Association between vmPFC gray matter volume and smoking initiation in adolescents.

Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic experience) highlights a potential reward-based mechanism for sustaining addictive behaviour. Taken together, our findings reveal vmPFC GMV as a possible biomarker for the early stages of nicotine addiction, with implications for its prevention and treatment.

Brain Networks and Adolescent Alcohol Use.

Importance: Alcohol misuse in adolescence is a leading cause of disability and mortality in youth and is associated with higher risk for alcohol use disorder. Brain mechanisms underlying risk of alcohol misuse may inform prevention and intervention efforts. Objective: To identify neuromarkers of alcohol misuse using a data-driven approach, with specific consideration of neurodevelopmental sex differences. Design, Setting, and Participants: Longitudinal multisite functional magnetic resonance imaging (fMRI) data collected at ages 14 and 19 years were used to assess whole-brain patterns of functional organization associated with current and future alcohol use risk as measured by the Alcohol Use Disorder Identification Test (AUDIT). Primary data were collected by the IMAGEN consortium, a European multisite study of adolescent neurodevelopment. Model generalizability was further tested using data acquired in a single-site study of college alcohol consumption conducted in the US. The primary sample was a developmental cohort of 1359 adolescents with neuroimaging, phenotyping, and alcohol use data. Model generalizability was further assessed in a separate cohort of 114 individuals. Main Outcomes and Measures: Brain-behavior model accuracy, as defined by the correspondence between model-predicted and actual AUDIT scores in held-out testing data, Bonferroni corrected across the number of models run at each time point, 2-tailed α < .008, as determined via permutation testing. Results: Among 1359 individuals in the study, the mean (SD) age was 14.42 (0.40) years, and 729 individuals (54%) were female. The data-driven, whole-brain connectivity approach identified networks associated with vulnerability for future and current AUDIT-defined alcohol use risk (primary outcome, as specified above, future: ρ, 0.22; P < .001 and present: ρ, 0.27; P < .001). Results further indicated sex divergence in the accuracies of brain-behavior models, such that female-only models consistently outperformed male-only models. Specifically, female-only models identified networks conferring vulnerability for future and current severity using data acquired during both reward and inhibitory fMRI tasks. In contrast, male-only models were successful in accurately identifying networks using data acquired during the inhibitory control-but not reward-task, indicating domain specificity of alcohol use risk networks in male adolescents only. Conclusions and Relevance: These data suggest that interventions focusing on inhibitory control processes may be effective in combating alcohol use risk in male adolescents but that both inhibitory and reward-related processes are likely of relevance to alcohol use behaviors in female adolescents. They further identify novel networks of alcohol use risk in youth, which may be used to identify adolescents who are at risk and inform intervention efforts.

Longitudinal associations between amygdala reactivity and cannabis use in a large sample of adolescents.

RATIONALE: The amygdala is a key brain structure to study in relation to cannabis use as reflected by its high-density of cannabinoid receptors and functional reactivity to processes relevant to drug use. Previously, we identified a correlation between cannabis use in early adolescence and amygdala hyper-reactivity to angry faces (Spechler et al. 2015). OBJECTIVES: Here, we leveraged the longitudinal aspect of the same dataset (the IMAGEN study) to determine (1) if amygdala hyper-reactivity predicts future cannabis use and (2) if amygdala reactivity is affected by prolonged cannabis exposure during adolescence. METHODS: First, linear regressions predicted the level of cannabis use by age 19 using amygdala reactivity to angry faces measured at age 14 prior to cannabis exposure in a sample of 1119 participants. Next, we evaluated the time course of amygdala functional development from age 14 to 19 for angry face processing and how it might be associated with protracted cannabis use throughout this developmental window. We compared the sample from Spechler et al. 2015, the majority of whom escalated their use over the 5-year interval, to a matched sample of non-users. RESULTS: Right amygdala reactivity to angry faces significantly predicted cannabis use 5 years later in a dose-response fashion. Cannabis-naïve adolescents demonstrated the lowest levels of amygdala reactivity. No such predictive relationship was identified for alcohol or cigarette use. Next, follow-up analyses indicated a significant group-by-time interaction for the right amygdala. CONCLUSIONS: (1) Right amygdala hyper-reactivity is predictive of future cannabis use, and (2) protracted cannabis exposure during adolescence may alter the rate of neurotypical functional development.

Correspondence Between Perceived Pubertal Development and Hormone Levels in 9-10 Year-Olds From the Adolescent Brain Cognitive Development Study.

Aim: To examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics. Methods: Cross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels. Results: PDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample. Conclusions: Sociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

Low Smoking Exposure, the Adolescent Brain, and the Modulating Role of CHRNA5 Polymorphisms.

