Altered prefrontal and insular cortical thickness in adolescent marijuana users

“Measures of current psychopathology were obtained using the Profile of Mood States (POMS), [59], the State-Trait Anxiety Inventory (STAI) [60], Hamilton Depression Rating Scale (HAM-D) [61] and the Hamilton Anxiety Scale (HAMA) [62].”

“Generally, gray matter maturation occurs via thinning of the cortical mantel and is presumed to be related to synaptic pruning [52,70,71].”

“, deafness, blindness, paralysis); estimated IQ <70 (based on measures of verbal fluency [55] and academic histories) or history of learning disabilities; history of claustrophobia, autism, schizophrenia, anorexia nervosa or bulimia, other drug or alcohol dependence/abuse (during 2 months prior to scan or total past h…”

“In addition, greater right anterior insular gray matter volumes have been correlated with increased accuracy in the subjective sense of the inner body, and with negative emotional experience [78].”

“Adolescence is also a critical developmental period during which higher cortical functions, such as decision-making, are still developing; thereby rendering adolescence a period of increased vulnerability to substance abuse and rapid drug use escalation [16–20].”

“Generally, gray matter maturation occurs via thinning of the cortical mantel and is presumed to be related to synaptic pruning [52,70,71].”

“Furthermore, previous studies have linked insular dysfunction with impaired decision making capacity and with the diminished capacity for behavioral monitoring [19,42–44].”

“Furthermore, in a recent investigation, cigarette smokers with insular lesions were more likely to quite smoking and have reduced cravings to smoke than individuals without insular lesions [77].”

“Moreover, numerous functional imaging studies have found both prefrontal and insular activation during conscious drug urges [38–42].”

“Specific to MJ related cravings, one study reported greater activation in the insula in 38 regular adult MJ users, who had abstained for 72 hours, when presented with MJ related cues [76].”

“Drug addiction has also been conceptualized as an inability to recognize internal and external drug-related cues [79].”

“The lingual gyrus has been linked to visual stimulus processing [85,86], including early components of facial processing [87,88], as well as spatial orientation [89].”

“Adolescent brains may be particularly vulnerable to the neurophysiologic effects of illicit substances, as adolescence is a critical period for brain maturation, including synaptic pruning of gray matter [12–15].”

“Moreover, numerous functional imaging studies have found both prefrontal and insular activation during conscious drug urges [38–42].”

“Although the effects of illicit drugs on brain structure and function have not been fully characterized, recent findings suggest negative neurobiological consequences of adolescent and young adult substance abuse, including changes in white matter, irregularities in cerebral electrophysiological functioning, and disru…”

“Adolescents under the age of 18 were administered the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Episode (K-SADS-PL) [56] with additional mood onset and offset items derived from the WASH-U K-SADS (K-SADS-PL-W) [57].”

“There has been a sharp resurgence in adolescent substance abuse since the early 1990’s [1,2].”

“In a study of heavy cigarette smokers a positive correlation was found between intensity of craving and glucose metabolism in the anterior insula bilaterally, DLPFC, and OFC [38].”

“Together these findings suggests that MJ may interfere with the development of visual processing ability [80] and potentially to changes in affective interactions.”

“The lingual gyrus has been linked to visual stimulus processing [85,86], including early components of facial processing [87,88], as well as spatial orientation [89].”

“Although the effects of illicit drugs on brain structure and function have not been fully characterized, recent findings suggest negative neurobiological consequences of adolescent and young adult substance abuse, including changes in white matter, irregularities in cerebral electrophysiological functioning, and disru…”

“Cortical thickness-based analytic techniques have been successfully utilized in other neurodevelopmental disorders such as in Attention-Deficit/Hyperactivity Disorder (ADHD) [46–48,72], autism spectrum disorder [49], and schizophrenia [50,51] and may be particularly sensitive to the detection of aberrant maturation or…”

“Furthermore, previous studies have linked insular dysfunction with impaired decision making capacity and with the diminished capacity for behavioral monitoring [19,42–44].”

