Laura Ferranti

Functional genetic variation of the cannabinoid receptor 1 and cannabis use interact on prefrontal connectivity and related working memory behavior

Cannabinoid signaling is involved in different brain functions and it is mediated by the cannabinoid receptor 1 (CNR1), which is encoded by the CNR1 gene. Previous evidence suggests an association between cognition and cannabis use. The logical interaction between genetically determined cannabinoid signaling and cannabis use has not been determined. Therefore, we investigated whether CNR1 variation predicts CNR1 prefrontal mRNA expression in postmortem prefrontal human tissue. Then, we studied whether functional variation in CNR1 and cannabis exposure interact in modulating prefrontal function and related behavior during working memory processing. Thus, 208 healthy subjects (113 males) were genotyped for the relevant functional SNP and were evaluated for cannabis use by the Cannabis Experience Questionnaire. All individuals performed the 2-back working memory task during functional magnetic resonance imaging. CNR1 rs1406977 was associated with prefrontal mRNA and individuals carrying a G allele had reduced CNR1 prefrontal mRNA levels compared with AA subjects. Moreover, functional connectivity MRI demonstrated that G carriers who were also cannabis users had greater functional connectivity in the left ventrolateral prefrontal cortex and reduced working memory behavioral accuracy during the 2-back task compared with the other groups. Overall, our results indicate that the deleterious effects of cannabis use are more evident on a specific genetic background related to its receptor expression.

DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine

RationalePharmacological stimulation of D2 receptors modulates prefrontal neural activity associated with working memory (WM) processing. The T allele of a functional single-nucleotide polymorphism (SNP) within DRD2 (rs1076560 G > T) predicts reduced relative expression of the D2S receptor isoform and less efficient neural cortical responses during WM tasks.ObjectiveWe used functional MRI to test the hypothesis that DRD2 rs1076560 genotype interacts with pharmacological stimulation of D2 receptors with bromocriptine on prefrontal responses during different loads of a spatial WM task (N-Back).MethodsFifty-three healthy subjects (38 GG and 15 GT) underwent two 3-T functional MRI scans while performing the 1-, 2- and 3-Back versions of the N-Back WM task. Before the imaging sessions, either bromocriptine or placebo was administered to all subjects in a counterbalanced order. A factorial repeated-measures ANOVA within SPM8 (p < 0.05, family-wise error corrected) was used.ResultsOn bromocriptine, GG subjects had reduced prefrontal activity at 3-Back together with a significant decrement in performance, compared with placebo. On the other hand, GT subjects had lower activity for the same level of performance at 1-Back but a trend for reduced behavioral performance in the face of unchanged activity at 2-Back.ConclusionsThese results indicate that bromocriptine stimulation modulates prefrontal activity in terms of disengagement or of efficiency depending on DRD2 genotype and working memory load.

The State of the Art of the DSM-5 “with Mixed Features” Specifier

The new DSM-5 “with mixed features” specifier (MFS) has renewed the interest of the scientific community in mixed states, leading not only to new clinical studies but also to new criticisms of the current nosology. Consequently, in our paper we have reviewed the latest literature, trying to understand the reactions of psychiatrists to the new nosology and its epidemiological, prognostic, and clinical consequences. It seems that the most widespread major criticism is the exclusion from the DSM-5 MFS of overlapping symptoms (such as psychomotor agitation, irritability, and distractibility), with a consequent reduction in diagnostic power. On the other hand, undoubtedly the new DSM-5 classification has helped to identify more patients suffering from a mixed state by broadening the narrow DSM-IV-TR criteria. As for the clinical presentation, the epidemiological data, and the therapeutic outcomes, the latest literature does not point out a univocal point of view and further research is needed to fully assess the implications of the new DSM-5 MFS. It is our view that a diagnostic category should be preferred to a specifier and mixed states should be better considered as a spectrum of states, according to what was stated many years ago by Kraepelin.

Prefrontal Activity and Connectivity with the Basal Ganglia during Performance of Complex Cognitive Tasks Is Associated with Apathy in Healthy Subjects.

Objective Convergent evidence indicates that apathy affects cognitive behavior in different neurological and psychiatric conditions. Studies of clinical populations have also suggested the primary involvement of the prefrontal cortex and the basal ganglia in apathy. These brain regions are interconnected at both the structural and functional levels and are deeply involved in cognitive processes, such as working memory and attention. However, it is unclear how apathy modulates brain processing during cognition and whether such a modulation occurs in healthy young subjects. To address this issue, we investigated the link between apathy and prefrontal and basal ganglia function in healthy young individuals. We hypothesized that apathy may be related to sub-optimal activity and connectivity in these brain regions. Methods Three hundred eleven healthy subjects completed an apathy assessment using the Starkstein’s Apathy Scale and underwent fMRI during working memory and attentional performance tasks. Using an ROI approach, we investigated the association of apathy with activity and connectivity in the DLPFC and the basal ganglia. Results Apathy scores correlated positively with prefrontal activity and negatively with prefrontal-basal ganglia connectivity during both working memory and attention tasks. Furthermore, prefrontal activity was inversely related to attentional behavior. Conclusions These results suggest that in healthy young subjects, apathy is a trait associated with inefficient cognitive-related prefrontal activity, i.e., it increases the need for prefrontal resources to process cognitive stimuli. Furthermore, apathy may alter the functional relationship between the prefrontal cortex and the basal ganglia during cognition.

Genetic variation is associated with RTN4R expression and working memory processing in healthy humans

The Nogo receptor (NgR) is implicated in neurodevelopmental processes and it participates in inhibiting axonal growth. Consistent with its high levels of expression in the prefrontal cortex, animal studies indicate that NgR is relevant for prefrontal-related cognitive processing. Given that genetic variation may alter mechanisms of gene expression impacting molecular and systems-level phenotypes, we investigated the association of genetic variation with the expression of the NgR coding gene (RTN4R), as well as with prefrontal correlates at progressively greater biological distance from gene effects. First, we studied the association of single nucleotide polymorphisms (SNPs) with RTN4R mRNA expression in postmortem prefrontal cortex of humans without psychiatric illnesses. Then, we probed in peripheral blood mononuclear cells (PBMCs) the association that we found in prefrontal tissue. Thus, we investigated whether functional genetic variation affecting RTN4R expression is also associated with prefrontal activity during working memory. We found that rs696884 (A/G) predicted these phenotypes. Specifically, the AA genotype was associated with lower RTN4R mRNA expression levels in the prefrontal cortex and PBMCs and inefficient prefrontal activity during working memory compared to the GG genotype. These results suggest that genetic variation associated with RTN4R mRNA expression influences prefrontal physiology in healthy individuals. Furthermore, they highlight the need for further investigations of the role of NgR in the pathophysiology of brain disorders associated with prefrontal dysfunction.