Tim McQueeny

Altered White Matter Integrity in Adolescent Binge Drinkers

BACKGROUND White matter integrity has been found to be compromised in adult alcoholics, but it is unclear when in the course of alcohol exposure white matter abnormalities become apparent. This study assessed microstructural white matter integrity among adolescent binge drinkers with no history of an alcohol use disorder. METHODS We used diffusion tensor imaging to examine fractional anisotropy (FA), a measure of directional coherence of white matter tracts, among teens with (n = 14) and without (n = 14) histories of binge drinking but no history of alcohol use disorder, matched on age, gender, and education. RESULTS Binge drinkers had lower FA than controls in 18 white matter areas (clusters > or =27 contiguous voxels, each with p < 0.01) throughout the brain, including the corpus callosum, superior longitudinal fasciculus, corona radiata, internal and external capsules, and commissural, limbic, brainstem, and cortical projection fibers, while exhibiting no areas of higher FA. Among binge drinkers, lower FA in 6 of these regions was linked to significantly greater lifetime hangover symptoms and/or higher estimated peak blood alcohol concentrations. CONCLUSIONS Binge drinking adolescents demonstrated widespread reductions of FA in major white matter pathways. Although preliminary, these results could indicate that infrequent exposure to large doses of alcohol during youth may compromise white matter fiber coherence.

Altered white matter microstructure in adolescent substance users

Chronic marijuana use during adolescence is frequently comorbid with heavy alcohol consumption and associated with CNS alterations, yet the influence of early cannabis and alcohol use on microstructural white matter integrity is unclear. Building on evidence that cannabinoid receptors are present in myelin precursors and affect glial cell processing, and that excessive ethanol exposure is associated with persistently impaired myelination, we used diffusion tensor imaging (DTI) to characterize white matter integrity in heavy substance using and non-using adolescents. We evaluated 36 marijuana and alcohol-using (MJ+ALC) adolescents (ages 16-19) and 36 demographically similar non-using controls with DTI. The diffusion parameters fractional anisotropy (FA) and mean diffusivity (MD) were subjected to whole-brain voxelwise group comparisons using tract-based spatial statistics (Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E., Watkins, K.E., Ciccarelli, O., Cader, M.Z., Matthews, P.M., Behrens, T.E., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487-1505). MJ+ALC teens had significantly lower FA than controls in 10 regions, including left superior longitudinal fasciculus (SLF), left postcentral gyrus, bilateral crus cerebri, and inferior frontal and temporal white matter tracts. These diminutions occurred in the context of increased FA in right occipital, internal capsule, and SLF regions. Changes in MD were less distributed, but increased MD was evident in the right occipital lobe, whereas the left inferior longitudinal fasciculus showed lower MD in MJ+ALC users. Findings suggest that fronto-parietal circuitry may be particularly impacted in adolescent users of the most prevalent intoxicants: marijuana and alcohol. Disruptions to white matter in this young group could indicate aberrant axonal and myelin maturation with resultant compromise of fiber integrity. Findings of increased anisotropic diffusion in alternate brain regions suggest possible neuroadaptive processes and can be examined in future studies of connectivity to determine how aberrancies in specific tracts might influence efficient cognitive processing.

White Matter Integrity in Adolescents with Histories of Marijuana Use and Binge Drinking

Structural brain abnormalities have been observed in adolescents with alcohol use disorders but less is known about neuropathological brain characteristics of teens with sub-diagnostic binge drinking or the common pattern of binge drinking combined with marijuana use. The goal of this study was to examine white matter integrity in adolescents with histories of binge drinking and marijuana use. Diffusion tensor imaging (DTI) was conducted with 42 adolescents (ages 16-19) classified as controls, binge drinkers, or binge drinkers who are also heavy marijuana users. Tract based spatial analysis identified shared fiber structure across individuals and facilitated voxelwise comparisons of fractional anisotropy (FA) and mean diffusivity (MD) between groups. Significant between group differences were found in FA in eight white matter regions (ps < or = .016) between the binge drink-only group and controls, including superior corona radiata, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and superior longitudinal fasciculus. Interestingly, in 4 of these same regions, binge drinkers who are also heavy marijuana users had higher FA than binge drinkers who did not use marijuana (ps<.05). MD did not differ between groups. Findings are largely consistent with research suggesting less neuropathology in adolescents without histories of substance use. However, binge drinkers who also use marijuana did not show as consistent a divergence from non-users as did the binge drink-only group. Detection of white matter alterations may have implications in identifying early cognitive dysfunction in substance using adolescents.

A preliminary study of functional magnetic resonance imaging response during verbal encoding among adolescent binge drinkers

Binge alcohol use is common among teenagers with 28% of 12th graders reporting getting drunk in the past month. Chronic heavy drinking has been associated with verbal learning and memory deficits in adolescents and adults, yet verbal encoding in less frequently drinking teens has not yet been studied. Here, we examined functional magnetic resonance imaging (fMRI) response during verbal encoding among adolescent binge drinkers. Participants recruited from local high schools were of ages 16-18 and consisted of 12 binge drinkers and 12 demographically similar nondrinkers. Participants were all nonsmokers, and drinkers were abstinent from alcohol for an average of 33 days at the time of scanning. Participants performed a verbal paired associates learning task during fMRI acquisition. Drinkers recalled marginally fewer words than nondrinkers (P=.07). Compared with nondrinkers, bingers showed more response in right superior frontal and bilateral posterior parietal cortices but less response in occipital cortex during novel encoding (Ps<.05, clusters >1,512microL). In addition, controls showed significant activation in the left hippocampus during novel encoding, whereas binge drinkers did not. Adolescent binge drinkers demonstrated (1) more response than nondrinkers in frontal and parietal regions, which could suggest greater engagement of working memory systems during encoding; (2) no hippocampal activation to novel word pairs; and (3) slightly poorer word pair recall, which could indicate disadvantaged processing of novel verbal information and a slower learning slope. Longitudinal studies will be needed to ascertain the degree to which emergence of binge drinking is linked temporally to these brain response patterns.