“One study of adult subjects reported that individuals who started using MJ before age 17 had smaller whole brain volumes, a smaller percentage of cortical gray matter volume and a larger percentage of white matter volume than non-users [27], suggesting earlier age of onset of MJ use may be associated with greater stru…”

“Finally, in an investigation of thirty-eight regular MJ users who were abstinent from use for 72 hours, structures in the reward pathway, including the insula and ACC, demonstrated greater activation in response to a MJ cue as compared with a neutral cue [40].”

“Adolescence is also a critical developmental period during which higher cortical functions, such as decision-making, are still developing; thereby rendering adolescence a period of increased vulnerability to substance abuse and rapid drug use escalation [16–20].”

“Cortical thickness-based analytic techniques have been successfully utilized in other neurodevelopmental disorders such as in Attention-Deficit/Hyperactivity Disorder (ADHD) [46–48,72], autism spectrum disorder [49], and schizophrenia [50,51] and may be particularly sensitive to the detection of aberrant maturation or…”

“Finally, Gruber and colleagues found that compared to nonusers, MJ smokers exhibited different patterns of BOLD response and error response during the Stroop interference condition despite similar task performance [17].”

“Furthermore, recent investigators have applied cortical thickness-based techniques to the study of changes in cortical gray matter from exposure to substances of abuse such as methamphetamine, alcohol, nicotine and MJ [51–54].”

“For instance, Kanayama utilized a spatial working memory task to examine brain activity in long-term heavy MJ users and found increased activation of brain regions typically used for spatial working memory tasks and additional regions not typically used for spatial working memory (such as regions in the basal ganglia)…”

“Functional magnetic resonance imaging (fMRI) studies in adult MJ users have reported altered activation in prefrontal and insular regions in MJ abusers performing cognitive tasks such as attention [28–31], working memory [32–34], inhibitory control [17,19,35,36] and decision making [16] during acute MJ use, chronic MJ…”

“The lingual gyrus has been linked to visual stimulus processing [85,86], including early components of facial processing [87,88], as well as spatial orientation [89].”

“Functional magnetic resonance imaging (fMRI) studies in adult MJ users have reported altered activation in prefrontal and insular regions in MJ abusers performing cognitive tasks such as attention [28–31], working memory [32–34], inhibitory control [17,19,35,36] and decision making [16] during acute MJ use, chronic MJ…”

“Functional magnetic resonance imaging (fMRI) studies in adult MJ users have reported altered activation in prefrontal and insular regions in MJ abusers performing cognitive tasks such as attention [28–31], working memory [32–34], inhibitory control [17,19,35,36] and decision making [16] during acute MJ use, chronic MJ…”

“For example, investigations of the cognitive effects of MJ following a brief abstinence period have reported that heavy MJ use is associated with deficits in the attentional/executive system [92,93].”

“Although the effects of illicit drugs on brain structure and function have not been fully characterized, recent findings suggest negative neurobiological consequences of adolescent and young adult substance abuse, including changes in white matter, irregularities in cerebral electrophysiological functioning, and disru…”

“Some studies have identified no significant anatomical changes associated with MJ use [21–24], while others report findings of cerebral atrophy [25], and decreased concavity of the sulci and thinner sulci in the right frontal lobe [26] in MJ users.”

“Cortical thickness-based analytic techniques have been successfully utilized in other neurodevelopmental disorders such as in Attention-Deficit/Hyperactivity Disorder (ADHD) [46–48,72], autism spectrum disorder [49], and schizophrenia [50,51] and may be particularly sensitive to the detection of aberrant maturation or…”

“Cortical thickness-based analytic techniques have been successfully utilized in other neurodevelopmental disorders such as in Attention-Deficit/Hyperactivity Disorder (ADHD) [46–48,72], autism spectrum disorder [49], and schizophrenia [50,51] and may be particularly sensitive to the detection of aberrant maturation or…”

“In addition, Campbell and colleagues noted cerebral atrophy in adult MJ users measured with air encephalography [25].”