BACKGROUND: Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown. METHODS: Structural and diffusion tensor magnetic resonance imaging data were acquired from a large sample of 14-year-old adolescents who completed an extensive battery of neuropsychological, clinical, personality, and drug-use assessments. Additional assessments were conducted at 16 years of age. RESULTS: Exposure to smoking in adolescents, even at low doses, is linked to volume changes in the ventromedial prefrontal cortex and to altered neuronal connectivity in the corpus callosum. The longitudinal analyses strongly suggest that these effects are not preexisting conditions in those who progress to smoking. There was a genetic contribution wherein the volume reduction effects were magnified in smokers who were carriers of the high-risk genotype of the alpha 5 nicotinic receptor subunit gene, rs16969968. CONCLUSIONS: These findings give insight into a mechanism involving genes, brain structure, and connectivity underlying why some adolescents find nicotine especially addictive.

Grey Matter Volume Differences Associated with Extremely Low Levels of Cannabis Use in Adolescence.

Rates of cannabis use among adolescents are high, and are increasing concurrent with changes in the legal status of marijuana and societal attitudes regarding its use. Recreational cannabis use is understudied, especially in the adolescent period when neural maturation may make users particularly vulnerable to the effects of Δ-9-tetrahydrocannabinol (THC) on brain structure. In the current study, we used voxel-based morphometry to compare gray matter volume (GMV) in forty-six 14-year-old human adolescents (males and females) with just one or two instances of cannabis use and carefully matched THC-naive controls. We identified extensive regions in the bilateral medial temporal lobes as well as the bilateral posterior cingulate, lingual gyri, and cerebellum that showed greater GMV in the cannabis users. Analysis of longitudinal data confirmed that GMV differences were unlikely to precede cannabis use. GMV in the temporal regions was associated with contemporaneous performance on the Perceptual Reasoning Index and with future generalized anxiety symptoms in the cannabis users. The distribution of GMV effects mapped onto biomarkers of the endogenous cannabinoid system providing insight into possible mechanisms for these effects.SIGNIFICANCE STATEMENT Almost 35% of American 10th graders have reported using cannabis and existing research suggests that initiation of cannabis use in adolescence is associated with long-term neurocognitive effects. We understand very little about the earliest effects of cannabis use, however, because most research is conducted in adults with a heavy pattern of lifetime use. This study presents evidence suggesting structural brain and cognitive effects of just one or two instances of cannabis use in adolescence. Converging evidence suggests a role for the endocannabinoid system in these effects. This research is particularly timely as the legal status of cannabis is changing in many jurisdictions and the perceived risk by youth associated with smoking cannabis has declined in recent years.

Multimodal Neuroimaging Differences in Nicotine Abstinent Smokers Versus Satiated Smokers.

INTRODUCTION: Research on cigarette smokers suggests cognitive and behavioral impairments. However, much remains unclear how the functional neurobiology of smokers is influenced by nicotine state. Therefore, we sought to determine which state, be it acute nicotine abstinence or satiety, would yield the most robust differences compared with nonsmokers when assessing neurobiological markers of nicotine dependence. METHODS: Smokers (N = 15) and sociodemographically matched nonsmokers (N = 15) were scanned twice using a repeated-measures design. Smokers were scanned after a 24-hour nicotine abstinence and immediately after smoking their usual brand cigarette. The neuroimaging battery included a stop-signal task of response inhibition and pseudocontinuous arterial spin labeling to measure cerebral blood flow (CBF). Whole-brain voxel-wise analyses of covariance were carried out on stop success and stop fail Stop-Signal Task contrasts and CBF maps to assess differences among nonsmokers, abstinent smokers, and satiated smokers. Cluster correction was performed using AFNI's 3dClustSim to achieve a significance of p < .05. RESULTS: Smokers exhibited higher brain activation in bilateral inferior frontal gyrus, a brain region known to be involved in inhibitory control, during successful response inhibitions relative to nonsmokers. This effect was significantly higher during nicotine abstinence relative to satiety. Smokers also exhibited lower CBF in the bilateral inferior frontal gyrus than nonsmokers. These hypoperfusions were not different between abstinence and satiety. CONCLUSIONS: These findings converge on alterations in smokers in prefrontal circuits known to be critical for inhibitory control. These effects are present, even when smokers are satiated, but the neural activity required to achieve performance equal to controls is increased when smokers are in acute abstinence. IMPLICATIONS: Our multimodal neuroimaging study gives neurobiological insights into the cognitive demands of maintaining abstinence and suggests targets for assessing the efficacy of therapeutic interventions.

