Krista M. Lisdahl

Dare to delay? The impacts of adolescent alcohol and marijuana use onset on cognition, brain structure, and function.

Throughout the world, drug and alcohol use has a clear adolescent onset (Degenhardt et al., 2008). Alcohol continues to be the most popular drug among teens and emerging adults, with almost a third of 12th graders and 40% of college students reporting recent binge drinking (Johnston et al., 2009, 2010), and marijuana (MJ) is the second most popular drug in teens (Johnston et al., 2010). The initiation of drug use is consistent with an overall increase in risk-taking behaviors during adolescence that coincides with significant neurodevelopmental changes in both gray and white matter (Giedd et al., 1996a; Paus et al., 1999; Sowell et al., 1999, 2002, 2004; Gogtay et al., 2004; Barnea-Goraly et al., 2005; Lenroot and Giedd, 2006). Animal studies have suggested that compared to adults, adolescents may be particularly vulnerable to the neurotoxic effects of drugs, especially alcohol and MJ (see Schneider and Koch, 2003; Barron et al., 2005; Monti et al., 2005; Cha et al., 2006; Rubino et al., 2009; Spear, 2010). In this review, we will provide a detailed overview of studies that examined the impact of early adolescent onset of alcohol and MJ use on neurocognition (e.g., Ehrenreich et al., 1999; Wilson et al., 2000; Tapert et al., 2002a; Hartley et al., 2004; Fried et al., 2005; Townshend and Duka, 2005; Medina et al., 2007a; McQueeny et al., 2009; Gruber et al., 2011, 2012; Hanson et al., 2011; Lisdahl and Price, 2012), with a special emphasis on recent prospective longitudinal studies (e.g., White et al., 2011; Hicks et al., 2012; Meier et al., 2012). Finally, we will explore potential clinical and public health implications of these findings.

Increased Marijuana Use and Gender Predict Poorer Cognitive Functioning in Adolescents and Emerging Adults

This study sought to characterize neuropsychological functioning in MJ-using adolescents and emerging adults (ages 18-26) and to investigate whether gender moderated these effects. Data were collected from 59 teens and emerging adults including MJ users (n = 23, 56% female) and controls (n = 35, 50% female) aged 18-26 (M = 21 years). Exclusionary criteria included independent Axis I disorders (besides SUD), and medical and neurologic disorders. After controlling for reading ability, gender, subclinical depressive symptoms, body mass index, and alcohol and other drug use, increased MJ use was associated with slower psychomotor speed/sequencing ability (p < .01), less efficient sustained attention (p < .05), and increased cognitive inhibition errors (p < .03). Gender significantly moderated the effects of MJ on psychomotor speed/sequencing ability (p < .003) in that males had a more robust negative relationship. The current study demonstrated that MJ exposure was associated with poorer psychomotor speed, sustained attention and cognitive inhibition in a dose-dependent manner in young adults, findings that are consistent with other samples of adolescent MJ users. Male MJ users demonstrated greater cognitive slowing than females. Future studies need to examine the neural substrates underlying with these cognitive deficits and whether cognitive rehabilitation or exercise interventions may serve as a viable treatments of cognitive deficits in emerging adult MJ users.

Recent binge drinking predicts smaller cerebellar volumes in adolescents

The current study examined the effects of recent binge drinking on cerebellar morphometry in a sample of healthy adolescents. Participants were 106 teenagers (46 bingers and 60 controls) aged 16-19 who received a high-resolution magnetic resonance imaging (MRI) scan. FreeSurfer segmented and quantified the volume of each cerebellum. Maximum drinks during a binge in the past 3 months and duration since last binge were examined as predictors of cerebellar volume, after controlling for potentially confounding variables. In the 106 teens, higher peak drinks predicted smaller left hemisphere cerebellar gray and whitematter, and right hemisphere cerebellar gray matter, and marginally predicted smaller right hemisphere cerebellar white matter. Gender did not moderate these effects. More intense adolescent binge drinking is linked to smaller cerebellar volumes even in healthy teens, above and beyond variability attributable to risk factors for binge drinking. Longitudinal research is needed to see if cerebellar volumes worsen with protracted drinking and recover with abstinence. Interventions aimed at improving brain structure in adolescent binge drinkers are necessary given the high prevalence of risky drinking in youth.