“Cortical thickness-based analytic techniques have been successfully utilized in other neurodevelopmental disorders such as in Attention-Deficit/Hyperactivity Disorder (ADHD) [46–48,72], autism spectrum disorder [49], and schizophrenia [50,51] and may be particularly sensitive to the detection of aberrant maturation or…”

“Cortical thickness-based analytic techniques have been successfully utilized in other neurodevelopmental disorders such as in Attention-Deficit/Hyperactivity Disorder (ADHD) [46–48,72], autism spectrum disorder [49], and schizophrenia [50,51] and may be particularly sensitive to the detection of aberrant maturation or…”

“Other research has shown that individuals who use MJ before age 18 are more likely to develop substance abuse or dependence than are those who use MJ when they are 18 or older [84].”

“Furthermore, chronic MJ use has been reported to change response to masked facial affect [91].”

“Our finding of reduced cortical gray matter in the insula is in line with previous functional imaging studies that have found both abnormal insula activity in abstinent and current adolescent MJ abusers [73,74] and abnormal insular activation during alcohol and drug urges [42,75,76].”

“Furthermore, recent investigators have applied cortical thickness-based techniques to the study of changes in cortical gray matter from exposure to substances of abuse such as methamphetamine, alcohol, nicotine and MJ [51–54].”

“Furthermore, recent investigators have applied cortical thickness-based techniques to the study of changes in cortical gray matter from exposure to substances of abuse such as methamphetamine, alcohol, nicotine and MJ [51–54].”

“Our finding of increased cortical thickness in the bilateral lingual, right superior temporal, right parietal and left paracentral regions in adolescent MJ users compared to non-users supports the idea of neuroadaptation or possible compensatory changes in cortical gray matter in association with MJ use [17,32,95].”

“Some studies have identified no significant anatomical changes associated with MJ use [21–24], while others report findings of cerebral atrophy [25], and decreased concavity of the sulci and thinner sulci in the right frontal lobe [26] in MJ users.”

“Functional magnetic resonance imaging (fMRI) studies in adult MJ users have reported altered activation in prefrontal and insular regions in MJ abusers performing cognitive tasks such as attention [28–31], working memory [32–34], inhibitory control [17,19,35,36] and decision making [16] during acute MJ use, chronic MJ…”

“Some studies have identified no significant anatomical changes associated with MJ use [21–24], while others report findings of cerebral atrophy [25], and decreased concavity of the sulci and thinner sulci in the right frontal lobe [26] in MJ users.”

“However, if verbal fluency measures were influencing our results, greater cortical thickness measures would have been expected, particularly in prefrontal and temporal regions in our MJ users, and this was not case [96,97].”

“Becker and colleagues found that earlier age of onset was associated with increased cortical activity in the inferior and superior frontal gyrus, superior temporal gyrus, and the insula while performing verbal working memory task [82].”

“Another investigation utilized a spatial working memory task while comparing 13 adolescents with recent MJ use, 13 adolescents who had been abstinent of MJ use for 27 days, and 18 non-using controls [74].”

“The lingual gyrus has been linked to visual stimulus processing [85,86], including early components of facial processing [87,88], as well as spatial orientation [89].”

“In this previous study, healthy controls were also noted to have decreasing gyrification and decreasing cortical thickness with age, which was not noted in MJ users [26].”

“Although the effects of illicit drugs on brain structure and function have not been fully characterized, recent findings suggest negative neurobiological consequences of adolescent and young adult substance abuse, including changes in white matter, irregularities in cerebral electrophysiological functioning, and disru…”

“Adolescent brains may be particularly vulnerable to the neurophysiologic effects of illicit substances, as adolescence is a critical period for brain maturation, including synaptic pruning of gray matter [12–15].”

