A critical overview of tools for assessing cognition in bipolar disorder

Cognitive deficits are prevalent in bipolar disorder even during the euthymic phase, having a negative impact on global functioning and quality of life. As such, more and more mental health professionals agree that neuropsychological assessment should be considered an essential component of the clinical management of bipolar patients. However, no gold standard tool has been established so far. According to bipolar disorder experts targeting cognition, appropriate cognitive tools should be brief, easy to administer, cost-effective and validated in the target population. In this commentary, we critically appraised the strengths and limitations of the tools most commonly used to assess cognitive functioning in bipolar patients, both for screening and diagnostic purposes

Neuroimaging studies exploring the neural basis of social isolation

According to the social brain hypothesis, the human brain includes a network designed for the processing of social information. This network includes several brain regions that elaborate social cues, interactions and contexts, i.e. prefrontal paracingulate and parietal cortices, amygdala, temporal lobes and the posterior superior temporal sulcus. While current literature suggests the importance of this network from both a psychological and evolutionary perspective, little is known about its neurobiological bases. Specifically, only a paucity of studies explored the neural underpinnings of constructs that are ascribed to the social brain network functioning, i.e. objective social isolation and perceived loneliness. As such, this review aimed to overview neuroimaging studies that investigated social isolation in healthy subjects. Social isolation correlated with both structural and functional alterations within the social brain network and in other regions that seem to support mentalising and social processes (i.e. hippocampus, insula, ventral striatum and cerebellum). However, results are mixed possibly due to the heterogeneity of methods and study design. Future neuroimaging studies with longitudinal designs are needed to measure the effect of social isolation in experimental v. control groups and to explore its relationship with perceived loneliness, ultimately helping to clarify the neural correlates of the social brain

Default mode network activity in bipolar disorder

Since its discovery in 1997, the default mode network (DMN) and its components have been extensively studied in both healthy individuals and psychiatric patients. Several studies have investigated possible DMN alterations in specific mental conditions such as bipolar disorder (BD). In this review, we describe current evidence from resting-state functional magnetic resonance imaging studies with the aim to understand possible changes in the functioning of the DMN in BD. Overall, several types of analyses including seed-based and independent component have been conducted on heterogeneous groups of patients highlighting different results. Despite the differences, findings seem to indicate that BD is associated with alterations in both frontal and posterior DMN structures, mainly in the prefrontal, posterior cingulate and inferior parietal cortices. We conclude this review by suggesting possible future research directions

Measuring white matter microstructure in 1,457 cannabis users and 1,441 controls : A systematic review of diffusion-weighted MRI studies

Introduction: Cannabis is the most widely used regulated substance by youth and adults. Cannabis use has been associated with psychosocial problems, which have been partly ascribed to neurobiological changes. Emerging evidence to date from diffusion-MRI studies shows that cannabis users compared to controls show poorer integrity of white matter fibre tracts, which structurally connect distinct brain regions to facilitate neural communication. However, the most recent evidence from diffusion-MRI studies thus far has yet to be integrated. Therefore, it is unclear if white matter differences in cannabis users are evident consistently in selected locations, in specific diffusion-MRI metrics, and whether these differences in metrics are associated with cannabis exposure levels. Methods: We systematically reviewed the results from diffusion-MRI imaging studies that compared white matter differences between cannabis users and controls. We also examined the associations between cannabis exposure and other behavioral variables due to changes in white matter. Our review was pre-registered in PROSPERO (ID: 258250; https://www.crd.york.ac.uk/prospero/). Results: We identified 30 diffusion-MRI studies including 1,457 cannabis users and 1,441 controls aged 16-to-45 years. All but 6 studies reported group differences in white matter integrity. The most consistent differences between cannabis users and controls were lower fractional anisotropy within the arcuate/superior longitudinal fasciculus (7 studies), and lower fractional anisotropy of the corpus callosum (6 studies) as well as higher mean diffusivity and trace (4 studies). Differences in fractional anisotropy were associated with cannabis use onset (4 studies), especially in the corpus callosum (3 studies). Discussion: The mechanisms underscoring white matter differences are unclear, and they may include effects of cannabis use onset during youth, neurotoxic effects or neuro adaptations from regular exposure to tetrahydrocannabinol (THC), which exerts its effects by binding to brain receptors, or a neurobiological vulnerability predating the onset of cannabis use. Future multimodal neuroimaging studies, including recently developed advanced diffusion-MRI metrics, can be used to track cannabis users over time and to define with precision when and which region of the brain the white matter changes commence in youth cannabis users, and whether cessation of use recovers white matter differences. Systematic review registration: www.crd.york.ac.uk/prospero/, identifier: 258250

Increased gyrification in schizophrenia and non affective first episode of psychosis

Prefrontal cortex gyrification has been suggested to be altered in patients with schizophrenia and first episode psychosis. Therefore, it may represent a possible trait marker for these illnesses and an indirect evidence of a disrupted underlying connectivity. The aim of this study was to add further evidence to the existing literature on the role of prefrontal gyrification in psychosis by carrying out a study on a sizeable sample of chronic patients with schizophrenia and non-affective first-episode psychosis (FEP-NA) patients. Methods: Seventy-two patients with schizophrenia, 51 FEP-NA patients (12 who later develop schizophrenia) and 95 healthy controls (HC) underwent magnetic resonance imaging (MRI). Cortical folding was quantified using the automated gyrification index (GI). GI values were compared among groups and related to clinical variables. Results: Both FEP-NA and patients with schizophrenia showed a higher mean prefrontal GI compared to HC (all p. <. 0.05). Interestingly, no differences have been observed between the two patients groups as well as between FEP-NA patients who did and did not develop schizophrenia. Conclusions: Our results suggest the presence of a shared aberrant prefrontal GI in subjects with both schizophrenia and first-episode psychosis. These findings support the hypothesis that altered GI represents a neurodevelopmental trait marker for psychosis, which may be involved in the associated neurocognitive deficits

