The influence of maternal and paternal parenting on adolescent brain structure.

BACKGROUND: Adolescents raised in families with different maternal and paternal parenting combinations exhibit variations in neurocognition and psychopathology; however, whether neural differences exist remains unexplored. This study used a longitudinal twin sample to delineate how different parenting combinations influence adolescent brain structure and to elucidate the genetic contribution. METHODS: A cohort of 216 twins participated in parenting assessments during early adolescence and underwent MRI scanning during middle adolescence. We utilized latent profile analysis to distinguish between various maternal and paternal parenting profiles and subsequently investigated their influences on brain anatomy. Biometric analysis was applied to assess the genetic influences on brain structure, and associations with internalizing symptoms were explored. RESULTS: In early adolescence, four parenting profiles emerged characterized by levels of harshness and hostility in one or both parents. Compared to adolescents in "catparent" families (low harshness/hostility in both parents), those raised in "tigermom" families (harsh/hostile mother only) exhibited smaller nucleus accumbens volume and larger temporal cortex surface area; those in "tigerdad" families demonstrated larger thalamus volumes; those in "tigerparent" families displayed smaller volumes in the mid-anterior corpus callosum. Genetic risk factors contributed significantly to the observed brain structural heterogeneity and internalizing symptoms. However, the influences of parenting profiles and brain structure on internalizing symptoms were not significant. CONCLUSIONS: The findings underscore distinct brain structural features linked to maternal and paternal parenting combinations, particularly in terms of subcortical volume and cortical surface area. This study suggests an interdependent role of maternal and paternal parenting in shaping adolescent neurodevelopment.

Family and parenting factors are associated with emotion regulation neural function in early adolescent girls with elevated internalizing symptoms.

A prominent tripartite model proposes that parent role modeling of emotion regulation, emotion socialization behaviors, and the emotional climate of the family are important for young people's emotional development. However, limited research has examined the neural mechanisms at play. Here, we examined the associations between family and parenting factors, the neural correlates of emotional reactivity and regulation, and internalizing symptoms in early adolescent girls. Sixty-four female adolescents aged 10-12 years with elevated internalizing symptoms completed emotional reactivity, implicit (affect labeling) and explicit (cognitive reappraisal) emotion regulation tasks during functional magnetic resonance imaging. Positive family emotional climate was associated with greater activation in the anterior cingulate and middle temporal cortices during emotional reactivity. Maternal emotion regulation difficulties were associated with increased frontal pole and supramarginal gyrus activation during affect labeling, whereas supportive maternal emotion socialization and positive family emotional climate were associated with activation in prefrontal regions, including inferior frontal and superior frontal gyri, respectively, during cognitive reappraisal. No mediating effects of brain function were observed in the associations between family/parenting factors and adolescent symptoms. These findings highlight the role of family and parenting behaviors in adolescent emotion regulation neurobiology, and contribute to prominent models of adolescent emotional development.

Prolonged cytopenias after immune effector cell therapy and lymphodepletion in patients with leukemia, lymphoma and solid tumors.