“Functional magnetic resonance imaging (fMRI) studies in adult MJ users have reported altered activation in prefrontal and insular regions in MJ abusers performing cognitive tasks such as attention [28–31], working memory [32–34], inhibitory control [17,19,35,36] and decision making [16] during acute MJ use, chronic MJ…”

“For example, early-onset MJ use appears to be related to a permanent deficit in visual scanning ability [80,81].”

“One recent study also suggests the lingual gyrus as being central for the processing of novel events that occur outside the focus of spatial attention [90].”

“Furthermore, recent investigators have applied cortical thickness-based techniques to the study of changes in cortical gray matter from exposure to substances of abuse such as methamphetamine, alcohol, nicotine and MJ [51–54].”

“compared to neutral cues in college students at high-risk for alcohol abuse, which is similar to insular activation abnormalities in individuals with substance dependence [41].”

“Although the effects of illicit drugs on brain structure and function have not been fully characterized, recent findings suggest negative neurobiological consequences of adolescent and young adult substance abuse, including changes in white matter, irregularities in cerebral electrophysiological functioning, and disru…”

“Adolescent brains may be particularly vulnerable to the neurophysiologic effects of illicit substances, as adolescence is a critical period for brain maturation, including synaptic pruning of gray matter [12–15].”

“In another investigation of the residual effects of MJ, chronic heavy smokers were enrolled in a 28 day supervised abstinence study using fMRI BOLD techniques and a modified version of the Stroop test [94].”

“Adolescent brains may be particularly vulnerable to the neurophysiologic effects of illicit substances, as adolescence is a critical period for brain maturation, including synaptic pruning of gray matter [12–15].”

“• Caudal Middle Frontal The caudal middle frontal cortex is a prefrontal cortical structure broadly associated with executive function 80,81 , top-down control 82 , and secondary motor processes 83,84 .”

“Results Of the 142 studies identified, thirty-six did not meet the a priori selection criteria [33,49–84] and sixty-two met the exclusion criteria [6,12,30,48,85–141] or were case/series reports [142] (for more detailed information, see Figure 1).”

“…users, including smaller whole brain and cortical grey matter volumes (Wilson et al., 2000), altered prefrontal and insular cortical thickness (Lopez-Larson et al., 2011), smaller right medial OFC volumes (Churchwell et al., 2010), smaller hippocampal volumes (Ashtari et al., 2011), greater…”

“Structural MRI studies have also found reduction of insula cortical thickness in chronic cannabis users (Lopez-Larson et al., 2011).”

“…dysfunction (Fontes et al., 2011; Gruber et al., 2011; Solowij et al., 2012), structural damage (Churchwell et al., 2010; Gruber et al., 2011; Lopez-Larson et al., 2011), and abnormal brain activation (Jager et al., 2010; Gruber et al., 2012) in the PFC. FIGURE 5 | Bivariate relationship…”

“, increased/ decreased in cortical thickness) in two ways, 1) premature development and/or alterations in neurodevelopmental trajectories or 2) tissue loss or remodeling associated with marijuanarelated toxicity [43].”

“T N: 0006-3223 B SEE COMMENTA 1 receptors, including the hippocampus (16–20), amygdala (20), striatum (21), and prefrontal cortex (PFC) (21–23).”

“Currently, the only study of cortical thickness in adolescent substance users compared 18 heavy marijuana users to 18 healthy controls and found that marijuana use was associated with both increased and decreased cortical thickness in frontal, parietal, temporal, and insular regions (Lopez-Larson et al. 2011).”

“…of use and the development of problematic patterns of use and misuse (Bonn-Miller & Zvolensky, 2009), which is of particular concern given that adolescence and early adulthood is a critical time for brain development (Gruber, Silveri, Dahlgren, & Yurgelun-Todd, 2011; Lopez-Larson et al., 2011).”

