Mega-analysis of the brain-age gap in substance use disorder: An ENIGMA Addiction working group study.

BACKGROUND AND AIMS: The brain age gap (BAG), calculated as the difference between a machine learning model-based predicted brain age and chronological age, has been increasingly investigated in psychiatric disorders. Tobacco and alcohol use are associated with increased BAG; however, no studies have compared global and regional BAG across substances other than alcohol and tobacco. This study aimed to compare global and regional estimates of brain age in individuals with substance use disorders and healthy controls. DESIGN: This was a cross-sectional study. SETTING: This is an Enhancing Neuro Imaging through Meta-Analysis Consortium (ENIGMA) Addiction Working Group study including data from 38 global sites. PARTICIPANTS: This study included 2606 participants, of whom 1725 were cases with a substance use disorder and 881 healthy controls. MEASUREMENTS: This study used the Kaufmann brain age prediction algorithms to generate global and regional brain age estimates using T1 weighted magnetic resonance imaging (MRI) scans. We used linear mixed effects models to compare global and regional (FreeSurfer lobestrict output) BAG (i.e. predicted minus chronological age) between individuals with one of five primary substance use disorders as well as healthy controls. FINDINGS: Alcohol use disorder (ß = -5.49, t = -5.51, p < 0.001) was associated with higher global BAG, whereas amphetamine-type stimulant use disorder (ß = 3.44, t = 2.42, p = 0.02) was associated with lower global BAG in the separate substance-specific models. CONCLUSIONS: People with alcohol use disorder appear to have a higher brain-age gap than people without alcohol use disorder, which is consistent with other evidence of the negative impact of alcohol on the brain.

Cannabis Dependence is Associated with Reduced Hippocampal Subregion Volumes Independently of Sex: Findings from an ENIGMA Addiction Working Group Multi-Country Study.

Background: Males and females who consume cannabis can experience different mental health and cognitive problems. Neuroscientific theories of addiction postulate that dependence is underscored by neuroadaptations, but do not account for the contribution of distinct sexes. Further, there is little evidence for sex differences in the neurobiology of cannabis dependence as most neuroimaging studies have been conducted in largely male samples in which cannabis dependence, as opposed to use, is often not ascertained. Methods: We examined subregional hippocampus and amygdala volumetry in a sample of 206 people recruited from the ENIGMA Addiction Working Group. They included 59 people with cannabis dependence (17 females), 49 cannabis users without cannabis dependence (20 females), and 98 controls (33 females). Results: We found no group-by-sex effect on subregional volumetry. The left hippocampal cornu ammonis subfield 1 (CA1) volumes were lower in dependent cannabis users compared with non-dependent cannabis users (p<0.001, d=0.32) and with controls (p=0.022, d=0.18). Further, the left cornu ammonis subfield 3 (CA3) and left dentate gyrus volumes were lower in dependent versus non-dependent cannabis users but not versus controls (p=0.002, d=0.37, and p=0.002, d=0.31, respectively). All models controlled for age, intelligence quotient (IQ), alcohol and tobacco use, and intracranial volume. Amygdala volumetry was not affected by group or group-by-sex, but was smaller in females than males. Conclusions: Our findings suggest that the relationship between cannabis dependence and subregional volumetry was not moderated by sex. Specifically, dependent (rather than non-dependent) cannabis use may be associated with alterations in selected hippocampus subfields high in cannabinoid type 1 (CB1) receptors and implicated in addictive behavior. As these data are cross-sectional, it is plausible that differences predate cannabis dependence onset and contribute to the initiation of cannabis dependence. Longitudinal neuroimaging work is required to examine the time-course of the onset of subregional hippocampal alterations in cannabis dependence, and their progression as cannabis dependence exacerbates or recovers over time.

Emerging antiresorptive medications and their potential implications for dental surgeries.

BACKGROUND: The aim of this review was to discuss the current and newly emerging antiresorptive medications and their potential implications for dental surgeries. TYPES OF STUDIES REVIEWED: The authors searched PubMed (MEDLINE), Cochrane, Embase, and other electronic databases for articles related to osteonecrosis of the jaw and medication-related osteonecrosis of the jaw (MRONJ). In addition, the authors hand searched the bibliographies of all relevant articles, the gray literature, textbooks, and guidelines in association position statements. RESULTS: The following information for MRONJ risk should be evaluated before any invasive dental procedure: metastatic carcinoma has a higher risk than osteoporosis; parenterally administered bisphosphonates and denosumab have a higher risk than orally administered bisphosphonates or antiangiogenic agents; dose and duration of medication received; adjunctive medications or combination of antiresorptive agents also may increase the risk of MRONJ; additive factors and comorbidities such as diabetes, autoimmune disease, immunosuppression, or any condition that might affect healing negatively would result in potentially higher risk of developing MRONJ; angiogenic inhibitors as part of a cancer treatment regimen, with or without antiresorptive medication, are considered high risk. PRACTICAL IMPLICATIONS: Patients who received antiresorptive therapy for malignancy were at higher risk of developing MRONJ than those who received the therapy for osteoporosis, regardless of the route of administration and type of drug. Antiangiogenic agents, bevacizumab, aflibercept, and tyrosine kinase inhibitors such as sunitinib were implicated most commonly in the development of MRONJ. Patients who are taking multiple doses of angiogenic inhibitors should be monitored closely for early diagnosis of possible MRONJ.

