Adolescent Cerebellar Development: An Underexplored Frontier

Adolescent cortical development has been heavily studied (1). In contrast, adolescent cerebellar development has been understudied, and there has been even less investigation of the impact of alcohol use during this critical developmental period (2). Tiemeier et al. (2) published one of the first longitudinal studies conducting an examination of the developmental trajectory of the cerebellum. Sufficient longitudinal data from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) study has now been collected to continue expanding our understanding of the developmental trajectory of the cerebellum (3). The Adolescent Brain Cognitive Development (ABCD) longitudinal study will provide even more data to further address questions regarding the neuro-developmental changes occurring in the cerebellum (Table 1) (4). In this issue of Biological Psychiatry, Sullivan et al. (3) provide a novel investigation of the cerebellar development trajectory as a result of alcohol use during adolescence

Table 1.

Timeline of Longitudinal Studies Allowing for Examination of the Developmental Trajectory of the Cerebellum

Study	Subjects, n	Age Range at Enrollment, Years	Scan Frequency	Sites, n	Year Enrollment Started
Tiemeier et al. (2)	50	5–24	3× at 2-year intervals	1	1989
Pfefferbaum et al. (1) (NCANDA Study)	831	12–21	Annual	5	2013
Hagler Jr et al. (4) (ABCD Study)	11,878	9–10	Biennial	21	2016

ABCD, Adolescent Brain Cognitive Development; NCANDA, National Consortium on Alcohol and Neurodevelopment in Adolescence.

Sullivan et al. (3) report the first investigation examining the role of lobular volume and sexual dimorphism in typical adolescent cerebellar development, as well as the impact of alcohol use. Moderate or heavy drinkers demonstrated faster declines in gray matter volumes of the anterior lobules and vermis and accelerated cerebrospinal fluid expansion of anterior lobules compared with no/low drinkers.

The rapid rate of neurodevelopment that occurs during adolescence is second only to that seen in infancy. A second lifetime period of synaptogenesis occurs during this transition between childhood and adulthood (5). Cerebellar atrophy in the anterior superior vermis is a well-characterized and commonly understood consequence of chronic, heavy alcohol consumption in adults. Surprisingly, differences in developmental trajectory for youths were found in the vermis and anterior superior lobules in parallel with findings in adults who struggle with chronic alcoholism. This suggests that these cerebellar regions in youths may be vulnerable to the effects of alcohol like those in the adult stage, in contrast to many other developmental changes in the adolescent brain that have not occurred by this point in time. While the prenatal period is a particularly sensitive period for cerebellar development as evidenced by fetal alcohol syndrome, later periods, such as adolescence, demonstrate developmental trajectories. The cerebellum is particularly vulnerable to damage caused by changes in chronic alcohol use (e.g., binge drinking). Ethanol-induced degeneration in mice has shown that frequent withdrawal and reinitiation of alcohol use leads to greater toxicity and potentially premature aging of the central nervous system. The similarity of these developmental changes in youths to adults may be better understood in the context of this model.

The effect of alcohol in a dose-related manner on the adult brain related to cognition and decision making has been extensively studied (6). Effects can vary widely based on genetics, environment, sex, recency of drinking, and other factors. Given the number of factors that impact the effects of alcohol, a more heterogeneous and hetero-chronic effect might be expected. Thus, it is remarkable that an alcohol-related dose effect and homogeneity of the developmental trajectory of the cerebellum was supported by their work. Positive correlations between greater percent changes per year of each tissue type and number of drinking days were observed. In addition, correlations of gray matter trajectories among the lobules were noted to be higher in moderate to heavy drinkers compared with no/ low drinkers. While no pairs of correlations met statistical significance, 53 of 55 pairs were higher for drinkers compared with no/low drinkers. This pattern suggests that future, higher-powered studies such as ABCD (4) may prove fruitful in demonstrating these patterns with statistical significance. The homogeneity of developmental trajectory of the cerebellum suggests the possibility of an alcohol-related global effect for structural development of the cerebellum.

The sex-related differences in the developmental trajectory of the cerebellum for youths identified by Sullivan et al. (3) raise an important area for future investigation. They found that gray matter volumes of lobules V and VI, crus II, lobule VIIB, and lobule X contracted more quickly with age in males compared with females. In contrast, white matter volumes in crus I and crus II and lobules VIIIA and VIIIB enlarged more quickly in females compared with males. Lastly, cerebrospinal fluid volume enlarged more quickly in most cerebellar regions in males compared with females. These differences have been explained by sex-specific developments of the cerebellum and sex-specific receptors, the production of trophic agents, and maturation of the pituitary hypophyseal axis (7–9). It remains to be seen if these changes precede the development of subsequent sex-specific preponderance of neuropsychiatric disorders (8,9).

Limited power in the NCANDA study precluded a detailed exploration of the effects of sole or co-occurring marijuana use. Differences in adult brain structure in the subcortical and cortical regions between cannabis nonusers and chronic/relatively frequent users were not found by Meier et al. (10). However, the introduction of higher-potency cannabis formulations and the small number of studies examining the cerebellar development trajectory leave this as an open question that will hopefully be answered more definitively by future studies with greater power, such as ABCD (4).

Sullivan et al. (3) focus on typical adolescent cerebellar development and the impact of alcohol use, highlighting unique changes during this stage in life, as well as similarities of alcohol-related effects with those seen in alcohol-dependent adults. Their article also raises possible future questions as to whether higher-potency cannabis formulations will further influence cerebellar developmental trajectories, which may be possible to explore in larger studies, such as ABCD (4), as the young cohort ages. Interesting questions regarding the future impact of developmental trajectory disturbance affecting the frontal-cingulate-cerebellar systems, in addition to potential changes related to recovery with sustained abstinence from alcohol, remain unexplored and are critically relevant to those with alcohol use disorder.

Sullivan et al. (3) provide a first look at the typical trajectory of adolescent cerebellar development and the impact of alcohol use using longitudinal data from the NCANDA. Larger studies will be critical to understanding how sexual dimorphism may relate to later development of mental illness and how abstinence from alcohol and other substances may modify cerebellar development and other systems, such as the frontal-cingulate-cerebellar circuitry.