“Results from human studies demonstrate that adolescent marijuana use leads to altered FC connectivity and volume (Churchwell et al. 2010; Lopez-Larson et al. 2011, 2015; Camchong et al. 2017); many of these outcomes being more severe with earlier onset ofmarijuana use.”

“Recent morphological studies of adults and adolescents have found structural abnormalities in CB1R-rich areas, particularly in the medial temporal and frontal cortices and cerebellum, and most notably among chronic cannabis users [6, 28, 49, 60–64].”

“…measures such as cortical thickness (CT), albeit recent structural studies emphasize the relevance of the thinning of the cortical surface for impulsiveness-related disorders such as ADHD (Almeida et al., 2010; Batty et al., 2010) and substanceuse (Lawyer et al., 2010; Lopez-Larson et al., 2011).”

“In a separate cross-sectional study of 16–19-year-old adolescents, marijuana users likewise had thicker temporal and parietal cortices, but less cortical thickness in frontal and insula regions (Lopez-Larson et al., 2011).”

“…also been observed in adolescent marijuana users, with arijuana-using adolescents having larger cerebellar volumes than on-users (Medina et al., 2010), thinner cortices in prefrontal and nsular regions, and thicker cortices in posterior regions when ompared to controls (Lopez-Larson et al., 2011).”

“In contrast, examination of volume [27], sulcal concavity [21, 28] and cortical thickness [28, 33] of a variety of PFC subregions revealed group effects, exception being for one study finding no difference between CB users and HC for OFC and ACC volumes [34].”

“Indirect support for this comes from studies showing that early adolescent CU is associated with poor white matter integrity in the PFC (Becker, Wagner, Gouzoulis-Mayfrank, Spuentrup, & Daumann, 2010a; Gruber, Dahlgren, Sagar, Gonenc, & Lukas, 2014), decreased cortical thickness in the superior PFC and frontal cortice…”

“Interestingly, earlier age of onset of cannabis use has also been associated with increase in white matter volume (83), orbitofrontal connectivity (120), and cortical thickness of the superior frontal gyrus (80).”

“Several studies also have documented neural structural and activation differences between adolescent substance users and controls.(19,20) There is longitudinal evidence that alcohol use in adolescence may negatively affect memory”

“Adolescent male cannabis users exhibit region-dependent alterations in thickness of the prefrontal cortex (a key structure involved in HPA axis functioning) relative to healthy controls (Lopez-Larson et al., 2011) and posttraumatic stress disorder has been reported to contribute to the etiology of cannabis abuse or de…”

“…found abnormalities in the brain structures of a variety of substance users, such as smokers (Kuhn et al., 2010; Makris et al., 2008), alcohol users (Yang et al., 2012), marijuana users (Lopez-Larson et al., 2011), and amphetamine-type stimulant users (Koester et al., 2012; Lawyer et al., 2010).”

“Additionally, recent volumetric studies with adolescent cannabis users have found reduced cortical thickness in the insula (Lopez-Larson et al., 2011), suggesting that an intact and functional insula may be protective against and/or reflective of lower levels of cannabis use.”

“Other laboratories report dose-dependent relationships with temporal lobe structures such as hippocampus and amygdala [47] and alterations in cortical thickness [27] in frontal and parietal regions.”

“Lopez-Larson et al. (2011) reported reduced cortical thickness (semi-automated method) in PFC regions including the right caudal middle frontal, bilateral insular and bilateral superior frontal cortices among daily adolescent MJ users compared to controls, although the study sample included…”

“Overall, these data provide initial evidence for alterations in frontoparietal CT [108, 109] and changes in NAcc and amygdala morphology [97] among adolescent CU.”

“This finding may reflect the existing compensatory mechanism or neuroadaptation in the addiction brain [53,54,55].”

“There are multiple studies documenting neural structural and activation differences between adolescent substance users and controls (e.g., Abdullaev, Posner, Nunnally, & Dishion, 2010; Crowley et al., 2010; Lopez-Larson et al., 2011).”

