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Selective serotonin reuptake inhibitors (SSRI) are frequently ineffective in treating depressive episodes and biomarkers are needed to optimize antidepressant treatment outcomes. DNA methylation levels of serotonin transporter (SLC6A4) and tryptophan hydroxylase 2 genes (TPH2) have been suggested to predict antidepressant clinical outcomes but their applicability remains uncertain. In this study, we: 1) evaluated SLC6A4/TPH2 methylation biomarker potential for predicting clinical outcomes after escitalopram treatment; 2) evaluated whether changes in SLC6A4/TPH2 methylation are informative of treatment mechanisms. We used a cohort of 90 unmedicated patients with major depressive disorder that were part of a 12-week open-label longitudinal trial and compared our observations with previous findings. Depressive symptoms were measured at baseline and after 8 and 12 weeks of treatment using the Hamilton Depression Rating Scale (HAMD 6/17 ). We found an association between baseline TPH2 methylation and both clinical response (β:3.43; p = 0.01; 95 % CI:[0.80; 6.06]) and change in depressive symptoms after 8 weeks (β:-45.44; p = 0.01; 95 %CI:[- -78.58; -12.30]). However, we found no evidence for predictive value of any gene (TPH2 AUC: 0.74 95 % CI:[0.42;0.79]; SLC6A4: AUC: 0.61; 95 % CI: [0.48-0.78]). Methylation levels changed at the trend level for CpG sites of SLC6A4 and TPH2 over the course of 12 weeks of treatment. In addition, similar to previous observations, we found a trend for an association between methylation of SLC6A4 CpG2 (chr17:30,236,083) and HAMD 17 change after 12 weeks. Our findings suggest that although TPH2 and SLC6A4 methylation may be informative of antidepressant treatment outcome, they are unlikely to prove useful as clinical predictor tools., Competing Interests: Declaration of competing interest VGF discloses that she has received honorarium for lectures from SAGE Therapeutics, Lundbeck Pharma A/S, Janssen Cilag A/S, Gedeon-Richter A/S, and Ferring A/S. The other authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT 4 ) in a cohort of healthy individuals (N = 254) and, for 5-HT 4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT 4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals., Results: We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity., Conclusions: We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms., (© 2024. The Author(s).)

The serotonin transporter (5-HTT) critically shapes serotonin neurotransmission by regulating extracellular brain serotonin levels; it remains unclear to what extent 5-HTT levels in the human brain are genetically determined. Here we applied [ 11 C]DASB positron emission tomography to image brain 5-HTT levels and evaluated associations with five common serotonin-related genetic variants that might indirectly regulate 5-HTT levels (BDNF rs6265, SLC6A4 5-HTTLPR, HTR1A rs6295, HTR2A rs7333412, and MAOA rs1137070) in 140 healthy volunteers. In addition, we explored whether these variants could predict in vivo 5-HTT levels using a five-fold cross-validation random forest framework. MAOA rs1137070 T-carriers showed significantly higher brain 5-HTT levels compared to C-homozygotes (2-11% across caudate, putamen, midbrain, thalamus, hippocampus, amygdala and neocortex). We did not observe significant associations for the HTR1A rs6295 and HTR2A rs7333412 genotypes. Our previously observed lower subcortical 5-HTT availability for rs6265 met-carriers remained in the presence of these additional variants. Despite this significant association, our prediction models showed that genotype moderately improved prediction of 5-HTT in caudate, but effects were not statistically significant after adjustment for multiple comparisons. Our observations provide additional evidence that serotonin-related genetic variants modulate adult human brain serotonin neurotransmission., (© 2023. Springer Nature Limited.)

Memory for sequences is a central topic in neuroscience, and decades of studies have investigated the neural mechanisms underlying the coding of a wide array of sequences extended over time. Yet, little is known on the brain mechanisms underlying the recognition of previously memorized versus novel temporal sequences. Moreover, the differential brain processing of single items in an auditory temporal sequence compared to the whole superordinate sequence is not fully understood. In this magnetoencephalography (MEG) study, the items of the temporal sequence were independently linked to local and rapid (2-8 Hz) brain processing, while the whole sequence was associated with concurrent global and slower (0.1-1 Hz) processing involving a widespread network of sequentially active brain regions. Notably, the recognition of previously memorized temporal sequences was associated to stronger activity in the slow brain processing, while the novel sequences required a greater involvement of the faster brain processing. Overall, the results expand on well-known information flow from lower- to higher order brain regions. In fact, they reveal the differential involvement of slow and faster whole brain processing to recognize previously learned versus novel temporal information., (© The Author(s) 2022. Published by Oxford University Press.)

