Investigation into functional large-scale networks in individuals with schizophrenia using fMRI data and Dynamic Causal Modelling

Schizophrenia is a complex and severe psychiatric disorder with positive symptoms, negative symptoms and cognitive deficits. Preclinical neurobiological studies showed that alterations of dopaminergic and glutamatergic neurotransmitter circuits involving the prefrontal cortex resulted in cognitive impairment such as working memory. Functional activation and functional connectivity findings of functional Magnetic Resonance Imaging (fMRI) data provided support for prefrontal dysfunction during fMRI working memory tasks in individuals with schizophrenia. However, these findings do not offer a neurobiological interpretation of the fMRI data. Biophysical modelling of functional large-scale networks has been designed for the analysis of fMRI data, which can be interpreted in a mechanistic way. This approach may enable the interpretation of fMRI data in terms of altered synaptic plasticity processes found in schizophrenia. One such process is gating mechanism, which has been shown to be altered for the thalamo-cortical and meso-cortical connection in schizophrenia. The primary aim of the thesis was to investigate altered synaptic plasticity and gating mechanisms with Dynamic Causal Modelling (DCM) within functional large-scale networks during two fMRI tasks in individuals with schizophrenia. Applying nonlinear DCM to the verbal fluency fMRI task of the Edinburgh High Risk Study, we showed that the connection strengths with nonlinear modulation for the thalamo-cortical connection was reduced in subjects at high familial risk of schizophrenia when compared to healthy controls. These results suggest that nonlinear DCM enables the investigation of altered synaptic plasticity and gating mechanism from fMRI data. For the Scottish Family Mental Health Study, we reported two different optimal linear models for individuals with established schizophrenia (EST) and healthy controls during working memory function. We suggested that this result may indicate that EST and healthy controls used different functional large-scale networks. The results of nonlinear DCM analyses may suggest that gating mechanism was intact in EST and healthy controls. In conclusion, the results presented in this thesis give evidence for the role of synaptic plasticity processes as assessed in functional large-scale networks during cognitive tasks in individuals with schizophrenia

Pathways of risk, resilience, and recovery: impact of stress and trauma on women and girls

Introduction Stress and trauma are ubiquitous experiences that have been identified as transdiagnostic factors associated with a higher risk for disproportionately detrimental physical and mental health outcomes for women and girls, including posttraumatic and affective disorders (1, 2). The underlying mechanisms of this increased risk likely involve complex biopsychosocial processes that have yet to be fully identified (3). Furthermore, the role of protective and resilience factors buffering these associations remain relatively unexamined. In this Research Topic, we aim to address this complexity from various interdisciplinary perspectives and discuss the biological, psychological, and social factors that may underpin both risk and resilience in the face of stressful and traumatic experiences. This collection of research includes biological substrates of risk, such as neural (Eder-Moreau et al.), genetic (Carvalho et al.) and endocrine (Brouillard et al.) factors. It also addresses potential social determinants of poor health, such as economic precarity and social isolation (Pazderka et al.) as well as the co-occurrence among mental health, risky behavior, and infectious disease among women released from incarceration (Johnson et al.). Social determinants also hold the potential for buffering potentially negative impact, through resources accessed in the face of adversity (Zamir et al.). The psychological underpinnings that may help explain the associations between stressful experience and compromised outcomes are also explored. These include interpretation of stressors from a social perspective (Azoulay and Gilboa-Schechtman) as well as from a psychological perspective, such as mentalizing (Ensink et al.). Finally, this Research Topic considers potential mechanisms for familial, intergenerational effects of maternal stress, such as parenting (Ahmad et al.)

Attention-deficit hyperactivity disorder (ADHD) and glial integrity: an exploration of associations of cytokines and kynurenine metabolites with symptoms and attention

<p>Abstract</p> <p>Background</p> <p>In contrast to studies of depression and psychosis, the first part of this study showed no major differences in serum levels of cytokines and tryptophan metabolites between healthy children and those with attention-deficit/hyperactivity disorder of the combined type (ADHD). Yet, small decreases of potentially toxic kynurenine metabolites and increases of cytokines were evident in subgroups. Therefore we examined predictions of biochemical associations with the major symptom clusters, measures of attention and response variability.</p> <p>Methods</p> <p>We explored systematically associations of 8 cytokines (indicators of pro/anti-inflammatory function) and 5 tryptophan metabolites with symptom ratings (e.g. anxiety, opposition, inattention) and continuous performance test (CPT) measures (e.g. movement, response time (RT), variability) in 35 ADHD (14 on medication) and 21 control children. Predictions from linear regressions (controlled by the false discovery rate) confirmed or disconfirmed partial correlations accounting for age, body mass and socio-economic status.</p> <p>Results</p> <p><b>(1) </b>Total symptom ratings were associated with increases of the interleukins IL-16 and IL-13, where relations of IL-16 (along with decreased S100B) with hyperactivity, and IL-13 with inattention were notable. Opposition ratings were predicted by increased IL-2 in ADHD and IL-6 in control children. <b>(2) </b>In the CPT, IL-16 related to motor measures and errors of commission, while IL-13 was associated with errors of omission. Increased RT variability related to lower TNF-α, but to higher IFN-γ levels. <b>(3) </b>Tryptophan metabolites were not significantly related to symptoms. But increased tryptophan predicted errors of omission, its breakdown predicted errors of commission and kynurenine levels related to faster RTs.</p> <p>Conclusions</p> <p>Many associations were found across diagnostic groups even though they were more marked in one group. This confirms the quantitative trait nature of these features. Conceptually the relationships of the pro- and antiinflammatory cytokines distinguished between behaviours associated more with cognitive or more with motor control respectively. Further study should extend the number of immunological and metabolic markers to confirm or refute the trends reported here and examine their stability from childhood to adolescence in a longitudinal design.</p