“This pattern s consistent with that of Lopez-Larson et al. (2011), who found educed cortical thickness in bilateral superior frontal cortices in dolescent CAN users, although they also found abnormalities in he insula, lingual gyrus, superior temporal, inferior and superior arietal, and left…”

“Further, more recent research has outlined plausible biological models for how early cannabis use has effects on brain development (Lopez-Larson et al. 2011; Alpar et al. 2015; Filbey et al. 2015) and how it might interact with risk genes for schizophrenia development (French et al.”

“This trend is concerning because marijuana use may affect the neuro-maturational development of the brain among youth [10-12], potentially compromising decision-making and inhibitory control functioning [10-13].”

“, 2002), cannabis users (Lopez-Larson et al., 2011), heavy alcohol users (Xiao et al.”

“, 2013) and cannabis and other drug use (e.g., Li et al., 2014; Lopez-Larson et al., 2011) are significantly associated with variation in cortical thickness.”

“…andNiesink, 2010), andpriormorphometric data demonstrating differences in cortical thickness and brain volumes associated with CUD in both typical (Lopez-Larson et al., 2011) and atypical development (Jarvis et al., 2008; Kumra et al., 2012); and (2) The magnitude of these alterations would be…”

“Frequent cannabis users may also have thinner prefrontal cortex [15, 25], although several studies have not replicated these findings [14, 26, 27].”

“Alterations in the superior frontal gyrus have previously been reported in cannabis users in terms of reduced thickness (Lopez-Larson et al, 2011) and enhanced activation during memory and inhibitory tasks (Smith et al, 2010; Tapert et al, 2007).”

“…and hard alcohol history have been removed since the cerebellum is heavily impacted by alcohol abuse/dependence (Sullivan et al., 2010) and there is also evidence to suggest that the cerebellum is impacted by marijuana as well (Block et al., 2000; Lopez-Larson et al., 2011; Solowij et al., 2011).”

“In both, earlier onset of marijuana use (ie, before age 16) was associated with thicker PFC. Lopez-Larson et al. (2011) examined participants while they were still adolescents (ie, 16–19 years old) and reported a negative correlation between age of onset of regular marijuana use and the superior frontal gyrus, whereas…”

“Substance use and abuse has been associated with a number of changes in PFC-mediated functions and networks (Lopez-Larson et al., 2011; Squeglia, Jacobus, & Tapert, 2009), and there is evidence from both human and animal research that younger brains are more susceptible to its deleterious effects…”

“While these findings are consistent with some studies on brain volume reductions among HIV-uninfected adolescents who use alcohol or marijuana, they also differ from others identifying increased volumes with marijuana use (Jacobus et al., 2015; Lopez-Larson et al., 2011).”

“Marijuana is the most commonly used illicit drug used during adolescence (Substance Abuse and Mental Health Service Administration, 2014b), with use adversely affecting neuromaturation of the vulnerable adolescent brain (Gruber et al., 2012; Lopez-Larson et al., 2011; Schepis et al., 2011).”

“Meanwhile, another two studies on adolescent cannabis users with an average age of 18 years show thicker cortex in the parietal region instead (Jacobus et al., 2015; Lopez-Larson et al., 2011).”

“Teenage cannabis users have similarly shown thinner cortices in frontal regions (Lopez-Larson et al., 2011).”

“25,26 Adolescent cannabis exposure has also been associated with compromised white matter integrity, 27–31 including microstructural abnormalities in the splenium of the corpus callosum and the fornix.”

“…brain regions; and thicker cortices in lingual, parietal, and paracentral regions, of early adolescent cannabis users relative to non-users (Jacobus et al., 2014; Lopez-Larson et al., 2011), making it difficult to infer a consistent effect of adolescent onset of cannabis use on cortical morphology.”

“Thus, it is unclear if cannabis-related structural brain differences were apparent in adolescence or early adulthood, as some (Batalla et al., 2013; Brumback et al., 2016; Churchwell et al., 2010; Gilman et al., 2014; Lopez-Larson et al., 2011), but not all (Rocchetti et al.”

