Resting-state, responsivity, and circadian rhythmicity: three different functional components of autonomic nervous system activity in the context of developmental psychopathology

First onset of psychiatric symptoms and disorders usually occurs in childhood or adolescence, presenting a significant portion of the burden of disease in young individuals. The disruption of physiological regulatory systems may present one patho-mechanism underlying the development of psychiatric symptoms and disorders in this age group. Altered autonomic nervous system (ANS) function has been shown to occur prior to observable clinical symptoms, and is typically characterized by an imbalance between its two branches, the sympathetic and parasympathetic nervous systems. Dysfunction of the ANS is frequently indexed by reduced vagally-mediated resting-state heart rate variability (vmHRV), reflecting parasympathetic (vagal) activity. Substantial neurophysiological evidence suggests a relationship between reduced vmHRV and psychiatric disorders characterized by impaired emotion regulation (ER). Alongside resting-state ANS activity, measures of ANS responsivity to challenge (i.e., cardiac reactivity and recovery in response and subsequent to psychological stress exposure) have been suggested as markers of ER, while existing findings on the respective relationships are mixed. Markers of cardiac vagal activity follow rhythmic pattern of circadian variation (circadian variation patterns, CVP), reaching peak levels during nighttime. Indices of CVP of ANS activity may quantify restorative physiological processes, and may be linked with the restoration of autonomic balance. CVP of ANS activity may therefore present further indices of socio-emotional regulatory capacity. The aim of the present thesis was to investigate different markers of cardiac autonomic activity indexing different functional components of ANS activity (i.e., resting-state, responsivity, and circadian rhythmicity) in developmental psychopathology. First, potential associations between experiences of severe adversity early in life (early life maltreatment, ELM), typically associated with deficient ER, and resting-state vmHRV were investigated in a comprehensive meta-analysis. Second, cardiac responsivity to a standardized stress task was assessed as potential predictor of treatment outcome over two years in a preliminary experimental psychotherapy study. Here, heart-rate (HR) and vmHRV responsivity were used as ANS markers. In a third study, CVP of cardiac autonomic activity was analyzed in female adolescents engaging in non-suicidal self-injury (NSSI). The meta-analytic study suggested no general association between resting-state vmHRV and ELM exposure, while accompanying meta-regression analyses revealed potential patterns of association between exposure to ELM and resting-state vmHRV as a function of several moderators, including mean age of and presence of psychopathology in the respective study sample. In the second study, resting-state and vmHRV recovery following stress exposure were identified as potential predictors of clinical improvement over the time course of two years in adolescent females with higher and lower dimensional manifestations of BPD. The third study revealed altered CVP of ANS activity in NSSI disorder compared to healthy controls, and in association with more severe ELM exposure, and critical confounders of the respective associations were identified. The present synopsis aims to integrate these findings into a psychophysiological framework of ER in development, and discuss methodological considerations, limitations, and potential future directions resulting from the studies that constitute the thesis at hand

Low heart rate variability is associated with a negativity valence bias in interpreting ambiguous emotional expressions

Most people tend to overstate positive aspects of their experiences, that is, a positive valence bias. However, some people tend to have attenuated attention for negative aspects of perceived information, that is, negative valence bias. This dispositional tendency in either valence is especially significant for emotion regulation as it influences the intensity of later stages of emotional experiences. Heart rate variability (HRV) is used as an index of emotion regulation and for the effect dispositional valence bias has on social cognition. The aim of the current study was to investigate whether a positivity or negativity bias in processing ambiguous facial expressions would predict high or lower HRV, respectively, in a healthy sample. The Reading the Mind in the Eyes Test was presented to a sample of 128 healthy participants (N = 86 women participants), and resting HRV was acquired. In multiple linear regression analyses, the mean accuracy scores for items with positive, negative, and neutral valences were included as predictors of HRV. As a follow-up analysis, we tested whether a general tendency to interpret negative stimulus as positive, that is, a positivity bias, predicted HRV. Higher accuracy on items with negative emotional valence predicted lower HRV. There was no association between accuracy scores on items of positive or neutral valence and HRV. Higher positivity bias predicted higher HRV. The present findings suggest that a dispositional valence bias relates to levels of HRV and, as such, is influenced by the functioning of the vagal system.acceptedVersio

Transcranial magnetic stimulation in the treatment of adolescent depression: a systematic review and meta-analysis of aggregated and individual-patient data from uncontrolled studies.