White matter microstructure differences in individuals with dependence on cocaine, methamphetamine, and nicotine: Findings from the ENIGMA-Addiction working group.

BACKGROUND: Nicotine and illicit stimulants are very addictive substances. Although associations between grey matter and dependence on stimulants have been frequently reported, white matter correlates have received less attention. METHODS: Eleven international sites ascribed to the ENIGMA-Addiction consortium contributed data from individuals with dependence on cocaine (n = 147), methamphetamine (n = 132) and nicotine (n = 189), as well as non-dependent controls (n = 333). We compared the fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) of 20 bilateral tracts. Also, we compared the performance of various machine learning algorithms in deriving brain-based classifications on stimulant dependence. RESULTS: The cocaine and methamphetamine groups had lower regional FA and higher RD in several association, commissural, and projection white matter tracts. The methamphetamine dependent group additionally showed lower regional AD. The nicotine group had lower FA and higher RD limited to the anterior limb of the internal capsule. The best performing machine learning algorithm was the support vector machine (SVM). The SVM successfully classified individuals with dependence on cocaine (AUC = 0.70, p < 0.001) and methamphetamine (AUC = 0.71, p < 0.001) relative to non-dependent controls. Classifications related to nicotine dependence proved modest (AUC = 0.62, p = 0.014). CONCLUSIONS: Stimulant dependence was related to FA disturbances within tracts consistent with a role in addiction. The multivariate pattern of white matter differences proved sufficient to identify individuals with stimulant dependence, particularly for cocaine and methamphetamine.

Sex and dependence related neuroanatomical differences in regular cannabis users: findings from the ENIGMA Addiction Working Group.

Males and females show different patterns of cannabis use and related psychosocial outcomes. However, the neuroanatomical substrates underlying such differences are poorly understood. The aim of this study was to map sex differences in the neurobiology (as indexed by brain volumes) of dependent and recreational cannabis use. We compared the volume of a priori regions of interest (i.e., amygdala, hippocampus, nucleus accumbens, insula, orbitofrontal cortex (OFC), anterior cingulate cortex and cerebellum) between 129 regular cannabis users (of whom 70 were recreational users and 59 cannabis dependent) and 114 controls recruited from the ENIGMA Addiction Working Group, accounting for intracranial volume, age, IQ, and alcohol and tobacco use. Dependent cannabis users, particularly females, had (marginally significant) smaller volumes of the lateral OFC and cerebellar white matter than recreational users and controls. In dependent (but not recreational) cannabis users, there was a significant association between female sex and smaller volumes of the cerebellar white matter and OFC. Volume of the OFC was also predicted by monthly standard drinks. No significant effects emerged the other brain regions of interest. Our findings warrant future multimodal studies that examine if sex and cannabis dependence are specific key drivers of neurobiological alterations in cannabis users. This, in turn, could help to identify neural pathways specifically involved in vulnerable cannabis users (e.g., females with cannabis dependence) and inform individually tailored neurobiological targets for treatment.

Mapping cortical and subcortical asymmetries in substance dependence: Findings from the ENIGMA Addiction Working Group.

Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.

Subcortical surface morphometry in substance dependence: An ENIGMA addiction working group study.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

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.

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.

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.

Crown lengthening in the maxillary anterior region: a 6-month prospective clinical study.

The purpose of this study was to assess osseous parameters and stability of maxillary anterior teeth following crown lengthening surgery. Thirty-six patients requiring facial crown lengthening of 277 maxillary anterior and first premolar teeth were included. Presurgical and intraoperative clinical measurements were recorded at baseline and 1, 3, and 6 months postsurgery at midfacial, mesiofacial, and distofacial line angles. The data presented here suggest that when crown lengthening anterior maxillary teeth, the distance between the desired gingival margin and alveolar crest is usually insufficient to allow for biologic width. In addition, there is significant tissue rebound that may stabilize by 6 months. Tissue rebound appears related to flap position relative to the alveolar crest at suturing. These findings suggest that clinicians should establish proper anterior crown length with osseous resection.