Prefrontal cortex morphometry in abstinent adolescent marijuana users: Subtle gender effects

Adult human studies suggest frontal dysfunction associated with chronic marijuana (MJ) use, but due to continued neuromaturation, adult studies may not generalize to adolescents. This study characterized prefrontal cortex (PFC) morphometry in chronic MJ‐using adolescents following 1 month of monitored abstinence. Data were collected from MJ users (n = 16) and controls (n = 16) aged 16–18. Extensive exclusionary criteria included co‐morbid psychiatric and neurologic disorders. Substance use and anatomical measures were collected after 28 days of monitored abstinence. PFC volumes were ascertained from manual tracing by reliable raters on high‐resolution magnetic resonance images. After controlling for lifetime alcohol use, gender and intracranial volume, MJ users did not differ from controls in PFC volume. However, marginal group‐by‐gender interactions were observed (P < 0.09): female MJ users demonstrated comparatively larger PFC volumes while male MJ users had smaller volumes compared with same‐gender controls. Further, group status and total PFC volume interacted in predicting executive functioning (P < 0.05). Among MJ users, smaller PFC total volume was associated with better executive functioning while the opposite pattern was seen among the controls. These preliminary results indicate that gender may moderate the relationship between MJ use and PFC morphometry. Given the relationship between larger PFC total volumes and poorer executive functioning among MJ users, female MJ users may be at increased risk for neurocognitive consequences. Future research will measure PFC gray and white matter separately and follow boys and girls over adolescence to examine the influence of MJ use on neurodevelopment.

Gender effects on amygdala morphometry in adolescent marijuana users

Adolescent developments in limbic structures and the endogenous cannabinoid system suggest that teenagers may be more vulnerable to the negative consequences of marijuana use. This study examined the relationships between amygdala volume and internalizing symptoms in teenaged chronic marijuana users. Participants were 35 marijuana users and 47 controls ages 16-19 years. Exclusions included psychiatric (e.g., mood and anxiety) or neurologic disorders. Substance use, internalizing (anxiety/depression) symptoms and brain scans were collected after 28 days of monitored abstinence. Reliable raters manually traced amygdala and intracranial volumes on high-resolution magnetic resonance images. Female marijuana users had larger right amygdala volumes and more internalizing symptoms than female controls, after covarying head size, alcohol, nicotine and other substance use (p<0.05), while male users had similar volumes as male controls. For female controls and males, worse mood/anxiety was linked to smaller right amygdala volume (p<0.05), whereas more internalizing problems was associated with bigger right amygdala in female marijuana users. Gender interactions may reflect marijuana-related interruptions to sex-specific neuromaturational processes and staging. Subtle amygdala development abnormalities may underlie particular vulnerabilities to sub-diagnostic depression and anxiety in teenage female marijuana users.

The Influence of Recency of Use on fMRI Response During Spatial Working Memory in Adolescent Marijuana Users

Abstract Some neurocognitive recovery occurs within a month of abstinence from heavy marijuana use, yet functional magnetic resonance imaging (fMRI) has revealed altered activation among recent and abstinent adult users. We compared fMRl response during a spatial working memory (SWM) task between adolescent marijuana users with brief and sustained durations of abstinence. Participants were 13 recent users (two to seven days abstinent), 13 abstinent users (27 to 60 days abstinent), and 18 nonusing controls, all ages 15 to 18. Groups were similar on demographics, had no psychiatric or medical disorders, and user groups were similar on substance histories. Teens performed a two-back SWM task during fMRI. Recent users showed greater fMRI response in medial and left superior prefrontal cortices, as well as bilateral insula. Abstinent users had increased response in the right precentral gyrus (clusters ≥ 1328 μ1, p < .05). Results suggest that adolescents who recently used marijuana show increased brain activity in regions associated with working memory updating and inhibition. This study preliminarily suggests that (1) recent marijuana use may disrupt neural connections associated with SWM and result in compensatory brain response, and (2) sustained abstinence from marijuana may be associated with improvements in SWM response among adolescents.

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.

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.

Superior longitudinal fasciculus and language functioning in healthy aging

Structural deterioration of brain tissue in older adults is thought to be responsible for the majority of age-related cognitive decline. Disruption of widespread cortical networks due to a loss of axonal integrity may also play an important role. Research examining correlations between structural change and functional decline has focused heavily on working memory, processing speed, and executive processes while other aspects of cognition, such as language functioning, have received less attention. The current study aimed to determine whether age-related changes in the superior longitudinal fasciculus (SLF), are responsible for the deterioration in language functioning associated with age. Subjects included 112 right-handed volunteers (ages 19-76). For each subject, the SLF of the left hemisphere was reconstructed from diffusion tensor images (DTI). Mean fractional anisotropy (FA) values were extracted from parietal (SLFp) and temporal (SLFt) bundles. Language functioning was measured using the Peabody Picture Vocabulary Test (PPVT), Boston Naming Test (BNT), Controlled Oral Word Association Test (COWAT), and Semantic Fluency Test (SFT). Regression analyses revealed that males and females showed a different pattern of decline in FA across adulthood. For males, greater SLFt FA was significantly associated with increased COWAT performance, and there was a positive relationship between both age and SLFp FA with BNT scores. In females, greater SLFp FA was related to lower COWAT performance. Taken together, the results suggest that white matter integrity of the SLF follows a different pattern of decline in adulthood for males and females, and this decline differentially affects language functioning.