BACKGROUND AIMS: The success of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell malignancies has led to the evaluation of CAR T-cells targeting a variety of other malignancies. Although the efficacy of CAR T-cells is enhanced when administered post-lymphodepleting chemotherapy, this can trigger bone marrow suppression and sustained cytopenia after CD19.CAR T-cell therapy. Additionally, systemic inflammation associated with CAR T-cell activity may contribute to myelosuppression. Cytopenias, such as neutropenia and thrombocytopenia, elevate the risk of severe infections and bleeding, respectively. However, data on the incidence of prolonged cytopenias after immune effector therapy in the solid tumor context remain limited. OBJECTIVE: We compared the incidence of prolonged cytopenias after immune effector therapy including genetically modified T-cells, virus-specific T-cells (VSTs) and NKT-cells, as well non-gene-modified VSTs for leukemia, lymphoma, and solid tumors (ST) to identify associated risk factors. METHODS: A retrospective analysis was conducted of 112 pediatric and adult patients with relapsed and/or refractory cancers who received lymphodepleting chemotherapy followed by immune effector therapy. Patients treated with 13 distinct immune effector cell therapies through 11 single-center clinical trials and 2 commercial products over a 6-year period were categorized into 3 types of malignancies: leukemia, lymphoma and ST. We obtained baseline patient characteristics and adverse events data for each participant, and tracked neutrophil and platelet counts following lymphodepletion. RESULTS: Of 112 patients, 104 (92.9%) experienced cytopenias and 88 (79%) experienced severe cytopenias. Patients with leukemia experienced significantly longer durations of severe neutropenia (median duration of 14 days) compared with patients with lymphoma (7 days) or ST (11 days) (P = 0.002). Patients with leukemia also had a higher incidence of severe thrombocytopenia (74.1%), compared with lymphoma (46%, P = 0.03) and ST (14.3%, P < 0.0001). Prolonged cytopenias were significantly associated with disease type (63% of patients with leukemia, 44% of patients with lymphoma, and 22.9% of patients with ST, P = 0.006), prior hematopoietic stem cell transplant (HSCT) (66.7% with prior HSCT versus 38.3% without prior HSCT, P = 0.039), and development of immune effector cell-associated neurotoxicity syndrome (ICANS) (75% with ICANS versus 38% without ICANS, P = 0.027). There was no significant association between prolonged cytopenias and cytokine release syndrome. CONCLUSIONS: Immune effector recipients often experience significant cytopenias due to marrow suppression following lymphodepletion regardless of disease, but prolonged severe cytopenias are significantly less common after treatment of patients with lymphoma and solid tumors.

Investigating Associations Between Maternal Behavior and the Development of Functional Connectivity During the Transition From Late Childhood to Early Adolescence.

BACKGROUND: Parenting behavior is thought to affect child brain development, with implications for mental health. However, longitudinal studies that use whole-brain approaches are lacking. In this study, we investigated associations between parenting behavior, age-related changes in whole-brain functional connectivity, and psychopathology symptoms in children and adolescents. METHODS: Two hundred forty (126 female) children underwent resting-state functional magnetic resonance imaging at up to two time points, providing a total of 398 scans covering the age range 8 to 13 years. Parenting behavior was self-reported at baseline. Parenting factors (positive parenting, inattentive parenting, and harsh and inconsistent discipline) were identified based on a factor analysis of self-report parenting questionnaires. Longitudinal measures of child internalizing and externalizing symptoms were collected. Network-based R-statistics was used to identify associations between parenting and age-related changes in functional connectivity. RESULTS: Higher maternal inattentive behavior was associated with lower decreases in connectivity over time, particularly between regions of the ventral attention and default mode networks and frontoparietal and default mode networks. However, this association was not significant after strict correction for multiple comparisons. CONCLUSIONS: While results should be considered preliminary, they suggest that inattentive parenting may be associated with a reduction in the normative pattern of increased network specialization that occurs with age. This may reflect a delayed development of functional connectivity.

Research Review: Child emotion regulation mediates the association between family factors and internalizing symptoms in children and adolescents - a meta-analysis.

BACKGROUND: Parental influence on children's internalizing symptoms has been well established; however, little is known about the underlying mechanisms. One possible mechanism is child emotion regulation given evidence (a) of its associations with internalizing symptoms and (b) that the development of emotion regulation during childhood and adolescence is influenced by aspects of the family environment. This meta-analysis aimed to systematically investigate the mediating role of child emotion regulation in the relationship between various family factors and internalizing symptoms in children and adolescents. METHODS: We searched Medline, Embase, PsychInfo, and Web of Science for English articles up until November 2022. We included studies that examined child emotion regulation as a mediator between a family factor and child/adolescent internalizing symptoms. Random-effects models were used to calculate pooled indirect effects and total effects for nine family factors. Heterogeneity and mediation ratio were also calculated. RESULTS: Of 49 studies with 24,524 participants in this meta-analysis, family factors for which emotion regulation mediated the association with child/adolescent internalizing symptoms included: unsupportive emotion socialization, psychological control, secure attachment, aversiveness, family conflict, parent emotion regulation and parent psychopathology, but not supportive emotion socialization and behavioral control. CONCLUSIONS: Various family factors impact children's emotion regulation development, and in turn, contribute to the risk of internalizing symptoms in young people. Findings from this study highlight the need for interventions targeting modifiable parenting behaviors to promote healthy emotion regulation and better mental health in children and adolescents.

The Social Determinants of Emotional and Behavioral Problems in Adolescents Experiencing Early Puberty.