The influence of 5-HTTLPR, BDNF Rs6265 and COMT Rs4680 polymorphisms on impulsivity in bipolar disorder: the role of gender

Impulsivity has been proposed as an endophenotype for bipolar disorder (BD); moreover, impulsivity levels have been shown to carry prognostic significance and to be quality-of-life predictors. To date, reports about the genetic determinants of impulsivity in mood disorders are limited, with no studies on BD individuals. Individuals with BD and healthy controls (HC) were recruited in the context of an observational, multisite study (GECOBIP). Subjects were genotyped for three candidate single-nucleotide polymorphisms (SNPs) (5-HTTLPR, COMT rs4680, BDNF rs6265); impulsivity was measured through the Italian version of the Barratt Impulsiveness Scale (BIS-11). A mixed-effects regression model was built, with BIS scores as dependent variables, genotypes of the three polymorphisms as fixed effects, and centers of enrollment as random effect. Compared to HC, scores for all BIS factors were higher among subjects with euthymic BD (adjusted β for Total BIS score: 5.35, p &lt; 0.001). No significant interaction effect was evident between disease status (HC vs. BD) and SNP status for any polymorphism. Considering the whole sample, BDNF Met/Met homozygosis was associated with lower BIS scores across all three factors (adjusted β for Total BIS score: -10.2, p &lt; 0.001). A significant 5-HTTLPR x gender interaction was found for the SS genotype, associated with higher BIS scores in females only (adjusted β for Total BIS score: 12.0, p = 0.001). Finally, COMT polymorphism status was not significantly associated with BIS scores. In conclusion, BD diagnosis did not influence the effect on impulsivity scores for any of the three SNPs considered. Only one SNP-the BDNF rs6265 Met/Met homozygosis-was independently associated with lower impulsivity scores. The 5-HTTLPR SS genotype was associated with higher impulsivity scores in females only. Further studies adopting genome-wide screening in larger samples are needed to define the genetic basis of impulsivity in BD

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

DECLINE OF PREVALENCE OF RESISTANCE ASSOCIATED SUBSTITUTIONS TO NS3 AND NS5A INHIBITORS AT DAA- FAILURE IN HEPATITIS C VIRUS IN ITALY OVER THE YEARS 2015 TO 2018

Background: A minority of patients fails to eliminate HCV and resistance-associated substitutions (RASs) are commonly detected at failure of interferon-free DAA regimens . Methods: Within the Italian network VIRONET-C, the prevalence of NS3/NS5A/NS5B RASs was retrospectively evaluated in patients who failed an EASL recommended DAA-regimen in 2015-2018 . The geno2pheno system and Sorbo MC et al. Drug Resistance Updates 2018 were used to infer HCV- genotype/subtype and predict drug resistance . The changes in prevalence of RASs over time were evaluated by chi-square test for trend, predictors of RASs at failure were analysed by logistic regression . Results: We included 386 HCV infected patients: 75% males, median age was 56 years (IQR 52-61), metavir fibrosis stage F4 in 76%; 106 (28%) were treatment- experienced: 91 (86%) with IFN-based treatments, 26 (25%) with DAAs. Patients with HIV and HBV coinfection were 10% (33/317) and 8% (6/72), respectively. HCV genotype was 1b in 122 pts (32%), 3 in 109 (28%), 1a in 97 (25%), 4 in 37 (10%), 2 in 21 (5%). DAA regimens were: LDV/SOF in 115 (30%), DCV/SOF in 103 (27%), 3D in 83 (21%), EBR/GRZ in 32 (8%), VEL/SOF in 29 (7%), GLE/PIB in 18 (5%) and 2D in 6 (2%); ribavirin was administered in 123 (32%) . The NS5A fasta-sequence was available for all patients, NS5B for 361 (94%), NS3 for 365 (95%) . According to the DAA failed the prevalence of any RASs was 90%, namely 80/135 (59%) in NS3, 313/359 (87%) in NS5A, 114/286 (40%) in NS5B . The prevalence of any RASs significantly declined from 2015 to 2018 (93% vs 70%, p=0.004): NS5A RASs from 90% to 72% (p=0 .29), NS3 RASs from 74% to 18% (p&lt;0 .001), while NS5B RASs remained stable . Independent predictors of any RASs included advanced fibrosis (AOR 6.1, CI 95% 1.8-20.3, p=0 .004) and genotype (G2 vs G1a AOR 0 .03, CI 95% 0 .002- 0 .31, p=0 .004; G3 vs G1a AOR 0 .08, CI 95% 0 .01-0 .62, p=0 .02; G4 vs G1a AOR 0 .05, CI 95% 0 .006-0 .46, p=0 .008), after adjusting for age, previous HCV treatment and year of genotype . Notably, full activity was predicted for GLE/PIB in 75% of cases and for at least two components of VEL/SOF/VOX in 53% of cases, no case with full-resistance to either regimen was found . Conclusion: Despite decreasing prevalence over the years, RASs remain common at virological failure of DAA treatment, particularly in patients with the highest grade of liver fibrosis. The identification of RASs after failure could play a crucial role in optimizing retreatment strategies

Sex differences in the neuroanatomy of alcohol dependence: hippocampus and amygdala subregions in a sample of 966 people from the ENIGMA Addiction Working Group

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

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types