Transcranial magnetic stimulation (TMS) is a non-invasive treatment for adolescent major depressive disorder (MDD). Existing evidence on the efficacy of TMS in adolescent MDD awaits quantitative synthesis. A systematic literature search was conducted, and data from eligible studies were synthesized using random-effects models. Treatment-covariate interactions were examined in exploratory analyses of individual-patient data (IPD). Systematic search of the literature yielded 1264 hits, of which 10 individual studies (2 randomized trials) were included for quantitative synthesis of mainly uncontrolled studies. Individual patient data (IPD) were available from five trials (all uncontrolled studies). Quantitative synthesis of aggregated data revealed a statistically significant negative overall standardized mean change (pooled SMCC = 2.04, 95% CI [1.46; 2.61], SE = 0.29, p < .001), as well as a significant overall treatment response rate (Transformed Proportion = 41.30%, 95% CI [31.03; 51.57], SE = 0.05; p < 0.001), considering data from baseline to post-treatment. Exploratory IPD analyses suggests TMS might be more effective in younger individuals and individuals with more severe depression, and efficacy might be enhanced with certain treatment modality settings, including higher number of TMS sessions, longer treatment durations, and unilateral and not bilateral stimulation. Existing studies exhibit methodological shortcomings, including small-study effects and lack of control group, blinding, and randomization-compromising the credibility of the present results. To date, two randomized controlled trials on TMS in adolescent depression have been published, and the only large-scale randomized trial suggests TMS is not more effective than sham stimulation. Future large-scale, randomized, and sham-controlled trials are warranted. Future trials should ensure appropriate selection of patients for TMS treatment and guide precision medicine approaches for stimulation protocols

A Presynaptic Role for the Cytomatrix Protein GIT in Synaptic Vesicle Recycling

Neurotransmission involves the exo-endocytic cycling of synaptic vesicles (SVs) within nerve terminals. Exocytosis is facilitated by a cytomatrix assembled at the active zone (AZ). The precise spatial and functional relationship between exocytic fusion of SVs at AZ membranes and endocytic SV retrieval is unknown. Here, we identify the scaffold G protein coupled receptor kinase 2 interacting (GIT) protein as a component of the AZ- associated cytomatrix and as a regulator of SV endocytosis. GIT1 and its D. melanogaster ortholog, dGIT, are shown to directly associate with the endocytic adaptor stonin 2/stoned B. In Drosophila dgit mutants, stoned B and synaptotagmin levels are reduced and stoned B is partially mislocalized. Moreover, dgit mutants show morphological and functional defects in SV recycling. These data establish a presynaptic role for GIT in SV recycling and suggest a connection between the AZ cytomatrix and the endocytic machinery

A high affinity RIM-binding protein/Aplip1 interaction prevents the formation of ectopic axonal active zones

Synaptic vesicles (SVs) fuse at active zones (AZs) covered by a protein scaffold, at Drosophila synapses comprised of ELKS family member Bruchpilot (BRP) and RIM-binding protein (RBP). We here demonstrate axonal co-transport of BRP and RBP using intravital live imaging, with both proteins co- accumulating in axonal aggregates of several transport mutants. RBP, via its C-terminal Src-homology 3 (SH3) domains, binds Aplip1/JIP1, a transport adaptor involved in kinesin-dependent SV transport. We show in atomic detail that RBP C-terminal SH3 domains bind a proline-rich (PxxP) motif of Aplip1/JIP1 with submicromolar affinity. Pointmutating this PxxP motif provoked formation of ectopic AZ-like structures at axonal membranes. Direct interactions between AZ proteins and transport adaptors seem to provide complex avidity and shield synaptic interaction surfaces of pre-assembled scaffold protein transport complexes, thus, favouring physiological synaptic AZ assembly over premature assembly at axonal membranes. - See more at: http://elifesciences.org/content/4/e06935#sthash.oVGZ8cdi.dpu