PURPOSE: Earlier pubertal timing is an important predictor of emotional and behavioral problems during adolescence. The current study undertook a comprehensive investigation of whether the social environment can buffer or amplify the associations between pubertal timing and emotional and behavioral problems. METHODS: Research questions were examined in the Adolescent Brain Cognitive Development (ABCD) Study, a large population representative sample in the United States. We examined interactions between pubertal timing and the shared effects of a range of proximal and distal social environmental influences (i.e., parents, peers, schools, neighborhoods, socioeconomic status) in 10- to 13-year-olds. RESULTS: Results revealed significant interaction between timing and proximal social influences (i.e., the "microsystem") in predicting emotional and behavioral problems. In general, adolescents with earlier pubertal timing and unfavorable (high levels of negative and low levels of positive) influences in the microsystem exhibited greater problems. Both males and females exhibited such associations for rule-breaking problems, while females alone exhibited associations for depressive problems. Results also illustrate the relative strength of each social context at moderating risk for emotional and behavioral problems in earlier versus later pubertal maturers. DISCUSSION: These findings highlight the importance of proximal social influences in buffering vulnerability for emotional and behavioral problems related to earlier puberty. Findings also illustrate the broad implications of latent environmental factors, reflecting common variance of multiple social influences that typically covary with one another.

"Puberty age gap": new method of assessing pubertal timing and its association with mental health problems.

Puberty is linked to mental health problems during adolescence, and in particular, the timing of puberty is thought to be an important risk factor. This study developed a new measure of pubertal timing that was built upon multiple pubertal features and their nonlinear changes over time (i.e., with age), and investigated its association with mental health problems. Using the Adolescent Brain Cognitive Development (ABCD) cohort (N ~ 9900, aged 9-13 years), we employed three different models to assess pubertal timing. These models aimed to predict chronological age based on: (i) observed physical development, (ii) hormone levels (testosterone and dehydroepiandrosterone [DHEA]), and (iii) a combination of both physical development and hormones. To achieve this, we utilized a supervised machine learning approach, which allowed us to train the models using the available data and make age predictions based on the input pubertal features. The accuracy of these three models was evaluated, and their associations with mental health problems were examined. The new pubertal timing model performed better at capturing age variance compared to the more commonly used linear regression method. Further, the model based on physical features accounted for the most variance in mental health, such that earlier pubertal timing was associated with higher symptoms. This study demonstrates the utility of our new model of pubertal timing and suggests that, relative to hormonal measures, physical measures of pubertal maturation have a stronger association with mental health problems in early adolescence.

Pathways from threat exposure to psychotic symptoms in youth: The role of emotion recognition bias and brain structure.

BACKGROUND: Research supports an association between threatening experiences in childhood and psychosis. It is possible that early threat exposure disrupts the development of emotion recognition (specifically, producing a bias for facial expressions relating to threat) and the brain structures subserving it, contributing to psychosis development. METHODS: Using data from the Philadelphia Neurodevelopmental Cohort, we examined associations between threat exposure and both the misattribution of facial expressions to fear/anger in an emotion recognition task, and gray matter volumes in key emotion processing regions. Our sample comprised youth with psychosis spectrum symptoms (N = 304), control youth (N = 787), and to evaluate specificity, youth with internalizing symptoms (N = 92). The moderating effects of group and sex were examined. RESULTS: Both the psychosis spectrum and internalizing groups had higher levels of threat exposure than controls. In the total sample, threat exposure was associated with lower left medial prefrontal cortex (mPFC) volume but not misattributions to fear/anger. The effects of threat exposure did not significantly differ by group or sex. CONCLUSIONS: The findings of this study provide evidence for an effect of threat exposure on mPFC morphology, but do not support an association between threat exposure and a recognition bias for threat-related expressions, that is particularly pronounced in psychosis. Future research should investigate factors linking transdiagnostic alterations related to threat exposure with psychotic symptoms, and attempt to clarify the mechanisms underpinning emotion recognition misattributions in threat-exposed youth.

Neurobiological correlates of resilience during childhood and adolescence - A systematic review.

