Adolescent substance use initiation and long-term neurobiological outcomes: insights, challenges and opportunities.

The increased frequency of risk taking behavior combined with marked neuromaturation has positioned adolescence as a focal point of research into the neural causes and consequences of substance use. However, little work has provided a summary of the links between adolescent initiated substance use and longer-term brain outcomes. Here we review studies exploring the long-term effects of adolescent-initiated substance use with structural and microstructural neuroimaging. A quarter of all studies reviewed conducted repeated neuroimaging assessments. Long-term alcohol use, as well as tobacco use were consistently associated with smaller frontal cortices and altered white matter microstructure. This association was mostly observed in the ACC, insula and subcortical regions in alcohol users, and for the OFC in tobacco users. Long-term cannabis use was mostly related to altered frontal cortices and hippocampal volumes. Interestingly, cannabis users scanned more years after use initiation tended to show smaller measures of these regions, whereas those with fewer years since initiation showed larger measures. Long-term stimulant use tended to show a similar trend as cannabis in terms of years since initiation in measures of the putamen, insula and frontal cortex. Long-term opioid use was mostly associated with smaller subcortical and insular volumes. Of note, null findings were reported in all substance use categories, most often in cannabis use studies. In the context of the large variety in study designs, substance use assessment, methods, and sample characteristics, we provide recommendations on how to interpret these findings, and considerations for future studies.

The Effect of Cerebellar tDCS on Sequential Motor Response Selection.

Transcranial direct current stimulation (tDCS) transiently alters cortical excitability and synaptic plasticity. So far, few studies have investigated the behavioral effects of applying tDCS to the cerebellum. Given the cerebellum's inhibitory effects on cortical motor areas as well as its role in fine motor control and motor coordination, we investigated whether cerebellar tDCS can modulate response selection processes and motor sequence learning. Seventy-two participants received either cerebellar anodal (excitatory), cathodal (inhibitory), or sham (placebo) tDCS while performing a serial reaction time task (SRTT). To compare acute and long-term effects of stimulation on behavioral performance, participants came back for follow-up testing at 24 h after stimulation. Results indicated no group differences in performance prior to tDCS. During stimulation, tDCS did not affect sequence-specific learning, but anodal as compared to cathodal and sham stimulations did modulate response selection processes. Specifically, anodal tDCS increased response latencies independent of whether a trained or transfer sequence was being performed, although this effect became smaller throughout training. At the 24-h follow-up, the group that previously received anodal tDCS again demonstrated increased response latencies, but only when the previously trained sequence and a transfer sequence had to be performed in the same experimental block. This increased behavioral interference tentatively points to a detrimental effect of anodal cerebellar tDCS on sequence consolidation/retention. These results are consistent with the notion that the cerebellum exerts an inhibitory effect on cortical motor areas, which can impair sequential response selection when this inhibition is strengthened by tDCS.

Brain morphology predictors of alcohol, tobacco, and cannabis use in adolescence: A systematic review.

In the last decade, extensive research has emerged on the predictive value of brain morphology for substance use initiation and related problems during adolescence. This systematic review provides an overview of longitudinal studies on pre-existing brain variations and later initiation of alcohol, tobacco, and cannabis use (N = 18). Adolescent structural neuroimaging studies that started before substance use initiation suggest that a smaller anterior cingulate cortex (ACC) volume, thicker or smaller superior frontal gyrus, and larger nucleus accumbens (NAcc) volume are associated with future alcohol use. Also, both smaller and larger orbitofrontal cortex (OFC) volumes were associated with future cannabis and combined alcohol/cannabis use. Smaller amygdala volumes were related to future daily tobacco smoking. These findings could point to specific vulnerabilities for adolescent substance use, as these brain areas are involved in cognitive control (ACC), reward (NAcc), motivation (OFC), and emotional memory (amygdala). However, the reported findings were inconsistent in directionality and laterality, and the largest study on alcohol use predictors reported null findings. Therefore, large population-based longitudinal studies should investigate the robustness and mechanisms of these associations. We suggested future research directions regarding sample selection, timing of baseline and follow-up measurements, and a harmonization approach of study methods.