Impact of ADHD and cannabis use on executive functioning in young adults

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) and cannabis use are each associated with specific cognitive deficits. Few studies have investigated the neurocognitive profile of individuals with both an ADHD history and regular cannabis use. The greatest cognitive impairment is expected among ADHD Cannabis Users compared to those with ADHD-only, Cannabis use-only, or neither. METHODS Young adults (24.2 ± 1.2 years) with a childhood ADHD diagnosis who did (n=42) and did not (n=45) report past year ≥ monthly cannabis use were compared on neuropsychological measures to a local normative comparison group (LNCG) who did (n=20) and did not (n=21) report past year regular cannabis use. Age, gender, IQ, socioeconomic status, and past year alcohol and smoking were statistical covariates. RESULTS The ADHD group performed worse than LNCG on verbal memory, processing speed, cognitive interference, decision-making, working memory, and response inhibition. No significant effects for cannabis use emerged. Interactions between ADHD and cannabis were non-significant. Exploratory analyses revealed that individuals who began using cannabis regularly before age 16 (n=27) may have poorer executive functioning (i.e., decision-making, working memory, and response inhibition), than users who began later (n=32); replication is warranted with a larger sample. CONCLUSIONS A childhood diagnosis of ADHD, but not cannabis use in adulthood, was associated with executive dysfunction. Earlier initiation of cannabis use may be linked to poor cognitive outcomes and a significantly greater proportion of the ADHD group began using cannabis before age 16. Regular cannabis use starting after age 16 may not be sufficient to aggravate longstanding cognitive deficits characteristic of ADHD.

Serotonin transporter gene moderates associations between mood, memory and hippocampal volume

BACKGROUND The short (S) allele of the serotonin transporter gene (5-HTTLPR) is associated with reduced serotonin turnover compared to the long (L) allele in Caucasians. Few studies have examined its impact on memory and brain structure in healthy young adults. METHODS Participants included 51 healthy young adults (25 female; ages 18-25). Multiple regressions examined the independent contribution of 5-HTTLPR biomarker genotype and its interactions with gender and sub-clinical depressive symptoms on hippocampal volumes and memory. RESULTS The 5-HTTLPR genotype significantly interacted with gender in predicting larger left hippocampal volumes in S-carrying females and smaller hippocampal volumes in males (p<.03). Gender also moderated the impact of the 5-HTTLPR on neurocognition. In females, S allele carriers had poorer visual recall compared to L carriers (p<.05). A three-way interaction between 5-HTTLPR, gender, and depressive symptoms was also observed (p<.04). In females, larger left hippocampal volumes were associated with increased depressive symptoms while the opposite was seen in males. Finally, in male and female S carriers, increased depressive symptoms were marginally associated with poorer verbal memory (p<.09). CONCLUSIONS In females, the 5-HTTLPR S allele was associated with poorer memory performance, increased depressive symptoms and larger hippocampal volumes. In males, the S allele predicted smaller hippocampal volumes and increased depressive symptoms. The opposite morphometric patterns likely reflect gender differences in adolescent hippocampal development. Larger longitudinal studies are needed to examine whether the impact of 5-HTTLPR genotype on neurocognition across development differs according to extent of mood symptoms and gender.

Poorer frontolimbic white matter integrity is associated with chronic cannabis use, FAAH genotype, and increased depressive and apathy symptoms in adolescents and young adults.

Background The heaviest period of cannabis use coincides with ongoing white matter (WM) maturation. Further, cannabis-related changes may be moderated by FAAH genotype (rs324420). We examined the association between cannabis use and FAAH genotype on frontolimbic WM integrity in adolescents and emerging adults. We then tested whether observed WM abnormalities were linked with depressive or apathy symptoms. Methods Participants included 37 cannabis users and 37 healthy controls (33 female; ages 18–25). Multiple regressions examined the independent and interactive effects of variables on WM integrity. Results Regular cannabis users demonstrated reduced WM integrity in the bilateral uncinate fasciculus (UNC) (MD, right: p = .009 and left: p = .009; FA, right: p = .04 and left: p = .03) and forceps minor (fMinor) (MD, p = .03) compared to healthy controls. Marginally reduced WM integrity in the cannabis users was found in the left anterior thalamic radiation (ATR) (FA, p = .08). Cannabis group ∗ FAAH genotype interaction predicted WM integrity in bilateral ATR (FA, right: p = .05 and left: p = .001) and fMinor (FA, p = .02). In cannabis users, poorer WM integrity was correlated with increased symptoms of depression and apathy in bilateral ATR and UNC. Conclusions Consistent with prior findings, cannabis use was associated with reduced frontolimbic WM integrity. WM integrity was also moderated by FAAH genotype, in that cannabis-using FAAH C/C carriers and A carrying controls had reduced WM integrity compared to control C/C carriers. Observed frontolimbic white matter abnormalities were linked with increased depressive and apathy symptoms in the cannabis users.

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

Highlights • We compare gyrification and surface area in prefrontal and parietal cortex in young cannabis users and controls.• Frequent cannabis use was associated with reduced gyrification in prefrontal subregions.• Reduced gyrification in cannabis users was associated with poorer performance.• Sensitive periods during neurodevelopment may be affected by frequent cannabis use.