Auditory predictive processing relies on a complex interaction between environmental, neurophysiological, and genetic factors. In this view, the mismatch negativity (MMN) and intensive training on a musical instrument for several years have been used for studying environment-driven neural adaptations in audition. In addition, brain-derived neurotrophic factor ( BDNF ) has been shown crucial for both the neurogenesis and the later adaptation of the auditory system. The functional single-nucleotide polymorphism (SNP) Val66Met (rs6265) in the BDNF gene can affect BDNF protein levels, which are involved in neurobiological and neurophysiological processes such as neurogenesis and neuronal plasticity. In this study, we hypothesised that genetic variation within the BDNF gene would be associated with different levels of neuroplasticity of the auditory cortex in 74 musically trained participants. To achieve this goal, musicians and non-musicians were recruited and divided in Val/Val and Met- (Val/Met and Met/Met) carriers and their brain activity was measured with magnetoencephalography (MEG) while they listened to a regular auditory sequence eliciting different types of prediction errors. MMN responses indexing those prediction errors were overall enhanced in Val/Val carriers who underwent intensive musical training, compared to Met-carriers and non-musicians with either genotype. Although this study calls for replications with larger samples, our results provide a first glimpse of the possible role of gene-regulated neurotrophic factors in the neural adaptations of automatic predictive processing in the auditory domain after long-term training., Competing Interests: The authors declare the following conflict of interests: We hereby disclose that Leonardo Bonetti and the co-author Elvira Brattico are associate editors and advisory board member of Heliyon, respectfully. We trust that will not bias the decision of the other excellent editors of Heliyon, but we wish to disclose it for ethical reasons., (© 2023 The Authors.)

Hormonal contraceptive drugs are used by adolescent and adult women worldwide. Increasing evidence from human neuroimaging research indicates that oral contraceptives can alter regional functional brain connectivity and brain chemistry. However, questions remain regarding static whole-brain and dynamic network-wise functional connectivity changes. A healthy woman (23 years old) was scanned every day over 30 consecutive days during a naturally occurring menstrual cycle and again a year later while using a combined hormonal contraceptive. Here we calculated graph theory-derived, whole-brain, network-level measures (modularity and system segregation) and global brain connectivity (characteristic path length) as well as dynamic functional brain connectivity using Leading Eigenvector Dynamic Analysis and diametrical clustering. These metrics were calculated for each scan session during the serial sampling periods to compare metrics between the subject's natural and contraceptive cycles. Modularity, system segregation, and characteristic path length were statistically significantly higher across the natural compared to contraceptive cycle scans. We also observed a shift in the prevalence of two discrete brain states when using the contraceptive. Our results suggest a more network-structured brain connectivity architecture during the natural cycle, whereas oral contraceptive use is associated with a generally increased connectivity structure evidenced by lower characteristic path length. The results of this repeated, single-subject analysis allude to the possible effects of oral contraceptives on brain-wide connectivity, which should be evaluated in a cohort to resolve the extent to which these effects generalize across the population and the possible impact of a year-long period between conditions., Competing Interests: DM’s salary was supported by an unrestricted grant from COMPASS Pathways Ltd., which had no involvement in this manuscript or related data collection. VF has received honorarium as a consultant for SAGE Therapeutics and Lundbeck Pharma A/S. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jensen, McCulloch, Olsen, Bruzzone, Larsen, Fisher and Frokjaer.)

Objective: Overlapping neurophysiological signals are the main obstacle preventing from using cortical auditory event-related potentials (AEPs) in clinical settings. Children AEPs are particularly affected by this problem, as their cerebral cortex is still maturing. To overcome this problem, we applied a new version of Spike-density Component Analysis (SCA), an analysis method recently developed, to isolate with high accuracy the neural components of auditory responses of 8-year-old children., Methods: Electroencephalography was used with 33 children to record AEPs to auditory stimuli varying in spectrotemporal features. Three different analysis approaches were adopted: the standard AEP analysis procedure, SCA with template-match (SCA-TM), and SCA with half-split average consistency (SCA-HSAC)., Results: SCA-HSAC most successfully allowed the extraction of AEPs for each child, revealing that the most consistent components were P1 and N2. An immature N1 component was also detected., Conclusion: Superior accuracy in isolating neural components at the individual level was demonstrated for SCA-HSAC over other SCA approaches even for children AEPs., Significance: Reliable methods of extraction of neurophysiological signals at the individual level are crucial for the application of cortical AEPs for routine diagnostic exams in clinical settings both in children and adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Predicting events in the ever-changing environment is a fundamental survival function intrinsic to the physiology of sensory systems, whose efficiency varies among the population. Even though it is established that a major source of such variations is genetic heritage, there are no studies tracking down auditory predicting processes to genetic mutations. Thus, we examined the neurophysiological responses to deviant stimuli recorded with magnetoencephalography (MEG) in 108 healthy participants carrying different variants of Val158Met single-nucleotide polymorphism (SNP) within the catechol-O-methyltransferase (COMT) gene, responsible for the majority of catecholamines degradation in the prefrontal cortex. Our results showed significant amplitude enhancement of prediction error responses originating from the inferior frontal gyrus, superior and middle temporal cortices in heterozygous genotype carriers (Val/Met) vs homozygous (Val/Val and Met/Met) carriers. Integrating neurophysiology and genetics, this study shows how the neural mechanisms underlying optimal deviant detection vary according to the gene-determined cathecolamine levels in the brain., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)