No differences were found between groups before initiation, suggesting alcohol use was related to aberrant cortical thinning, as opposed to cortical thickness being predictive of initiation of alcohol use. Furthermore, widespread cortical thinning and volume reduction has also been reported in alcohol dependent adults in frontal, temporal, and occipital regions . The goals of this study were to use a set of novel analytic approaches to carefully examine within-subjects changes in morphometry and quantify cortical volume changes over time in youth who remained non-drinkers compared to those who initiated heavy drinking. We hypothesized that adolescents who transitioned into moderate to heavy drinking would show smaller cortical volumes, similar as has been seen in adolescent drinkers and adult alcoholics , but after a brief period of heavy alcohol exposure.The sample was obtained from a larger ongoing neuroimaging study of 296 adolescents examining neurocognition in youth at-risk for substance use disorders . Participants were recruited through flyers sent to households of students attending local middle schools, describing the study as a project looking at adolescent brain development in youth who do or do not use alcohol, and included major eligibility criteria, financial compensation , and contact information. Informed consent and assent were obtained, and included approval for youth and parents be contacted for follow-up interviews and scans. Eligibility criteria, substance use history, family history of substance use, developmental,greenhouse tables and mental health functioning data were obtained from the youth, their biological parent, and one other parent or close relative.
The study protocol was executed in accordance with the standards approved by the University of California, San Diego Human Research Protections Program. Participants for this study each had one brain scan acquired before the adolescent had any significant alcohol or drug use, and one follow-up scan approximately 3 years later after half transitioned into heavy substance use, for a total of 80 scans. At baseline, inclusionary criteria included being between the ages of 12 and 17 and having minimal to no experience with substances: ≤10 total drinks in their life, never with more than 2 drinks in a week; ≤5 lifetime experiences with marijuana and none in the past three months; ≤5 lifetime cigarette uses; and no history of other intoxicant use . Youth with any indication of a history of a DSM-IVAx is I disorder, determined by the NIMH Diagnostic Interview Schedule for Children –version 4.0 were excluded, as were youth who had any indicator of prenatal substance exposure, any history of traumatic brain injury, loss of consciousness , learning disorder, migraine, neurological problem, serious medical condition, or were taking a medication that could alter brain functioning or brain blood flow. After screening, approximately 12% remained eligible . Participants in the larger study completed substance use interviews every 3 months, and those who started heavy drinking were selected for a comprehensive annual follow-up with neuroimaging, and matched to a non-using control subject on baseline and follow-up age and pubertal development level, gender, race, family history of alcohol use disorders, and socioeconomic status. At follow-up, 20 were defined as heavy drinkers; 20 continuous non-drinkers were selected to match the characteristics of the heavy drinkers . Participants were assessed using rigorous follow-up procedures , with an overall follow-up rate of 99% through Year 6. Specifically, every three months after the baseline interview and imaging were complete, participants were interviewed to assess current substance use and psychiatric functioning. Those who met criteria for heavy drinking were invited to return and complete annual full in-person assessments , including neuroimaging. Each participant that endorsed heavy drinking was matched to a demographically similar participant who continued to endorse no substance use throughout the follow-up for comparison. Moderate drinkers were excluded from analysis in this paper.
Free Surfer 4.5.0 was used and required ~24-h computational time for image construction, using a dual quad core Intel Xeon CPU E5420 with a processing speed of 2.50 GHz and 16 GB ram.Subtle longitudinal morphometric changes in brain structure were measured by using a method developed at UCSD’s Multi-modal Imaging Laboratory, called “quantitative anatomic regional change analysis,” or QUARC . In the QUARC procedure, each subject’s follow-up image is registered to the baseline image using a 12-parameter affine registration and then intensity normalized to the baseline image by an iterative procedure. A deformation field is then calculated from the nonlinear registration , and used to align the images at the sub-voxel level, resulting in a one-to-one correspondence between each vertex on the baseline and follow-up images. Subcortical segmentation and cortical parcellation labels from the baseline image were used to extract an average volume change for each region of interest. A visual quality control in the volume change field was performed by a trained technician and supervised by an image analysis expert . The goal the present study was to use a recently developed longitudinal MRI paradigm to investigate brain volume differences pre- and post-substance use initiation to disentangle normal adolescent cortical thinning from alcohol-related brain changes. Cortical pruning is a key component of adolescent neural development ; however, the heavy drinking group showed exaggerated volume reductions in these areas when compared to controls, consistent with findings from adolescent and adult populations . Overall, adolescent drinkers showed greater volume reductions than demographically matched controls over the ~3 year follow-up period in the left ventral diencephalon, left inferior and middle temporal gyrus, left caudate, and brain stem. These volumetric changes were positively correlated with lifetime alcohol use and peak number of drinks on an occasion in the past year, suggesting a dose-dependent effect of substance use on cortical thinning. These findings suggest a possible effect of alcohol on neural pruning, in a way that amplifies cortical volume reductions during adolescence. These results parallel previous longitudinal functional MRI findings showing increasing brain activation over time in adolescents who initiate heavy drinking . These observed alcohol-related cortical reductions may help explain why youth required greater brain activation to complete at the same performance level as abstinent youth .