Research examining the neurobiological mechanisms of resilience has grown rapidly over the past decade. However, there is vast heterogeneity in research study design, methods, and in how resilience is operationalized, making it difficult to gauge what we currently know about resilience biomarkers. This preregistered systematic review aimed to review and synthesize the extant literature to identify neurobiological correlates of resilience to adversity during childhood and adolescence. Literature searches on MEDLINE and PsycINFO yielded 3834 studies and a total of 49 studies were included in the final review. Findings were synthesized based on how resilience was conceptualized (e.g., absence of psychopathology, trait resilience), and where relevant, the type of outcome examined (e.g., internalizing symptoms, post-traumatic stress disorder). Our synthesis showed that findings were generally mixed. Nevertheless, some consistent findings suggest that resilience neural mechanisms may involve prefrontal and subcortical regions structure/activity, as well as connectivity between these regions. Given substantial heterogeneity in the definition and operationalization of resilience, more methodological consistency across studies is required for advancing knowledge in this field.

The neural, stress hormone and inflammatory correlates of childhood deprivation and threat in psychosis: A systematic review.

Childhood adversity increases the risk of developing psychosis, but the biological mechanisms involved are unknown. Disaggregating early adverse experiences into core dimensions of deprivation and threat may help to elucidate these mechanisms. We therefore systematically searched the literature investigating associations between deprivation and threat, and neural, immune and stress hormone systems in individuals on the psychosis spectrum. Our search yielded 74 articles, from which we extracted and synthesized relevant findings. While study designs were heterogeneous and findings inconsistent, some trends emerged. In psychosis, deprivation tended to correlate with lower global cortical volume, and some evidence supported threat-related variation in prefrontal cortex morphology. Greater threat exposure was also associated with higher C-reactive protein, and higher and lower cortisol measures. When examined, associations in controls were less evident. Overall, findings indicate that deprivation and threat may associate with partially distinct biological mechanisms in the psychosis spectrum, and that associations may be stronger than in controls. Dimensional approaches may help disentangle the biological correlates of childhood adversity in psychosis, but more studies are needed.

Corticolimbic connectivity mediates the relationship between pubertal timing and mental health problems.

BACKGROUND: Undergoing puberty ahead of peers ('earlier pubertal timing') is an important risk factor for mental health problems during early adolescence. The current study examined pathways between pubertal timing and mental health via connectivity of neural systems implicated in emotional reactivity and regulation (specifically corticolimbic connections) in 9- to 14-year-olds. METHOD: Research questions were examined in the Adolescent Brain Cognitive Development (ABCD) Study, a large population representative sample in the United States. Linear mixed models examined associations between pubertal timing and resting-state corticolimbic connectivity. Significant connections were examined as potential mediators of the relationship between pubertal timing and mental health (withdrawn depressed and rule-breaking) problems. Exploratory analyses interrogated whether the family environment moderated neural risk patterns in those undergoing puberty earlier than their peers. RESULTS: Earlier pubertal timing was related to decreased connectivity between limbic structures (bilateral amygdala and right hippocampus) and the cingulo-opercular network, left amygdala and somatomotor (mouth) network, as well as between the left hippocampus and ventral attention network and visual network. Corticolimbic connections also mediated the relationship between earlier pubertal timing and increased withdrawn depressed problems (but not rule-breaking problems). Finally, parental acceptance buffered against connectivity patterns that were implicated in withdrawn depressed problems in those undergoing puberty earlier than their peers. CONCLUSION: Findings highlight the role of decreased corticolimbic connectivity in mediating pathways between earlier pubertal timing and withdrawn depressed problems, and we present preliminary evidence that the family environment may buffer against these neural risk patterns during early adolescence.

A longitudinal study of childhood maltreatment, subcortical development, and subcortico-cortical structural maturational coupling from early to late adolescence.