“Furthermore, earlier onset of MJ use may result in atypical cortical gray matter development and abnormal gyrification patterns not characteristic of those with later onset of MJ use (Mata et al., 2010; Lopez-Larson et al., 2011).”

“Studies published after 2008 provide strong support that marijuana use is associated with brain volume deficits (Ashtari et al. 2009, 2011 ; Medina et al. 2009, 2010 ; Mata et al. 2010 ; Lopez-Larson et al. 2011 ; McQueeny et al. 2011 ; Solowij et al. 2011).”

“ISSN:2155-6105 JART, an open access journal J Addict Res Ther Behavioral Pharmacology Magnetic resonance imaging (MRI) methods, including diffusion tensor imaging (DTI), have been utilized to investigate the effects of MJ on brain structure [18,21].”

“Narayan et al. (2007) studied cortical thickness in violent patients with schizophrenia and/or antisocial personality disorder in comparison to healthy control subjects.”

“Cortical thickness is sensitive to a range of environmental risks during childhood and adolescence but not with pre- or perinatal events (Merkley et al. 2008; Haukvik et al. 2009; Woodward et al. 2009; Kuhn et al. 2010, 2011; Habets et al. 2011; Lopez-Larson et al. 2011).”

“Certainly, location matters because both increases and decreases in thickness were observed in separate brain regions of the same adolescent users (Lopez-Larson et al., 2011).”

“Similarly, environmental factors such as substance abuse (Lopez-Larson et al. 2011; Gavrieli et al. 2011), sleep deprivation (Spiegel et al.”

“Another study found negative correlations between the age of initiation of cannabis use and altered thickness of the right superior frontal gyrus [54].”

“…studies of adolescent substance use have noted decreased cortical thickness to be associated with heavier cannabis use in areas surrounding the cIFG (e.g., caudal middle frontal gyrus, insula, paracentral lobule), but not specifically in the cIFG (Jacobus et al. 2014; Lopez-Larson et al. 2011).”

“…substance users have lower insula volume and cortical thinning compared to controls (e.g., alcohol dependent adults: Durazzo et al., 2011; cocaine dependent adults: Makris et al., 2008; stimulant dependent adults: Tanabe et al., 2013; adolescent heavy cannabis users: Lopez-Larson et al., 2011).”

“In keeping with Stone et al. (2012), Lopez-Larson et al. (2011) reported reduced cortical thickness bilaterally in the superior frontal region in healthy cannabis users.”

“CT abnormalities have been observed to be associated with SUD such as alcohol dependence (57), marijuana misuse (58), and nicotine smoking (59), as well as nonsubstance-related disorders such as excessive internet use (60) and online gaming (61).”

“Animal studies reported differential changes in cortical thickness in adolescent animals exposed to substances (Vetreno et al. 2016), while adolescent marijuana users showed reduced cortical thicknesses relative to non-users (Lopez-Larson et al. 2011).”

“cannabis users and controls, including: vmPFC (91, 92), ACC (81, 93, 94), insula (95), and amygdala (88, 96, 97).”

“This approach to perform both wholebrain and a priori identified ROI analyses follows procedures used in past studies [31, 48].”

“Brain morphological studies also revealed abnormalities in the frontal cortex of drug users, which have reported decreases in gray matter volume/density or in cortical thickness of the PFC in addicts compared to control subjects [5, 8, 12, 24].”

“Conversely, in several samples, particularly in young adolescent samples, cannabis use has also been associated with larger subcortical volumes (e.g., hippocampus and amygdala) [60, 76, 79, 80].”

“During reward, those with ASD had less activation in ACC, temporal and parietal association cortices, fusiform gyrus, precuneus, cerebellum whereas during losses they showed greater activity in OFC, dorsolateral PFC, brain stem, cerebellum, and various temporal and parietal cortices.”