Direct intranigral administration of an ubiquitin proteasome system inhibitor in rat: behavior, positron emission tomography, immunohistochemistry.

Several independent lines of research suggest that disruption of the ubiquitin proteasome system (UPS) may play a role in the pathophysiology of Parkinson's disease. Direct intracerebral injection of UPS inhibitors (e.g. lactacystin) in animals has consistently produced important features of the disease. In this study, a range of lactacystin doses (0.5, 1, 2, 10 and 20 µg) were injected into the right substantia nigra in rats to determine the ideal dose required to produce a robust and specific lesion of the dopamine nigro-striatal system and motor deficits. Motor behavior, assessed with the tapered ledged beam task, was severely affected in animals that received high doses (10 and 20 µg) but only mild, impairments were observed in animals that received low doses (0.5, 1, and 2 µg). Positron emission tomography was performed with a dedicated small animal scanner on the rats following the injection of the radio-labeled tracer (±)[(11)C]dihydrotetrabenazine (DTBZ) which labels vesicular monoamine transporter type 2. Severe loss of [(11)C]DTBZ binding in the ipsilateral striatum was observed in the higher dose groups and mild loss was observed in the low dose groups. Stereological cell counting of tyrosine hydroxylase immunoreactive cells in the substantia nigra and the ventral tegmental area indicated a dose dependent loss of dopaminergic neurons. Significant correlations were found between the behavioral motor deficits, striatal [(11)C]DTBZ binding and cell counts of tyrosine hydroxylase immunoreactive cells. Taken together these results indicate that intranigral injection of lactacystin produces dose dependent effects on the dopamine nigro-striatal system and a dose of 10 µg will produce a consistent severe lesion.

Case report: Diagnosis and treatment of a botryoid odontogenic cyst found in the maxillary anterior region.

INTRODUCTION: The botryoid odontogenic cyst (BOC) is a multicompartmentalized variant of the lateral periodontal cyst (LPC) that is typically found in the premolar-canine region of the mandible. METHODS: A 60-year old man was referred for evaluation of a radiolucent lesion discovered on a routine examination. Radiographs revealed a unilocular radiolucency between the roots of teeth #10 and #11. Clinically, the site appeared normal with minimal probing depths, and there were no signs of swelling, bleeding, or mobility of the adjacent teeth. The pulps of both teeth responded to cold without lingering. After patient consent, the lesion was accessed by a mucoperiosteal flap, curetted from its bony cavity, and submitted for biopsy. The site was then treated with a bone allograft and a collagen membrane. RESULTS: The diagnosis of a BOC was made based on location and the histopathological findings of multiple cystic spaces lined by nonkeratinized stratified squamous epithelium. The 22-month follow-up revealed a normal clinical appearance with evidence of radiographic bone fill at the site of the lesion. CONCLUSION: This case shows an unusual presentation of a BOC in both location and radiographic appearance and emphasizes the importance of a microscopic examination of unilocular lesions when associated with teeth having normal responding vital pulps. The relatively high recurrence rate for the BOC warrants periodic follow-up.

Periodontal wound healing with and without platelet-rich plasma: histologic observations and assessment of flap tensile strength.

BACKGROUND: Platelet-rich plasma (PRP) has been promoted as a surgical adjunct to enhance hard and soft tissue wound healing. Although anecdotally reported to be of value, the results of controlled studies examining the added effects of PRP on surgical procedures have been mixed. The purpose of this study was to test the effect of PRP on flap strength at various post-surgical time points in a minipig animal model. METHODS: Twelve Yucatan minipigs provided four sites per animal. PRP was prepared from each animal at the time of surgery. Following reflection of a mucoperiosteal flap in each quadrant, subgingival plaque and calculus were removed. Each surgical site was irrigated with sterile saline; prior to suturing, one randomly selected test quadrant in each arch was treated with PRP. Four animals were euthanized at day 14, and two animals were euthanized at 2, 7, 10, and 28 days. The flap strength in each quadrant was tested by attaching to a loop of 3-0 silk suture through the tissue; the force required to separate the flap from the tooth/bone interface was recorded for each site. A separate portion of each flap site was prepared for descriptive histologic examination, including inflammation, hemorrhage, and new bone growth. RESULTS: Flap strength was significantly less on day 2 compared to later time points, and there were no significant differences between the test and control groups. No histologic differences in healing between test and control sites were seen at any time point. CONCLUSIONS: PRP did not seem to contribute to greater flap strength at any post-surgical time point, nor was it associated with any histologic differences in wound healing in this Yucatan minipig model. The time points chosen for observation post-surgery, as well as the variability in the PRP platelet count, may have contributed to the lack of positive findings in this study.