BACKGROUND: Examining neurobiological mechanisms that may transmit the effects of childhood maltreatment on mental health in youth is crucial for understanding vulnerability to psychopathology. This study investigated associations between childhood maltreatment, adolescent structural brain development, and mental health trajectories into young-adulthood. METHODS: Structural magnetic resonance imaging data was acquired from 144 youth at three time points (age 12, 16, and 18 years). Childhood maltreatment was reported to occur prior to the first scan. Linear mixed models were utilized to examine the association between total childhood maltreatment, neglect, abuse and (i) amygdala and hippocampal volume development, and (ii) maturational coupling between amygdala/hippocampus volume and the thickness of prefrontal regions. We also examined whether brain development mediated the association between maltreatment and depressive and anxiety symptoms trajectories from age 12 to 28. RESULTS: Total maltreatment, and neglect, were associated with positive maturational coupling between the amygdala and caudal anterior cingulate cortex (cACC), whereby at higher and lower levels of amygdala growth, maltreatment was associated with lower and higher PFC thinning, respectively. Neglect was also associated with maturational coupling of the hippocampus with prefrontal regions. While positive amygdala-cACC maturational coupling was associated with greater increases in anxiety symptoms, it did not significantly mediate the association between maltreatment and anxiety symptom trajectories. CONCLUSION: We found maltreatment to be associated with altered patterns of coupling between subcortical and prefrontal regions during adolescence, suggesting that maltreatment is associated with the development of socio-emotional neural circuitry. The implications of these findings for mental health require further investigation.

Childhood socioeconomic status and the pace of structural neurodevelopment: accelerated, delayed, or simply different?

Socioeconomic status (SES) is associated with children's brain and behavioral development. Several theories propose that early experiences of adversity or low SES can alter the pace of neurodevelopment during childhood and adolescence. These theories make contrasting predictions about whether adverse experiences and low SES are associated with accelerated or delayed neurodevelopment. We contextualize these predictions within the context of normative development of cortical and subcortical structure and review existing evidence on SES and structural brain development to adjudicate between competing hypotheses. Although none of these theories are fully consistent with observed SES-related differences in brain development, existing evidence suggests that low SES is associated with brain structure trajectories more consistent with a delayed or simply different developmental pattern than an acceleration in neurodevelopment.

Corporal punishment of children in Australia: The evidence-based case for legislative reform.

OBJECTIVE: Across all of Australia's states and territories, it is legal for a parent or carer to hit their child. In this paper, we outline the legal context for corporal punishment in Australia and the argument for its reform. METHODS: We review the laws that allow corporal punishment, the international agreements on children's rights, the evidence on the effects of corporal punishment, and outcomes of legislative reform in countries that have changed their laws to prohibit corporal punishment. RESULTS: Legislative reform typically precedes attitude changes and reductions in the use of corporal punishment. Countries with the most ideal outcomes have instigated public health campaigns educating the population about law reform while also providing access to alternative non-violent discipline strategies. CONCLUSIONS: Extensive evidence exists demonstrating the adverse effects of corporal punishment. When countries change legislation, educate the public about these effects, and provide alternative strategies for parents, rates of corporal punishment decrease. IMPLICATIONS FOR PUBLIC HEALTH: We recommend law reform in Australia to prohibit corporal punishment, a public health campaign to increase awareness of corporal punishment and its effects, provision of access for parents to alternative evidence-based strategies to assist in parenting, and a national parenting survey to monitor outcomes.

Developmental brain changes during puberty and associations with mental health problems.

BACKGROUND: Our understanding of the mechanisms relating pubertal timing to mental health problems via brain development remains rudimentary. METHOD: Longitudinal data was sourced from ∼11,500 children from the Adolescent Brain Cognitive Development (ABCD) Study (age 9-13years). We built models of "brain age" and "puberty age" as indices of brain and pubertal development. Residuals from these models were used to index individual differences in brain development and pubertal timing, respectively. Mixed-effects models were used to investigate associations between pubertal timing and regional and global brain development. Mediation models were used to investigate the indirect effect of pubertal timing on mental health problems via brain development. RESULTS: Earlier pubertal timing was associated with accelerated brain development, particularly of subcortical and frontal regions in females and subcortical regions in males. While earlier pubertal timing was associated with elevated mental health problems in both sexes, brain age did not predict mental health problems, nor did it mediate associations between pubertal timing and mental health problems. CONCLUSION: This study highlights the importance of pubertal timing as a marker associated with brain maturation and mental health problems.

Longitudinal changes in within-salience network functional connectivity mediate the relationship between childhood abuse and neglect, and mental health during adolescence.

