Impact of FAAH Genotype and Marijuana Use on Brain Structure and Neuropsychological Performance in Emerging Adults

Introduction: Chronic MJ use may be associated with higher cognitive ability impairments (see Lisdahl et al., 2013). Regions undergoing later maturation (Gogtay 2004), may be at increased risk for MJ-induced alterations. Endogenous cannabinoid signaling (ECS) is modulated by the function the enzyme Fatty Acid Amide Hydrolase (see Ho & Hilard, 2005), thus the gene encoding for this enzyme (FAAH) impacts ECS (Sipe et al., 2002). Here, we examine the impact of MJ use and FAAH genotype on PFC complexity and underlying frontal white matter (WM) integrity in young adults. Methods: Participants included 37 MJ users and 37 non-using young adults (ages 18-25). Of those, 27 were FAAH A carriers and 47 were homozygous (C/C) carriers. Exclusion criteria included co-morbid psychiatric and neurologic disorders and excessive other drug use. Brain complexity and WM integrity was measured using local gyrification index and Tracula programs. The Letter Number Sequencing, PASAT and D-Kefs c/w interference measured complex attention and inhibition. Multiple regressions and Pearson r correlations were used to predict LGI, WM integrity and cognitive performance indices from MJ use status, FAAH status, and MJ*FAAH interactions controlling for demographic variables and comorbid drug use. Results: MJ users demonstrated decreased LGI in bilateral vmPFC (RH: [beta=-.54, p\u3c.001] and LH: [beta=-.55, p\u3c.001]); bilateral mPFC (RH: [beta=-.48, p=.001] and LH: [beta=-.51, p\u3c.001]); and bilateral frontal poles (RH: [beta=-.31, p=.02]; LH: [beta=-.43, p=.004]), with increased LGI in LH DLPFC [beta=.40, p=.004]. Controlling for the same variables, reduced WM integrity was found in bilateral UCF (RH: [beta=.32, p=.03] and LH: [beta=.31, p=.03]) and fMinor [beta=.27, p=.05] tracts of MJ users. Significant interactions between MJ*FAAH were seen predicting LGI in LH OFC [beta=-.24, p=.04] and WM integrity in fMinor [beta=.26, p=.04] and LH ATR [beta=.36, p=.003]. In MJ users, increased gyrification was associated with better LNS performance in RH mPFC [r=.51, p=.001], RH vmPFC [r=.41, p=.01], and RH frontal pole [r=.45, p=.005] and a negative correlation with gyrification and color-word completion time in LH vmPFC [r=-.32, p=.05]. In MJ users, decreased WM integrity was associated with greater PASAT performance in the RH UNC [r=.38, p=.02]. Discussion: MJ use was associated with reduced LGI in several PFC regions with one region showing an opposite relationship. These results are consistent with Mata and colleagues (2010). We also found reduced WM integrity in fronto-temporal tracts, which may have important emotion regulation implications. These brain characteristics were also moderated by FAAH genotype. Additional implications of ECS and brain health will be discussed

Intrinsic Frontolimbic Connectivity and Associated Patterns on Reported Mood Symptoms in Young Adult Cannabis Users

