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•Competitive null models may yield false positives from co-expression.•Self-contained null models may yield false positives from bimodal correlations.•Test statistics interact differently with two types of null models.•Supplementary analyses with various configurations support the findings. Correlating transcriptional profiles with imaging-derived phenotypes has the potential to reveal possible molecular architectures associated with cognitive functions, brain development and disorders. Competitive null models built by resampling genes and self-contained null models built by spinning brain regions, along with varying test statistics, have been used to determine the significance of transcriptional associations. However, there has been no systematic evaluation of their performance in imaging transcriptomics analyses. Here, we evaluated the performance of eight different test statistics (mean, mean absolute value, mean squared value, max mean, median, Kolmogorov-Smirnov (KS), Weighted KS and the number of significant correlations) in both competitive null models and self-contained null models. Simulated brain maps (n = 1,000) and gene sets (n = 500) were used to calculate the probability of significance (Psig) for each statistical test. Our results suggested that competitive null models may result in false positive results driven by co-expression within gene sets. Furthermore, we demonstrated that the self-contained null models may fail to account for distribution characteristics (e.g., bimodality) of correlations between all available genes and brain phenotypes, leading to false positives. These two confounding factors interacted differently with test statistics, resulting in varying outcomes. Specifically, the sign-sensitive test statistics (i.e., mean, median, KS, Weighted KS) were influenced by co-expression bias in the competitive null models, while median and sign-insensitive test statistics were sensitive to the bimodality bias in the self-contained null models. Additionally, KS-based statistics produced conservative results in the self-contained null models, which increased the risk of false negatives. Comprehensive supplementary analyses with various configurations, including realistic scenarios, supported the results. These findings suggest utilizing sign-insensitive test statistics such as mean absolute value, max mean in the competitive null models and the mean as the test statistic for the self-contained null models. Additionally, adopting the confounder-matched (e.g., coexpression-matched) null models as an alternative to standard null models can be a viable strategy. Overall, the present study offers insights into the selection of statistical tests for imaging transcriptomics studies, highlighting areas for further investigation and refinement in the evaluation of novel and commonly used tests.

Leveraging ~10 years of prospective longitudinal data on 704 participants, we examined the effects of adolescent versus young adult cannabis initiation on MRI-assessed cortical thickness development and behavior. Data were obtained from the IMAGEN study conducted across eight European sites. We identified IMAGEN participants who reported being cannabis-naïve at baseline and had data available at baseline, 5-year, and 9-year follow-up visits. Cannabis use was assessed with the European School Survey Project on Alcohol and Drugs. T1-weighted MR images were processed through the CIVET pipeline. Cannabis initiation occurring during adolescence (14–19 years) and young adulthood (19–22 years) was associated with differing patterns of longitudinal cortical thickness change. Associations between adolescent cannabis initiation and cortical thickness change were observed primarily in dorso- and ventrolateral portions of the prefrontal cortex. In contrast, cannabis initiation occurring between 19 and 22 years of age was associated with thickness change in temporal and cortical midline areas. Follow-up analysis revealed that longitudinal brain change related to adolescent initiation persisted into young adulthood and partially mediated the association between adolescent cannabis use and past-month cocaine, ecstasy, and cannabis use at age 22. Extent of cannabis initiation during young adulthood (from 19 to 22 years) had an indirect effect on psychotic symptoms at age 22 through thickness change in temporal areas. Results suggest that developmental timing of cannabis exposure may have a marked effect on neuroanatomical correlates of cannabis use as well as associated behavioral sequelae. Critically, this work provides a foundation for neurodevelopmentally informed models of cannabis exposure in humans.

Males and females with alcohol dependence have distinct mental health and cognitive problems. Animal models of addiction postulate that the underlying neurobiological mechanisms are partially distinct, but there is little evidence of sex differences in humans with alcohol dependence as most neuroimaging studies have been conducted in males. We examined hippocampal and amygdala subregions in a large sample of 966 people from the ENIGMA Addiction Working Group. This comprised 643 people with alcohol dependence (225 females), and a comparison group of 323 people without alcohol dependence (98 females). Males with alcohol dependence had smaller volumes of the total amygdala and its basolateral nucleus than male controls, that exacerbated with alcohol dose. Alcohol dependence was also associated with smaller volumes of the hippocampus and its CA1 and subiculum subfield volumes in both males and females. In summary, hippocampal and amygdalar subregions may be sensitive to both shared and distinct mechanisms in alcohol-dependent males and females.