A Syd-1 homologue regulates pre- and postsynaptic maturation in Drosophila

A proteomics approach identifies Drosophila Syd-1 as a Bruchpilot binding partner that controls maturation on both sides of the neuromuscular junction

GeMMA: functional subfamily classification within superfamilies of predicted protein structural domains

GeMMA (Genome Modelling and Model Annotation) is a new approach to automatic functional subfamily classification within families and superfamilies of protein sequences. A major advantage of GeMMA is its ability to subclassify very large and diverse superfamilies with tens of thousands of members, without the need for an initial multiple sequence alignment. Its performance is shown to be comparable to the established high-performance method SCI-PHY. GeMMA follows an agglomerative clustering protocol that uses existing software for sensitive and accurate multiple sequence alignment and profile–profile comparison. The produced subfamilies are shown to be equivalent in quality whether whole protein sequences are used or just the sequences of component predicted structural domains. A faster, heuristic version of GeMMA that also uses distributed computing is shown to maintain the performance levels of the original implementation. The use of GeMMA to increase the functional annotation coverage of functionally diverse Pfam families is demonstrated. It is further shown how GeMMA clusters can help to predict the impact of experimentally determining a protein domain structure on comparative protein modelling coverage, in the context of structural genomics

InterPro in 2022.

The InterPro database (https://www.ebi.ac.uk/interpro/) provides an integrative classification of protein sequences into families, and identifies functionally important domains and conserved sites. Here, we report recent developments with InterPro (version 90.0) and its associated software, including updates to data content and to the website. These developments extend and enrich the information provided by InterPro, and provide a more user friendly access to the data. Additionally, we have worked on adding Pfam website features to the InterPro website, as the Pfam website will be retired in late 2022. We also show that InterPro's sequence coverage has kept pace with the growth of UniProtKB. Moreover, we report the development of a card game as a method of engaging the non-scientific community. Finally, we discuss the benefits and challenges brought by the use of artificial intelligence for protein structure prediction

The InterPro protein families database: the classification resource after 15 years

The InterPro database (http://www.ebi.ac.uk/interpro/) is a freely available resource that can be used to classify sequences into protein families and to predict the presence of important domains and sites. Central to the InterPro database are predictive models, known as signatures, from a range of different protein family databases that have different biological focuses and use different methodological approaches to classify protein families and domains. InterPro integrates these signatures, capitalizing on the respective strengths of the individual databases, to produce a powerful protein classification resource. Here, we report on the status of InterPro as it enters its 15th year of operation, and give an overview of new developments with the database and its associated Web interfaces and software. In particular, the new domain architecture search tool is described and the process of mapping of Gene Ontology terms to InterPro is outlined. We also discuss the challenges faced by the resource given the explosive growth in sequence data in recent years. InterPro (version 48.0) contains 36 766 member database signatures integrated into 26 238 InterPro entries, an increase of over 3993 entries (5081 signatures), since 201

InterPro: the integrative protein signature database

The InterPro database (http://www.ebi.ac.uk/interpro/) integrates together predictive models or ‘signatures' representing protein domains, families and functional sites from multiple, diverse source databases: Gene3D, PANTHER, Pfam, PIRSF, PRINTS, ProDom, PROSITE, SMART, SUPERFAMILY and TIGRFAMs. Integration is performed manually and approximately half of the total ∼58 000 signatures available in the source databases belong to an InterPro entry. Recently, we have started to also display the remaining un-integrated signatures via our web interface. Other developments include the provision of non-signature data, such as structural data, in new XML files on our FTP site, as well as the inclusion of matchless UniProtKB proteins in the existing match XML files. The web interface has been extended and now links out to the ADAN predicted protein-protein interaction database and the SPICE and Dasty viewers. The latest public release (v18.0) covers 79.8% of UniProtKB (v14.1) and consists of 16 549 entries. InterPro data may be accessed either via the web address above, via web services, by downloading files by anonymous FTP or by using the InterProScan search software (http://www.ebi.ac.uk/Tools/InterProScan/