Introduction: Recent legislation changes regarding cannabis in the United States highlights the importance of investigating the impact of regular cannabis use on populations, such as emerging adults, that will likely drive the market given their greater daily use (see Johnston et al., 2014). The endocannbinoid system plays a role in neurodevelopment (see Bossong & Niesink, 2010) and has been implicated in behavioral and emotional processing (see Moreira & Lutz, 2008; see Solinas et al., 2008; see Covey et al., 2014). The current study utilized a multisite functional magnetic resonance imaging (fMRI) dataset of intrinsic (a.k.a. no task/resting state) frontolimbic connectivity among healthy emerging adults. A secondary aim examined the relationship between cannabis group connectivity differences and self-reported mood and affect symptoms. Methods: Participants included consortium data totaling 79 cannabis users (average of 58 past month joints) and 80 controls (0 past month joints & no history of regular use) emerging adults (ages of 18-30), balanced for gender, reading ability, and age. Exclusion criteria included history of medical/neurological illness or injury, independent DSM-IV-TR axis I disorders, and inability to maintain monitored abstinence. Structural and functional neuroimages were preprocessed and analyzed using CPAC software. Regions of interest included: anterior cingulate (rostral and caudal subdivisions), amygdala, insula, and ventral medial prefrontal cortex. Behavioral measurements included the Beck Depression Inventory-II, Beck Anxiety Scale, and the State Trait Anxiety Inventory-Y1. Standard multiple regressions were used to predict if cannabis group status was associated with frontolimbic connectivity after controlling for site, past month alcohol and nicotine use, and days of abstinence from cannabis. Pearson r correlations were run to examine the relationship between group differences in connectivity and self-reported depression and anxiety total scores. Results: On self-reported measures, cannabis users reported significantly more total depression (p=.02) and anxiety (p=.04) symptoms. After controlling for site, past month alcohol and nicotine use, and days of abstinence from cannabis, cannabis users demonstrated significantly greater connectivity between left rACC and the following: left amygdala (p=.03; corrected p=.47; ƒ2 = .17), left insula (p=.03; corrected p=.47; ƒ2 = .16), and right rACC (p=.001; corrected p=.05; ƒ2 =.55). Among cannabis users, greater bilateral rACC connectivity was associated with significantly greater total depressive scores (p=.02). Discussion: Cannabis using young adults demonstrated greater connectivity within frontolimbic regions compared to controls with no recent or regular cannabis use. In cannabis users, greater bilateral rACC intrinsic connectivity was associated with higher levels of depression symptoms. Current findings suggest that regular cannabis use during neurodevelopmental periods may alter intrinsic brain characteristics involved in cognitive control and emotion regulation, and this finding should be considered when designing clinical interventions for this population. Future research may investigate the mechanisms underlying altered rACC connectivity, such as GABA and GLUT signaling, and the impact on mood in young cannabis users

Intrinsic Frontolimbic Connectivity and Mood Symptoms in Young Adult Cannabis Users.

Objective: The endocannbinoid system and cannabis exposure has been implicated in emotional processing. The current study examined whether regular cannabis users demonstrated abnormal intrinsic (a.k.a. resting state) frontolimbic connectivity compared to non-users. A secondary aim examined the relationship between cannabis group connectivity differences and self-reported mood and affect symptoms. Method: Participants included 79 cannabis-using and 80 non-using control emerging adults (ages of 18-30), balanced for gender, reading ability, and age. Standard multiple regressions were used to predict if cannabis group status was associated with frontolimbic connectivity after controlling for site, past month alcohol and nicotine use, and days of abstinence from cannabis. Results: After controlling for research site, past month alcohol and nicotine use, and days of abstinence from cannabis, cannabis users demonstrated significantly greater connectivity between left rACC and the following: right rACC (p = 0.001; corrected p = 0.05; f 2 = 0.55), left amygdala (p = 0.03; corrected p = 0.47; f 2 = 0.17), and left insula (p = 0.03; corrected p = 0.47; f 2 = 0.16). Among cannabis users, greater bilateral rACC connectivity was significantly associated with greater subthreshold depressive symptoms (p = 0.02). Conclusions: Cannabis using young adults demonstrated greater connectivity within frontolimbic regions compared to controls. In cannabis users, greater bilateral rACC intrinsic connectivity was associated with greater levels of subthreshold depression symptoms. Current findings suggest that regular cannabis use during adolescence is associated with abnormal frontolimbic connectivity, especially in cognitive control and emotion regulation regions

Impact of cannabis use on prefrontal and parietal cortex gyrification and surface area in adolescents and emerging adults

Background: Regions undergoing maturation with CB1 receptors may be at increased risk for cannabis-induced alterations. Here, we examine the relationships between cannabis use and prefrontal (PFC) and inferior parietal gyrification and surface area (SA) in youth. Methods: Participants included 33 cannabis users and 35 controls (ages 18–25). Exclusions included co-morbid psychiatric/neurologic disorders and heavy other drug use. Multiple regressions and Pearson r correlations examined the effects of cannabis use on gyrification, SA and cognition. Results: Cannabis use was associated with decreased gyrification in: ventral-medial PFC (RH: [FDR corrected p = .02], LH: [FDR corrected p = .02]); medial PFC (RH: [FDR corrected p = .02], LH: [FDR corrected p = .02]); and frontal poles (RH: [FDR corrected p = .02], LH: [FDR corrected p = .02]). No differences were observed in bilateral hemispheres, PFC, dorsolateral, ventrolateral, or inferior parietal ROIs. Cannabis use was associated with marginally decreased SA in left: medial PFC [FDR corrected p = .09], and ventral lateral PFC: [FDR corrected p = .09]. In cannabis users, increased gyrification was associated with improved working-memory performance in right medial (p = .003), ventral-medial (p = .03), and frontal pole ROIs (p = .007). Conclusions: Cannabis use was associated with reduced gyrification in PFC regions implicated in self-referential thought and social cognition. Results suggest that these gyrification characteristics may have cognitive implications

Cortical Gyrification Patterns Associated with Trait Anxiety.