Association of Maternal Tobacco Use During Pregnancy With Preadolescent Brain Morphology Among Offspring.

Importance: Maternal tobacco use during pregnancy has been associated with various health consequences, including suboptimal neurodevelopment in offspring. However, the effect of prenatal exposure to maternal smoking on child brain development has yet to be elucidated. Objective: To investigate the association between maternal smoking during pregnancy and offspring brain development in preadolescence as well as the mediating pathways. Design, Setting, and Participants: This prospective, population-based cohort study was embedded in the Generation R Study, Rotterdam, the Netherlands. The Generation R Study was launched in 2002, with follow-up ongoing. Child brain morphology was assessed at 9 to 11 years of age (ie, 10-12 years between exposure and outcome assessment). Data analysis was performed from March 1, 2021, to February 28, 2022, and at the time of manuscript revision. Participants included the singleton children of pregnant women residing in the study area with an expected date of delivery between April 1, 2002, and January 31, 2006; 2704 children with information on maternal smoking during pregnancy and structural neuroimaging at 9 to 11 years of age were included. A subsample of 784 children with data on DNA methylation at birth was examined in the mediation analysis. Exposures: Information on maternal smoking during pregnancy was collected via a questionnaire in each trimester. As a contrast, paternal smoking was assessed at recruitment. Main Outcomes and Measures: Brain morphology, including brain volumes and surface-based cortical measures (thickness, surface area, and gyrification), was assessed with magnetic resonance imaging. For mediation analysis, DNA methylation at birth was quantified by a weighted methylation risk score. Results: The 2704 participating children (1370 [50.7%] girls and 1334 [49.3%] boys) underwent brain imaging assessment at a mean (SD) age of 10.1 (0.6) years. Compared with nonexposed children (n = 2102), exposure to continued maternal smoking during pregnancy (n = 364) was associated with smaller total brain volume (volumetric difference [b] = -14.5 [95% CI, -25.1 to -4.0] cm3), cerebral gray matter volume (b = -7.8 [95% CI, -13.4 to -2.3] cm3), cerebral white matter volume (b = -5.9 [95% CI, -10.7 to -1.0] cm3), and surface area and less gyrification. These associations were not explained by paternal smoking nor mediated by smoking-associated DNA methylation patterns at birth. Children exposed to maternal smoking only in the first trimester (n = 238) showed no differences in brain morphology compared with nonexposed children. Conclusions and Relevance: The findings of this cohort study suggest that continued maternal tobacco use during pregnancy was associated with lower brain volumes and suboptimal cortical traits of offspring in preadolescence, which seemed to be independent of shared family factors. Tobacco cessation before pregnancy, or as soon as pregnancy is known, should be recommended to women for optimal brain development of their offspring.

Perceived stress as mediator for longitudinal effects of the COVID-19 lockdown on wellbeing of parents and children.

Dealing with a COVID-19 lockdown may have negative effects on children, but at the same time might facilitate parent-child bonding. Perceived stress may influence the direction of these effects. Using a longitudinal twin design, we investigated how perceived stress influenced lockdown induced changes in wellbeing of parents and children. A total of 106 parents and 151 children (10-13-year-olds) filled in questionnaires during lockdown and data were combined with data of previous years. We report a significant increase in parental negative feelings (anxiety, depression, hostility and interpersonal sensitivity). Longitudinal child measures showed a gradual decrease in internalizing and externalizing behavior, which seemed decelerated by the COVID-19 lockdown. Changes in parental negative feelings and children's externalizing behavior were mediated by perceived stress: higher scores prior to the lockdown were related to more stress during the lockdown, which in turn was associated with an increase in parental negative feelings and children's' externalizing behavior. Perceived stress in parents and children was associated with negative coping strategies. Additionally, children's stress levels were influenced by prior and current parental overreactivity. These results suggest that children in families with negative coping strategies and (a history of) parental overreactivity might be at risk for negative consequences of the lockdown.