BACKGROUND: Understanding the neurobiological underpinnings of childhood maltreatment is vital given consistent links with poor mental health. Dimensional models of adversity purport that different types of adversity likely have distinct neurobiological consequences. Adolescence is a key developmental period, during which deviations from normative neurodevelopment may have particular relevance for mental health. However, longitudinal work examining links between different forms of maltreatment, neurodevelopment, and mental health is limited. METHODS: In the present study, we explored associations between abuse, neglect, and longitudinal development of within-network functional connectivity of the salience (SN), default mode (DMN), and executive control network in 142 community residing adolescents. Resting-state fMRI data were acquired at age 16 (T1; M = 16.46 years, s.d. = 0.52, 66F) and 19 (T2; mean follow-up period: 2.35 years). Mental health data were also collected at T1 and T2. Childhood maltreatment history was assessed prior to T1. RESULTS: Abuse and neglect were both found to be associated with increases in within-SN functional connectivity from age 16 to 19. Further, there were sex differences in the association between neglect and changes in within-DMN connectivity. Finally, increases in within-SN connectivity were found to mediate the association between abuse/neglect and lower problematic substance use and higher depressive symptoms at age 19. CONCLUSIONS: Our findings suggest that childhood maltreatment is associated with altered neurodevelopmental trajectories, and that changes in salience processing may be linked with risk and resilience for the development of depression and substance use problems during adolescence, respectively. Further work is needed to understand the distinct neurodevelopmental and mental health outcomes of abuse and neglect.

The Role of School Environment in Brain Structure, Connectivity, and Mental Health in Children: A Multimodal Investigation.

BACKGROUND: Much work has been dedicated to understanding the effects of adverse home environments on brain development. While the school social and learning environment plays a role in child development, little work has been done to investigate the impact of the school environment on the developing brain. The goal of the present study was to examine associations between the school environment, brain structure and connectivity, and mental health. METHODS: In this preregistered study we investigated these questions in a large sample of adolescents (9-10 years of age) from the Adolescent Brain Cognitive Development (ABCD) Study. We examined the association between school environment and gray matter (n = 10,435) and white matter (n = 10,770) structure and functional connectivity (n = 9528). We then investigated multivariate relationships between school-associated brain measures and mental health. RESULTS: School environment was associated with connectivity of the auditory and retrosplenial temporal network as well as of higher-order cognitive networks like the cingulo-opercular, default mode, ventral attention, and frontoparietal networks. Multivariate analyses revealed that connectivity of the cingulo-opercular and default mode networks was also associated with mental health. CONCLUSIONS: Findings shed light on the neural mechanisms through which favorable school environments may contribute to positive mental health outcomes in children. Our findings have implications for interventions targeted at promoting positive youth functioning through improving school environments.

Brain Anatomical Alterations in Young Cannabis Users: Is it All Hype? A Meta-Analysis of Structural Neuroimaging Studies.

Introduction: Cannabis use has a high prevalence in young youth and is associated with poor psychosocial outcomes. Such outcomes have been ascribed to the impact of cannabis exposure on the developing brain. However, findings from individual studies of volumetry in youth cannabis users are equivocal. Objectives: Our primary objective was to systematically review the evidence on brain volume differences between young cannabis users and nonusers aged 12-26 where profound neuromaturation occurs, accounting for the role of global brain volumes (GBVs). Our secondary objective was to systematically integrate the findings on the association between youth age and volumetry in youth cannabis users. Finally, we aimed to evaluate the quality of the evidence. Materials and Methods: A systematic search was run in three databases (PubMed, Scopus, and PsycINFO) and was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We run meta-analyses (with and without controlling for GBV) of brain volume differences between young cannabis users and nonusers. We conducted metaregressions to explore the role of age on volumetric differences. Results: Sixteen studies were included. The reviewed samples included 830 people with mean age 22.5 years (range 14-26 years). Of these, 386 were cannabis users (with cannabis use onset at 15-19 years) and 444 were controls. We found no detectable group differences in any of the GBVs (intracranium, total brain, total white matter, and total gray matter) and regional brain volumes (i.e., hippocampus, amygdala, orbitofrontal cortex, and total cerebellum). Age and cannabis use level did not predict (standardized mean) volume group differences in metaregression. We found little evidence of publication bias (Egger's test p>0.1). Conclusions: Contrary to evidence in adult samples (or in samples mixing adults and youth), previous single studies in young cannabis users, and meta-analyses of brain function in young cannabis users, this early evidence suggests nonsignificant volume differences between young cannabis users and nonusers. While prolonged and long-term exposure to heavy cannabis use may be required to detect gross volume alterations, more studies in young cannabis users are needed to map in detail cannabis-related neuroanatomical changes.