• cites Abdolahi et al., 2015bNot checked yet

  Not checked in the free run.

• cites Abdolahi et al., 2017Not checked yet

  Not checked in the free run.

May combine two claims.

The presentation of amphetamine-induced CPP activates the pGIC and inactivation of the subregion prevents the presentation of said place preference.

“The presentation of amphetamine-induced CPP activates the pGIC and inactivation of the subregion prevents the presentation of said place preference”

• cites Contreras et al., 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Insular damage is associated with increased odds of smoking cessation, and those who relapse tend to remain abstinent for longer periods than those with non-insular damage.

“Although, insular damage is associated with increased odds of smoking cessation, those that do relapse tend to remain abstinent for longer periods than those with non-insular damage (Abdolahi et al., 2015a).”

• cites Abdolahi et al., 2015aNot checked yet

  Not checked in the free run.

May combine two claims.

Overall, there is evidence of some role for the IC in the neurocircuitry underlying all stages of the addictive cycle, clearly implicating the IC as a fundamental region in the maintenance and relapse to addictive drugs.

“Overall, there is evidence of some role for the IC in the neurocircuitry underlying all stages of the addictive cycle, clearly implicating the IC as a fundamental region in the maintenance and relapse to addictive drugs.”

• AssumptionRests on an assumption: Findings from rodent models of the stages of addiction translate to human SUDs.

May combine two claims.

The IC appears to play a greater role in the binge/intoxication stage for some addictive drugs (e.g., nicotine, alcohol) over others (e.g., cocaine), but the region does appear to play some role in the neurocircuitry underlying this stage for all addictive drugs examined.

“Though the IC appears to play a greater role in the binge/intoxication stage for some addictive drugs (e.g., nicotine, alcohol) over others (e.g., cocaine), the region does appear to play some role in the neurocircuitry underlying this stage of addiction for all addictive drugs examined.”

May combine two claims.

Inactivation of the aAgIC, but not the pGIC, attenuates cue-induced cocaine seeking, while having no effect on drug priming-induced cocaine seeking or food seeking induced by either cues and/or priming.

“Inactivation of the aAgIC, but not the pGIC, attenuates cue-induced cocaine seeking, while having no effect on drug priming-induced cocaine seeking or food seeking induced by either cues and/or priming”

• cites Cosme et al., 2015Not checked yet

  Not checked in the free run.

May combine two claims.

Patients with insular damage who used opium prior to stroke were significantly more likely to quit using opium, and this effect was more significant among younger patients.

“For instance, in a comparison between ischemic stroke patients who used opium prior to their stroke, patients with insular damage were significantly more likely to quit using opium; this effect was more significant among younger patients (Yousefzadeh-Fard et al., 2013).”

• cites Yousefzadeh-Fard et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

Alcohol users had lower SN connectivity than controls and an attenuated blood flow to the insula.

“Similarly, alcohol users had lower SN connectivity than controls and an attenuated blood flow to the insula (Sullivan et al., 2013), whereas individuals with heroin use disorder had an increased SN connectivity (Wang et al., 2010).”

• cites Sullivan et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

Individuals with inability to control Internet use showed significantly lower gray matter density in the left insula and lower white matter density in the right insula.

“Individuals with the inability to control Internet use even when accompanied by negative consequences to their life showed significantly lower gray matter density in the left insula and lower white matter density in the right insula (Lin et al., 2015).”

• cites Lin et al., 2015Not checked yet

  Not checked in the free run.

May combine two claims.

Adolescents with alcohol use disorder had greater white matter volume in the left insula, correlated with enhancement motives for drinking and with frequency of binge drinking at baseline and 1-year follow-up.

“Adolescents with alcohol use disorder had greater white matter volume in the left insula, which was correlated with enhancement motives (i.e., the feeling of “being high”) for drinking and with the frequency of binge drinking at baseline and 1-year follow-up.”

• cites Chung and Clark, 2014Not checked yet

  Not checked in the free run.

May combine two claims.

Cocaine dependence and duration of dependence is correlated with decreased gray matter volume of the insula, which in turn is associated with greater impulsivity.

“For instance, cocaine dependence and duration of dependence has been shown to be correlated with decreased gray matter volume of the insula, which in turn was associated with greater impulsivity (Ersche et al., 2011).”

• cites Ersche et al., 2011 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Smokers have lower rsFC between the insula and executive functions regions such as the OFC and superior frontal gyrus, whereas rsFC between the insula and anterior ACC is negatively correlated with FTND scores.