Checklist for co-creating safe spaces with young people participating in research

Creating safe spaces in research As researchers, it is imperative that we provide safe spaces for young people to participate in research. This is particularly relevant to the field of mental health research, where participants may be asked to engage in activities that require them to discuss or reflect on experiences of poor mental health. Such activities can be upsetting for participants and so it is important to consider what actions can be taken to best reduce risks of negative experience for participants. This will also lead to improved research data quality. Currently, there is limited information to inform the creation of safe spaces for young people participating in research. We felt that there was a need to address this gap through the creation of a new checklist resource that was co-developed with young people. To facilitate this, we worked with the Institute for Mental Health’s Youth Advisory Group (IMH YAG), based at the University of Birmingham. The IMH YAG is made up of young people aged 18-25 with lived experience of mental health difficulty or experience of supporting a young person with lived experience of mental health difficulty. We identified three key themes: confidentiality and consent, fostering trust and feeling safe. Our checklist centres around how to best accommodate these needs and we have presented practical tips on how this can be addressed at three different stages of research participation: before, during and after.  We hope that this checklist will support researchers to consider what steps can be taken to ensure that children and young people participate in research that makes them feel safe and empowered.</p

Модифицирование биодеградируемых полимеров методом DC магнетронного распыления титановой мишени

Объектом исследования являлись матриксы для тканевой инженерии, изготовленные методом электроспиннига из биорезорбируемого полимерного материала (PLLA). Целью данной работы является данной работы является подбор технологических режимов модифицирования полимеров полимолочной кислоты в плазме магнетронного разряда, возникающего при распылении титановой мишени в атмосфере азота, а так же изучение влияния данного способа модифицирования на комплекс физико-химических свойств. В работе показано, что воздействие плазмы и осаждение материала мишени в соединении с атомами реактивного газа при выбранных технологических режимах не приводит к изменению морфологии биорезорбируемого полимера, однако приводит к гидрофилизации поверхности и его упрочнению.Poly L-lactic acid (PLLA) biodegradable matrix were modified by plasma of DC magnetron discharge with titanium target sputtering in nitrogen atmosphere. The influence of the plasma treatment time on the structure and properties of the electrospun matrix was investigated. It was shown that increasing the plasma treatment time increases hydrophilicity of matrix by increasing the content of titanium and nitrogen, without changing the mean diameter of the matrix. Also plasma treatment does not change chemical composition and defined parameters leads to hardening of the initial matrix

Attention-deficit hyperactivity disorder (ADHD) and glial integrity: S100B, cytokines and kynurenine metabolism--effects of medication

Children with attention-deficit/hyperactivity disorder (ADHD) show a marked temporal variability in their display of symptoms and neuropsychological performance. This could be explained in terms of an impaired glial supply of energy to support neuronal activity

Investigating the Neural Correlates of Voice versus Speech-Sound Directed Information in Pre-School Children

Studies in sleeping newborns and infants propose that the superior temporal sulcus is involved in speech processing soon after birth. Speech processing also implicitly requires the analysis of the human voice, which conveys both linguistic and extra-linguistic information. However, due to technical and practical challenges when neuroimaging young children, evidence of neural correlates of speech and/or voice processing in toddlers and young children remains scarce. In the current study, we used functional magnetic resonance imaging (fMRI) in 20 typically developing preschool children (average age = 5.8 y; range 5.2–6.8 y) to investigate brain activation during judgments about vocal identity versus the initial speech sound of spoken object words. FMRI results reveal common brain regions responsible for voice-specific and speech-sound specific processing of spoken object words including bilateral primary and secondary language areas of the brain. Contrasting voice-specific with speech-sound specific processing predominantly activates the anterior part of the right-hemispheric superior temporal sulcus. Furthermore, the right STS is functionally correlated with left-hemispheric temporal and right-hemispheric prefrontal regions. This finding underlines the importance of the right superior temporal sulcus as a temporal voice area and indicates that this brain region is specialized, and functions similarly to adults by the age of five. We thus extend previous knowledge of voice-specific regions and their functional connections to the young brain which may further our understanding of the neuronal mechanism of speech-specific processing in children with developmental disorders, such as autism or specific language impairments

Are working memory and glutamate concentrations involved in early-life stress and severity of psychosis?

Objective Occurrences of early‐life stress (ELS) are associated with the severity of psychotic symptoms and working memory (WM) deficits in patients with psychosis (PSY). This study investigated potential mediation roles of WM behavioral performance and glutamate concentrations in prefrontal brain regions on the association between ELS and psychotic symptom severity in PSY. Method Forty‐seven patients with PSY (established schizophrenia, n = 30; bipolar disorder, n = 17) completed measures of psychotic symptom severity. In addition, data on ELS and WM performance were collected in both patients with PSY and healthy controls (HC; n = 41). Resting‐state glutamate concentrations in the bilateral dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) were also assessed with proton magnetic resonance spectroscopy for both PSY and HC groups. t tests, analyses of variance, and regression analyses were utilized. Results Participants with PSY reported significantly more ELS occurrences and showed poorer WM performance than HC. Furthermore, individuals with PSY displayed lower glutamate concentrations in the left DLPFC than HC. Neither ELS nor WM performance were predictive of severity of psychotic symptoms in participants with PSY. However, we found a significant negative correlation between glutamate concentrations in the left DLPFC and ELS occurrence in HC only. Conclusion In individuals with PSY, the current study found no evidence that the association between ELS and psychotic symptoms is mediated by WM performance or prefrontal glutamate concentrations. In HC, the association between ELS experience and glutamate concentrations may indicate a neurometabolite effect of ELS that is independent of an illness effect in psychosis