The impact of ADHD persistence, recent cannabis use, and age of regular cannabis use onset on subcortical volume and cortical thickness in young adults

BACKGROUND Both Attention Deficit Hyperactivity Disorder (ADHD) and chronic cannabis (CAN) use have been associated with brain structural abnormalities, although little is known about the effects of both in young adults. METHODS Participants included: those with a childhood diagnosis of ADHD who were CAN users (ADHD_CAN; n=37) and non-users (NU) (ADHD_NU; n=44) and a local normative comparison group (LNCG) who did (LNCG_CAN; n=18) and did not (LNCG_NU; n=21) use CAN regularly. Multiple regressions and MANCOVAs were used to examine the independent and interactive effects of a childhood ADHD diagnosis and CAN group status and age of onset (CUO) on subcortical volumes and cortical thickness. RESULTS After controlling for age, gender, total brain volume, nicotine use, and past-year binge drinking, childhood ADHD diagnosis did not predict brain structure; however, persistence of ADHD was associated with smaller left precentral/postcentral cortical thickness. Compared to all non-users, CAN users had decreased cortical thickness in right hemisphere superior frontal sulcus, anterior cingulate, and isthmus of cingulate gyrus regions and left hemisphere superior frontal sulcus and precentral gyrus regions. Early cannabis use age of onset (CUO) in those with ADHD predicted greater right hemisphere superior frontal and postcentral cortical thickness. DISCUSSION Young adults with persistent ADHD demonstrated brain structure abnormalities in regions underlying motor control, working memory and inhibitory control. Further, CAN use was linked with abnormal brain structure in regions with high concentrations of cannabinoid receptors. Additional large-scale longitudinal studies are needed to clarify how substance use impacts neurodevelopment in youth with and without ADHD.

Go/No Go task performance predicts cortical thickness in the caudal inferior frontal gyrus in young adults with and without ADHD

Response inhibition deficits are widely believed to be at the core of Attention-Deficit Hyperactivity Disorder (ADHD). Several studies have examined neural architectural correlates of ADHD, but research directly examining structural correlates of response inhibition is lacking. Here we examine the relationship between response inhibition as measured by a Go/No Go task, and cortical surface area and thickness of the caudal inferior frontal gyrus (cIFG), a region implicated in functional imaging studies of response inhibition, in a sample of 114 young adults with and without ADHD diagnosed initially during childhood. We used multiple linear regression models to test the hypothesis that Go/No Go performance would be associated with cIFG surface area or thickness. Results showed that poorer Go/No Go performance was associated with thicker cIFG cortex, and this effect was not mediated by ADHD status or history of substance use. However, independent of Go/No Go performance, persistence of ADHD symptoms and more frequent cannabis use were associated with thinner cIFG. Go/No Go performance was not associated with cortical surface area. The association between poor inhibitory functioning and thicker cIFG suggests that maturation of this region may differ in low performing participants. An independent association of persistent ADHD symptoms and frequent cannabis use with thinner cIFG cortex suggests that distinct neural mechanisms within this region may play a role in inhibitory function, broader ADHD symptomatology, and cannabis use. These results contribute to Research Domain Criteria (RDoC) by revealing novel associations between neural architectural phenotypes and basic neurobehavioral processes measured dimensionally.

Craving is associated with amygdala volumes in adolescent marijuana users during abstinence

Abstract Background: Amygdala volume abnormalities have been reported in relation to craving in substance-dependent adults, but it remains unclear if these effects are seen in adolescent marijuana (MJ) users, particularly following abstinence. Objectives: The aim of this study was to examine the relationship between amygdala volume and craving during 28 days of abstinence in adolescent MJ users. Methods: MJ-using adolescents (n = 22) aged 16–19 were recruited as part of a larger study on brain function in teen drug users. Craving measures were collected twice per week throughout a 28-day abstinence period. High-resolution anatomical magnetic resonance imaging data were collected at the end of the 28 days of confirmed abstinence. Left and right amygdala volumes were traced by hand (ICC > 0.86). Composite scores for self-reported craving and withdrawal symptoms throughout the 28-day abstinence period were calculated to provide four composite measures of total craving, mood, sleep, and somatic complaints. Results: Results revealed that greater craving during abstinence was significantly associated with smaller left and right amygdala volumes, after controlling for age and gender. Other measures of withdrawal, including mood, somatic complaints and sleep problems, were not related to amygdala morphometry. Conclusion: These results are consistent with previous findings in adult alcohol- and cocaine-dependent individuals, who demonstrated a relationship between reduced amygdala volumes and increased craving. Future studies are needed to determine if these brain-behavior relationships are attributable to MJ use or predate the onset of substance use.