Mega-Analysis of Gray Matter Volume in Substance Dependence: General and Substance-Specific Regional Effects.

OBJECTIVE: Although lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes. METHOD: Brain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings. RESULTS: Lower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subjects. CONCLUSIONS: The results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine.

Arterial hypertension impact on cerebral blood flow in patients with Alzheimer's disease / Impacto da hipertensão arterial sobre fluxo de sangue cerebral em pacientes com a doença de Alzheimer

Background: Studies show the potential deterioration of brain vascularization and probable involvement of hypertension in Alzheimer disease (AD). Objective: The objective was to evaluate the potential impact of hypertension on cerebral vascular flows in a sample of Alzheimer's patients. Methods: 19 patients with AD, including 10 with hypertension (aHT+) and 9 without hypertension (aHT-) were recruited. They underwent clinical evaluation and phase-contrast MRI protocol for flow assessment. Cerebral arterial flow distributions were evaluated using kurtosis and skewness indices at the intracranial and extracranial levels. Results: No significant differences were found in the mean arterial flow, pulse flow and kurtosis between the levels in the AD aHT+ population. There was a significant difference in skewness between extra- and intracranial levels (p = 0.01). No significant differences were found in the mean arterial flow between the levels in the AD aHT- population. A significant difference was observed in the pulse flow (p = 0.03), kurtosis (p = 0.02) and skewness (p = 0.008) between the levels. At the extracranial level we did not find any significant differences in the mean arterial flow, pulse flow or skewness between aHT+ and aHT-. There was a significant difference in kurtosis at the extracranial level between the aHT+ and aHT- (p = 0.03). At the intracranial level, there were no significant differences in all parameters. Conclusion: Results showed a difference between cerebral vasculature in AD for aHT+ and aHT- groups. This is probably related to the loss of arterial compliance induced by the degradation of the vascular system.

Introdução: Estudos demonstram a potencial deterioração da vascularização cerebral e a provável relação da hipertensão na doença de Alzheimer (DA). Objetivo: O objetivo foi avaliar o potencial impacto da hipertensão no fluxo vascular cerebral numa amostra de pacientes de Alzheimer. Métodos: foram selecionados 19 pacientes com DA, incluindo 10 com hipertensão (aHT+) e 9 sem hipertensão (aHT+). Foram submetidos a avaliação clínica e a um protocolo de ressonância magnética de contraste de fase para avaliação de fluxo. A distribuição de fluxo arterial cerebral foi avaliada através dos índices de curtose e assimetria nos níveis intra e extracraniano. Resultados: Não foram encontradas diferenças significativas no fluxo arterial médio, no fluxo de pulso e curtose entre os níveis da população DA aHT+. Houve uma diference significativa na assimetria entre os níveis extra e intracranianos (p = 0,01). Não foram encontradas diferenças significativas no fluxo arterial médio entre os níveis da população DA aHT-. Uma diferença significativa foi observada no fluxo de pulso (p = 0,03), na curtose (p = 0,02) e na assimetria (p = 0,008) entre os níveis. Não foram observadas diferenças significativas no fluxo arterial médio, no fluxo de pulso ou na assimetria entre aHT+ e aHT- para o nível extracraniano. Foi observada diferença significativa na curtose extracraniana entre aHT+ e AHT- (p = 0,03). Não houve diferença significativa em todos os parâmetros do nível intracraniano. Conclusão: Os resultados mostraram uma diferença entre a vasculatura cerebral nos grupos de DA aHT+ e aHT-. Isso está provavelmente relacionado à perda de complacência arterial induzida pela degradação do sistema vascular.

The role of PC-MRI in neurodegenerative diseases / O papel da RM com contraste nas doenças neurodegenerativas

Introduction: Neurodegenerative diseases, a major public health problem, could have a vascular origin. Phase-contrast magnetic resonance imaging (PC-MRI) enables reliable, non-invasive, and rapid measurements of cerebrospinal fluid (CSF) and blood flows, and evaluation of the mechanical coupling between cerebral blood and CSF flows throughout the cardiac cycle (CC). Objectives: Our purpose was to evaluate the potential of PC-MRI to the study of cerebral blood and CSF flows in patients with neurodegenerative diseases such as Alzheimer's disease (AD), Mild cognitive impairment with amnesic disorders (MCIa) and Vascular Dementia (VD). Methods: The elderly population consisted of 20 AD (age: 80 ± 5 years); 12 AD patients with vascular cerebral lesions (ADvasc) (age: 81 ± 5 years), 10 MCIa patients (age: 80 ± 7 years), and 8 VD patients (age: 78 ± 7 years) were identified. They underwent the same PC-MRI protocol and were compared to 13 age-matched Healthy Elderly (HE) (age: 71± 9 years). Arterial blood pressure was analyzed to detect patients with hypertension. Results: Significantly higher cerebral blood and CSF flows were observed in HE when compared to VD, AD and ADvasc, (p<0.05), but not MCIa patients who yielded the highest cerebral arterial and venous blood flows and stroke volumes compared to the other patients, (p<0.05). The highest oscillations of CSF were also detected in MCIa patients (p<0.05). Conclusion: Our preliminary data suggests an increase in cerebral arterial blood and CSF flows in MCIa. PC-MRI provides a new hydrodynamic view, which may help evaluate a potential role of cardiovascular alterations in neurodegenerative diseases.