“Furthermore, smokers were found to have lower rsFC between the insula, executive functions regions, such as the OFC, and superior frontal gyrus, whereas the rsFC between the insula and anterior ACC seems to be negatively correlated with FTND scores (Zhou et al., 2017).”

• cites Zhou et al., 2017Not checked yet

  Not checked in the free run.

May combine two claims.

Changes in insular cortex density are more pronounced in older, more established smokers as opposed to younger smokers, and young smokers (aged 16-21) did not differ in insula thickness compared to non-smokers.

“Also, it appears that the changes in insular cortex density are more pronounced in older, more established, smokers as opposed to younger smokers (Hanlon et al., 2016). Young smokers (aged 16–21) did not differ in insula thickness compared to non-smokers (Morales et al., 2014).”

• cites Hanlon et al., 2016Not checked yet

  Not checked in the free run.

• cites Morales et al., 2014Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

This may be interpreted as the SN impaired ability to switch from cognitive states of interoceptive cravings to cognitive control.

“This may be interpreted as the SN impaired ability to switch from cognitive states of interoceptive cravings to cognitive control.”

May combine two claims.

Gray matter density of the insula is negatively correlated with daily cigarettes smoked, FTND scores, and pack year smoking.

“In terms of correlations with smoking behaviors and markers, there is evidence showing that gray matter density of the insula is negatively correlated with daily cigarettes smoked (Stoeckel et al., 2016), Fagerström Test for Nicotine Dependence (FTND) scores (Wang et al., 2019), and pack year smoking (Morales et al., 2014).”

• cites Stoeckel et al., 2016Not checked yet

  Not checked in the free run.

• cites Wang et al., 2019Not checked yet

  Not checked in the free run.

• cites Morales et al., 2014Not checked yet

  Not checked in the free run.

May combine two claims.

Acutely abstinent smokers demonstrate increased rsFC of the insula-DMN compared to non-smokers and satiated smokers, though satiated smokers still have higher insula-DMN rsFC than non-smokers.

“Acutely abstinent smokers also demonstrate increased rsFC of the insula-DMN when compared to both non-smokers (Huang et al., 2014) and satiated smokers, though satiated smokers still have higher insula-DMN rsFC than non-smokers.”

• cites Huang et al., 2014Not checked yet

  Not checked in the free run.

May combine two claims.

Abstaining from smoking for 12 h results in increased rsFC between the right aIC and executive functions regions as well as increased interconnectivity in the SN.

“Abstaining from smoking for just 12 h resulted in increased rsFC between the right aIC and executive functions regions (i.e., right OFC, and vmPFC) as well as the interconnectivity in the SN (Bi et al., 2017).”

• cites Bi et al., 2017Not checked yet

  Not checked in the free run.

May combine two claims.

Altogether the evidence suggests that structural changes to the insula occur in addicted individuals, thus further demonstrating its involvement in addiction.

“Altogether the evidence suggests that structural changes to the insula occur in addicted individuals, thus further demonstrating its involvement in addiction.”

May combine two claims.

Smoking cues resulted in greater left insula functional connectivity with the right insula, OFC, and striatum, with that greater connectivity being positively correlated with nicotine dependence, as judged by scores on the FTND.

“Smoking cues resulted in greater left insula functional connectivity with the right insula, OFC, and striatum with that greater connectivity being positively correlated with nicotine dependence, as judged by scores on the FTND (Claus et al., 2013).”

• cites Claus et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

Individuals with cocaine use disorder had greater connectivity within the SN and weaker connectivity between the SN and the striatum.

“In terms of other SUDs, individuals with cocaine use disorder had greater connectivity within the SN and weaker connectivity between the SN and the striatum.”

• cites Wisner et al., 2013Not checked yet

  Not checked in the free run.

May combine two claims.

Alterations in the SN function and in the connectivity of the insula to executive functions regions were seen in rsFC studies.

“Alterations in the SN function and in the connectivity of the insula to executive functions regions were seen.”

May combine two claims.

Neuroimaging studies showed increased activation of the insula, thereby suggesting a gain of function.

“On the contrary, neuroimaging studies showed increased activation of the insula, thereby suggesting a gain of function.”

May combine two claims.

Primary stimulation may lead to secondary activations, which can occur due to neurotransmitter release or from back propagation of action potentials from the primary site of activation.

“These activations can occur due to neurotransmitter release or from back propagation of action potentials from the primary site of activation (Diana et al., 2017).”