Dispositional anxiety is a stable personality trait that is a key risk factor for internalizing disorders, and understanding the neural correlates of trait anxiety may help us better understand the development of these disorders. Abnormal cortical folding is thought to reflect differences in cortical connectivity occurring during brain development. Therefore, assessing gyrification may advance understanding of cortical development and organization associated with trait anxiety. Previous literature has revealed structural abnormalities in trait anxiety and related disorders, but no study to our knowledge has examined gyrification in trait anxiety. We utilized a relatively novel measure, the local gyrification index (LGI), to explore differences in gyrification as a function of trait anxiety. We obtained structural MRI scans using a 3T magnetic resonance scanner on 113 young adults. Results indicated a negative correlation between trait anxiety and LGI in the left superior parietal cortex, specifically the precuneus, reflecting less cortical complexity among those high on trait anxiety. Our findings suggest that aberrations in cortical gyrification in a key region of the default mode network is a correlate of trait anxiety and may reflect disrupted local parietal connectivity

Average Verbal Memory Performance According to Drug Group and 5-HTTLPR Genotype.

<p><i>5-HTTLPR</i> genotype interacted with ecstasy group to predict (a) total recall of the first 5 trials; (b) average short delay free recall; (c) average long delay (20 minute) verbal recall; and (d) average recognition. In the non-using controls, the S allele was associated with poorer verbal memory while in the ecstasy users, the L/L genotypes performed worse than S carriers and both control groups.</p

<i>5-HTTLPR</i> Genotype Moderates the Effects of Past Ecstasy Use on Verbal Memory Performance in Adolescent and Emerging Adults: A Pilot Study

<div><p>Objective</p><p>Ecstasy use is associated with memory deficits. Serotonin transporter gene (<i>5-HTTLPR</i>) polymorphisms have been linked with memory function in healthy samples. The present pilot study investigated the influence of <i>5-HTTLPR</i> polymorphisms on memory performance in ecstasy users, marijuana-using controls, and non-drug-using controls, after a minimum of 7 days of abstinence.</p><p>Method</p><p>Data were collected from 116 young adults (18–25 years-old), including 45 controls, 42 marijuana users, and 29 ecstasy users, and were balanced for <i>5-HTTLPR</i> genotype. Participants were abstinent seven days prior to completing memory testing. Three MANCOVAs and one ANCOVA were run to examine whether drug group, <i>5-HTTLPR</i> genotype, and their interactions predicted verbal and visual memory after controlling for gender, past year alcohol use, other drug use, and nicotine cotinine levels.</p><p>Results</p><p>MANCOVA and ANCOVA analysis revealed a significant interaction between drug group and genotype (<i>p</i> = .03) such that ecstasy users with the L/L genotype performed significantly worse on CVLT-2 total recall (<i>p</i> = .05), short (<i>p</i> = .008) and long delay free recall (<i>p</i> = .01), and recognition (<i>p</i> = .006), with the reverse pattern found in controls. Ecstasy did not significantly predict visual memory. <i>5-HTTLPR</i> genotype significantly predicted memory for faces (p = .02); short allele carriers performed better than those with L/L genotype.</p><p>Conclusions</p><p><i>5-HTTLPR</i> genotype moderated the effects of ecstasy on verbal memory, with L/L carriers performing worse compared to controls. Future research should continue to examine individual differences in ecstasy’s impact on neurocognitive performance as well as relationships with neuronal structure. Additional screening and prevention efforts focused on adolescents and emerging adults are necessary to prevent ecstasy consumption.</p></div

Correlations between LGI and other cortical measurements.

<p>(A) Scatterplot of the correlation between total surface area and average LGI within the precuneus. (B) Scatterplot demonstrating a negative correlation between average cortical thickness and average LGI within the precuneus. (C) Scatterplot demonstrating the correlation between trait anxiety and LGI when controlling for both cortical surface area and thickness.</p

Decreased precuneus gyrification is associated with trait anxiety.

<p>(A) Inflated and pial surface maps of the left hemisphere demonstrating decreased gyrification in the precuneus as a function of trait anxiety. Images on the left depict the medial view of the left hemisphere. Images on the right are a view from the top of the right hemisphere and are tilted 30 degrees to provide a better angle for viewing the cluster extent. (B) Scatterplot of the correlation between trait anxiety and average LGI within the precuneus cluster.</p