Introdução: As doenças neurodegenerativas, um grande problema de saúde pública, podem ser de origem vascular. A ressonância magnética (RM) com contraste de fase permite medições confiáveis, não invasivas e rápidas do líquido cefalorraquidiano (LCR) e dos fluxos sanguíneos para avaliação do acoplamento mecânico de circulação cerebral e fluxo de LCR ao longo do ciclo cardíaco (CC). Objetivos: Nosso objetivo foi avaliar o potencial da RM com contraste de fase para o estudo do fluxo sanguíneo no cérebro e LCR em pacientes com doenças neurodegenerativas, como doença de Alzheimer (DA), comprometimento cognitivo leve (CCL) com distúrbios amnésicos e demência vascular (DV). Métodos: A população foi composta por 20 sujeitos idosos com DA (idade: 80 ± 5 anos); foram identificados 12 pacientes com lesões cerebrais vasculares (idade: 81 ± 5 anos), 10 pacientes com CCL e distúrbios amnésicos (idade: 80 ± 7 anos) e 8 com DV (idade: 78 ± 7 anos). Eles foram submetidos ao mesmo protocolo de RM com contraste de fase e comparados a 13 idosos saudáveis (idade: 71 ± 9 anos). A pressão arterial foi aferida para detectar pacientes com hipertensão arterial. Resultados: Observaram-se fluxos sanguíneos cerebrais e CSF significativamente maiores em pacientes com DV, DA e com lesões cerebrais (p<0,05), mas não nos pacientes com CCL, que tiveram os maiores fluxos arteriais e venosos cerebrais em relação aos demais pacientes (p<0,05). Maiores oscilações de LCR também foram detectadas em pacientes com CCL (p<0,05). Conclusão: Nossos dados preliminares sugerem um aumento no fluxo arterial cerebral e nos fluxos de LCR na CCL. A RM com contraste e fase fornece uma nova visão hidrodinâmica, o que pode ajudar a avaliar o possível papel das alterações cardiovasculares em doenças neurodegenerativas.

Cannabis use in early adolescence: Evidence of amygdala hypersensitivity to signals of threat.

Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group (n=70) of 14-year olds with a history of cannabis use to a group (n=70) of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at-risk for mood disorders in adulthood.

Measurement of choroid plexus perfusion using dynamic susceptibility MR imaging: capillary permeability and age-related changes.

INTRODUCTION: The cerebrospinal fluid (CSF) plays a major role in the physiology of the central nervous system. The continuous turnover of CSF is mainly attributed to the highly vascularized choroid plexus (CP) located in the cerebral ventricles which represent a complex interface between blood and CSF. We propose a method for evaluating CP functionality in vivo using perfusion MR imaging and establish the age-related changes of associated parameters. METHODS: Fifteen patients with small intracranial tumors were retrospectively studied. MR Imaging was performed on a 3T MR Scanner. Gradient-echo echo planar images were acquired after bolus injection of gadolinium-based contrast agent (CA). The software developed used the combined T1- and T2-effects. The decomposition of the relaxivity signals enables the calculation of the CP capillary permeability (K2). The relative cerebral blood volume (rCBV), mean transit time (MTT), and signal slope decrease (SSD) were also calculated. RESULTS: The mean permeability K2 of the extracted CP was 0.033+/-0.18 s(-1). K2 and SSD significantly decreased with subject's age whereas MTT significantly increased with subject's age. No significant correlation was found for age-related changes in rCBV and rCBF. CONCLUSION: The decrease in CP permeability is in line with the age-related changes in CSF secretion observed in animals. The MTT increase indicates significant structural changes corroborated by microscopy studies in animals or humans. Overall, DSC MR-perfusion enables an in vivo evaluation of the hemodynamic state of CP. Clinical applications such as neurodegenerative diseases could be considered thanks to specific functional studies of CP.