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.

Abstract Background In Louisiana, deaths related to COVID-19 have disproportionately occurred in Black persons. Granular data are needed to better understand inequities and develop prevention strategies to mitigate further impact on Black communities. Methods We conducted a retrospective study of patients admitted to an urban safety net hospital in New Orleans, Louisiana, with reactive SARS-CoV-2 testing from March 9 to 31, 2020. Clinical characteristics of Black and other racial/ethnic group patients were compared using Wilcoxon rank-sum test and Fisher exact tests. The relationship between race and outcome was assessed using day 14 status on an ordinal scale. Results This study included 249 patients. The median age was 59, 44% were male, and 86% were age ≥65 years or had ≥1 comorbidity. Overall, 87% were Black, relative to 55% Black patients typically hospitalized at our center. Black patients had longer symptom duration at presentation (6.41 vs 5.88 days; P = .05) and were more likely to have asthma (P = .008) but less likely to have dementia (P = .002). There were no racial differences in initial respiratory status or laboratory values except for higher lactate dehydrogenase in Black patients. Patient age and initial oxygen requirement, but not race (adjusted proportional odds ratio, 0.92; 95% CI, 0.70–1.20), were associated with worse day 14 outcomes. Conclusions Our results demonstrate minor racial differences in comorbidities or disease severity at presentation, and day 14 outcomes were not different between groups. However, Black patients were disproportionately represented in hospitalizations, suggesting that prevention efforts should include strategies to limit SARS-CoV-2 exposures and transmission in Black communities as one step toward reducing COVID-19-related racial inequities.

Broca's area: monkeys too In 1861 a physician, Paul Broca, described a patient with speech problems who said only one word: ‘tan’. When the patient died, brain damage was discovered in part of the left frontal cortex, which became known as Broca's speech production area, or human architectronic area 44. Today there is controversy as to whether nonhuman primates possess a comparable cortical area. Now Petrides et al . show that monkeys do possess such an area, and that it is involved with facial musculature. The area may have evolved to control the jaw and other actions including those related to communication. In the ventrolateral frontal lobe of the human brain there is a distinct entity, cytoarchitectonic area 44 (Broca's area), which is crucial in speech production 1 , 2 , 3 , 4 . There has been controversy 5 , 6 over whether monkeys possess an area comparable to human area 44. We have addressed this question in the macaque monkey by combining quantitative architectonic analysis of the cortical areas within the ventrolateral frontal region with electrophysiological recording of neuron activity and electrical intracortical microstimulation. Here we show that, immediately in front of the ventral part of the agranular premotor cortical area 6, there is a distinct cortical area that is architectonically comparable to human area 44 and that this monkey area 44 is involved with the orofacial musculature. We suggest that area 44 might have evolved originally as an area exercising high-level control over orofacial actions, including those related to communicative acts, and that, in the human brain, area 44 eventually also came to control certain aspects of the speech act.

Alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with brain alterations particularly involving fronto‐cerebellar and meso‐cortico‐limbic circuitry. However, such abnormalities have additionally been reported in other psychiatric conditions, and until recently there has been few large‐scale investigations to compare such findings. The current study uses the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) consortium method of standardising structural brain measures to quantify case–control differences and to compare brain‐correlates of substance use disorders with those published in relation to other psychiatric disorders. Using the ENIGMA protocols, we report effect sizes derived from a meta‐analysis of alcohol (seven studies, N = 798, 54% are cases) and cannabis (seven studies, N = 447, 45% are cases) dependent cases and age‐ and sex‐matched controls. We conduct linear analyses using harmonised methods to process and parcellate brain data identical to those reported in the literature for ENIGMA case–control studies of major depression disorder (MDD), schizophrenia (SCZ) and bipolar disorder so that effect sizes are optimally comparable across disorders. R elationships between substance use disorder diagnosis and subcortical grey matter volumes and cortical thickness were assessed with intracranial volume, age and sex as co‐variates . After correcting for multiple comparisons, AUD case–control meta‐analysis of subcortical regions indicated significant differences in the thalamus, hippocampus, amygdala and accumbens, with effect sizes (0.23) generally equivalent to, or larger than |0.23| those previously reported for other psychiatric disorders (except for the pallidum and putamen). On measures of cortical thickness, AUD was associated with significant differences bilaterally in the fusiform gyrus, inferior temporal gyrus, temporal pole, superior frontal gyrus, and rostral and caudal anterior cingulate gyri. Meta‐analysis of CUD case–control studies indicated reliable reductions in amygdala, accumbens and hippocampus volumes, with the former effect size comparable to, and the latter effect size around half of that reported for alcohol and SCZ. CUD was associated with lower cortical thickness in the frontal regions, particularly the medial orbitofrontal region, but this effect was not significant after correcting for multiple testing. This study allowed for an unbiased cross‐disorder comparison of brain correlates of substance use disorders and showed alcohol‐related brain anomalies equivalent in effect size to that found in SCZ in several subcortical and cortical regions and significantly greater alterations than those found in MDD in several subcortical and cortical regions. Although modest, CUD results overlapped with findings reported for AUD and other psychiatric conditions, but appear to be most robustly related to reduce thickness of the medial orbitofrontal cortex. We compared the impact of alcohol and cannabis use disorders to other major psychiatric conditions using standardised objectively brain derived metrics. Through a meta‐analytic cross‐disorder framework, comparable and unique volumetric variations were observed in participants with addiction.

This research investigates the trend following relationships between Commodity Trading Advisor (CTA) Indexes and a widely known trend following proxy Index using a database covering 21 years with 24 CTA, Managed Futures, and Hedge Fund (that can trade CTA-like) Indexes. The trend following relationships are tested using a modification of the Methodology employed by Baesel, Gonzalez-Heres, Chen, & Shin (2012). A unique Alpha adjustment is proposed to include the traditional Alpha plus or minus a reward or penalty for displaying relationships to the larger positive and negative returns of the trend following Index proxy. Results for the first sample period show evidence of at least some association of the returns of the trend following proxy to those of the individual CTA Indexes; however, most of the Indexes showed little to no statistical support for much traditional or adjusted Total Alpha generation. For the second sample period the regression results show that almost none of the Indexes had a statistically significant association with the monthly total returns of the trend following proxy Index. Instead, generally all of the Indexes showed the impact of the larger monthly returns of the trend following proxy Index such that the Alpha adjustments overall were positive and, on average, generated approximately 50% of the Total Alpha of the individual CTA Indexes.

The parietal lobe is a region of especially pronounced change in human brain evolution. Based on comparative neuroanatomical studies, the inferior parietal lobe (IPL) has been shown to be disproportionately larger in humans relative to chimpanzees and macaques. However, it remains unclear whether the underlying histological architecture of IPL cortical areas displays human-specific organization. Chimpanzees are among the closest living relatives of humans, making them an ideal comparative species to investigate potential evolutionary changes in the IPL. We parcellated the chimpanzee IPL using cytoarchitecture and myeloarchitecture, in combination with quantitative comparison of cellular features between the identified cortical areas. Four major areas on the lateral convexity of the chimpanzee IPL (PF, PFG, PG, OPT) and two opercular areas (PFOP, PGOP) were identified, similar to what has been observed in macaques. Analysis of the quantitative profiles of cytoarchitecture showed that cell profile density was significantly different in a combination of layers III, IV, and V between bordering cortical areas, and that the density profiles of these six areas supports their classification as distinct. The similarity to macaque IPL cytoarchitecture suggests that chimpanzees share homologous IPL areas. In comparison, human rostral IPL is reported to differ in its anatomical organization and to contain additional subdivisions, such as areas PFt and PFm. These changes in human brain evolution might have been important as tool making capacities became more complex.