The regions showing alcohol-related volume reductions included subcortical structures , which are important for sensory integration, motor control, feedback processing, and habit learning, as well as inferior and middle temporal cortical structures important in visual object recognition and language comprehension. Previous findings suggest alcohol use interferes with language and visuospatial abilities during adolescence, which are consistent with the brain regions found in this study; continued volume reductions related to sustained drinking during adulthood might also relate to motor issues and spatial impairments found in adult alcoholics . Volume reductions in the caudate parallel findings from adult alcoholics , while reduced medial temporal volumes parallel previous results seen in adolescent heavy drinkers . While the cause of the accelerated cortical thinning is unclear, alcohol-induced dys regulated developmental timing may be responsible for the observed effects . NMDA receptor functioning could help explain accelerated thinning in heavy drinkers, as NMDA is vital for strengthening synapses and contributing to the loss of less important connections throughout development . Thus, it is possible that repeated alcohol exposure during adolescence may interfere with normal NMDA-mediated synaptic pruning. Baseline group differences were found in several frontal cortical volumes. Specifically, youth who initiated heavy drinking over the follow-up showed smaller cortical volume in three frontal regions,vertical farming as well as less cerebellar white matter volume, when compared to youth who remained substance-naïve over the follow-up. At baseline, smaller right rostral anterior cingulate volume was related to poorer performance on a test of executive functioning . These findings suggest heavy drinking youth have subtle brain abnormalities that exist prior to the onset of drinking. These findings are highly consistent with other recent functional MRI findings which found pre-existing lower frontal brain activation in teens who later initiated heavy drinking when compared to continuous controls over a three year follow-up . The current findings might help explain previous findings where heavy drinking transitioners showed less brain activation in frontal regions before they initiated alcohol use. Furthermore, the frontal regions found in this study are important brain regions for executive control, including inhibitory functioning, attention, impulsivity, and self-regulation . Poorer inhibitory functioning in sub-stance naïve youth has been found to be predictive of future substance use , and structural brain differences could help explain these behavioral findings. Limitations should be noted. Although overall groups were very well matched, follow-up lifetime cannabis use days significantly differed between groups. Cannabis use was related to increasing volume over time, possibly countering the volume reductions related to alcohol use. There is research that suggests cannabis may act as a protective factor for white matter integrity in binge drinking ; therefore, volume reductions may have been even more pronounced if we had a completely non-cannabis using comparison group. There are also statistical limitations to be considered in this preliminary study.
Findings did not survive Bonferroni or false discovery rate correction; however, the processing technique utilized is highly sensitive to morphometric brain changes, as each subject’s follow-up image was registered to the baseline image. Furthermore, a typical cubic millimeter of gray matter in an adult contains 35 to 70 million neurons and almost twice as many glial cells , as well as over 500 billion synapses , so even slight differences in cortical thickness could be associated with significant divergence from typical synaptic pruning and gray matter loss across adolescent development. Previous findings suggest that female heavy drinkers may be more vulnerable to aberrant cortical thinning than male drinkers . Unfortunately, our sample size did not allow sufficient power to detect gender effects. The parent study is ongoing and will offer larger sample sizes with more equal gender distributions, which will allow us to more fully address the moderating role of gender on the relationship between drinking and cortical thinning during adolescence. Additionally, the sample is comprised of healthy, high functioning adolescents, so findings may not generalize to clinical or lower functioning samples. The observed pattern of results may be more pronounced in those with higher levels of drinking . Despite these limitations, these findings have important clinical and public health implications, particularly given the participants’ limited, sub-diagnostic alcohol use, limited other substance use, and absence of psychopathology. Further work with larger populations is needed to increase statistical power to observe moderating effects of variables of interest and help advance the understanding of the relationship between alcohol exposure and brain morphometry, and subsequent cognitive functioning. The prevalence of alcohol, tobacco, and other substance use is higher among gay, bisexual, and other men who have sex with men than in the overall population . Although Hughes and Eliasonnoted that substance and alcohol use have declined in lesbian, gay, bisexual, and transgender populations, the prevalence of heavy alcohol and substance use remains high among younger lesbians and gay men, and in some cases older lesbians and gay men. Marginalization on the basis of sexual orientation increases the risk for problematic substance use. For example, GBM men were approximately one and half times more likely to have reported being diagnosed with a substance use disorder during their lifetime than heterosexual men , and one and a half times more likely to have been dependent on alcohol or other substances in the past year . GBM also have higher rates of mental health issues than their heterosexual counterparts . In a review of 10 studies, Meyer found that gay men were twice as likely to have experienced a mental disorder during their lives as heterosexual men. More specifically, gay men were approximately two and a half times more likely to have reported a mood disorder or an anxiety disorder than heterosexual men. A review by King and colleagues found that lesbian, gay, and bisexual individuals were more than twice as likely as heterosexuals to attempt suicide over their lifetime and one and a half times more likely to experience depression and anxiety disorders in the past year, as well as over their lifetime. Few Canadian studies have explored population-based estimates for mental health outcomes among GBM. In one cross-sectional study of Canadian gay/“homosexual” and bisexual men using 2003 Canadian Community Health Survey data, Brennan and colleagues found participants were nearly three times as likely to report a mood or anxiety disorder than heterosexual men. Pakula & Shoveller conducted a more recent cross-sectional analysis that used 2007–2008 Canadian Community Health Survey data and found again that GBM were 3.5 times more likely to report a mood disorder compared with heterosexual males.