• cites Diana et al., 2017Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Neurocircuits centered in the insula may represent a biomarker for acute withdrawal.

“Sutherland and Stein suggested that neurocircuits centered in the insula may represent a biomarker for acute withdrawal (Sutherland and Stein, 2018).”

• cites Sutherland and Stein, 2018Not checked yet

  Not checked in the free run.

May combine two claims.

Decreased insula activation leads to decreased inhibitory control, which could be an indicator of relapse.

“Therefore decreased insula activation leads to decreased inhibitory control, which could be an indicator of relapse (Gilman et al., 2018).”

• cites Gilman et al., 2018Not checked yet

  Not checked in the free run.

May combine two claims.

We can learn from lesion studies that a loss of function improves cessation probability, therefore it might be that the gain of function is the key factor in addictions.

“However, we can learn from lesion studies that a loss of function improves cessation probability, therefore it might be that the gain of function is the key factor in addictions.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

The insula should not be thought of in isolation but rather as part of a network.

“However, understanding of the reciprocal relationship of the insula and other brain regions will lead to a better understand in its role in addiction, as the insula should not be thought of in isolation but rather as part of a network.”

May combine two claims.

No studies have yet to investigate brain stimulation of the insula in addiction, with the exception of one clinical trial in smokers that targeted the insula and PFC together.

“No studies have yet to investigate brain stimulation of the insula in addiction, with the exception of one clinical trial in smokers that targeted the insula and PFC together (Dinur-Klein et al., 2014).”

• cites Dinur-Klein et al., 2014 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In smokers (n = 115), high-frequency deep TMS (10 Hz) to the lateral PFC and insula bilaterally significantly reduced cigarette consumption, as well as nicotine dependence.

“High-frequency deep TMS (10 Hz) was found to significantly reduce cigarette consumption, as well as nicotine dependence.”

• cites Dinur-Klein et al., 2014 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Modafinil, ketamine, baclofen, oxytocin, and varenicline have an effect on the insula.

“There is evidence that modafinil (Cera et al., 2014), ketamine (Carlson et al., 2013; Höflich et al., 2017; Evans et al., 2018), baclofen (Franklin et al., 2011; Franklin et al., 2012), oxytocin (Riem et al., 2011) and varenicline (Sutherland et al., 2013a) have an effect on the insula.”

• cites Cera et al., 2014Not checked yet

  Not checked in the free run.

• cites Carlson et al., 2013Not checked yet

  Not checked in the free run.

• cites Franklin et al., 2011Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Most participants in the clinical studies are males.

“the absolute number of participants in these studies is small, and most are males.”

May combine two claims.

Structural studies showed that addiction resulted in a loss of gray matter in the insula, thus suggesting a loss of function.

“Structural studies showed that addiction resulted in a loss of gray matter in the insula, thus suggesting a loss of function.”

Classified as probably not a substantial claim. May combine two claims.

It has been suggested in several studies that insula-related activation patterns can be used as a prognostic tool, as well as the link between the insula and striatum, which might suggest that an adequate striatal inhibition by the insula might be a good prognostic factor.

“In summary, it has been suggested in several studies that insula-related activation patterns can be used as a prognostic tool, as well as the link between the insula and striatum, which might suggest that an adequate striatal inhibition by the insula might be a good prognostic factor.”

May combine two claims.

Studies targeting the insula are lacking as there is currently only one study completed thus far.

“Studies targeting the insula are lacking as there is currently only one study completed thus far (Dinur-Klein et al., 2014).”

• cites Dinur-Klein et al., 2014 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Although the evidence of the involvement of the insula in addiction is convincing, there is a lack of research translating this into treatment for addicted individuals.

“Although the evidence of the involvement of the insula in addiction is convincing, there is a lack of research translating this into treatment for addicted individuals.”

May combine two claims.

The imaging studies presented are correlational and not causative.

“the imaging studies presented are correlational and not causative”

Probably not a substantial claim: may not pass S3 (load-bearing).

The methods of the studies vary, for example different resting-state functional connectivity protocols.

“The methods of the studies also vary (i.e., different rsFC protocols)”

Probably not a substantial claim: may not pass S3 (load-bearing).

Variation in methods could lead to variability in findings.

“which could lead to variability in findings.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Studies approached different phases of addiction, such as abstinent versus non-abstinent users.

“studies approached different phases of addiction (i.e., abstinent vs non-abstinent users).”