Deterioration in cognitive control related mPFC function underlying development of treatment resistance in early psychosis.

One third of people with psychosis become antipsychotic treatment-resistant and the underlying mechanisms remain unclear. We investigated whether altered cognitive control function is a factor underlying development of treatment resistance. We studied 50 people with early psychosis at a baseline visit (mean < 2 years illness duration) and follow-up visit (1 year later), when 35 were categorized at treatment-responsive and 15 as treatment-resistant. Participants completed an emotion-yoked reward learning task that requires cognitive control whilst undergoing fMRI and MR spectroscopy to measure glutamate levels from Anterior Cingulate Cortex (ACC). Changes in cognitive control related activity (in prefrontal cortex and ACC) over time were compared between treatment-resistant and treatment-responsive groups and related to glutamate. Compared to treatment-responsive, treatment-resistant participants showed blunted activity in right amygdala (decision phase) and left pallidum (feedback phase) at baseline which increased over time and was accompanied by a decrease in medial Prefrontal Cortex (mPFC) activity (feedback phase) over time. Treatment-responsive participants showed a negative relationship between mPFC activity and glutamate levels at follow-up, no such relationship existed in treatment-resistant participants. Reduced activity in right amygdala and left pallidum at baseline was predictive of treatment resistance at follow-up (67% sensitivity, 94% specificity). The findings suggest that deterioration in mPFC function over time, a key cognitive control region needed to compensate for an initial dysfunction within a social-emotional network, is a factor underlying development of treatment resistance in early psychosis. An uncoupling between glutamate and cognitive control related mPFC function requires further investigation that may present a future target for interventions.

Understanding the mechanisms underlying cognitive control in psychosis.

BACKGROUND: Cognitive control (CC) involves a top-down mechanism to flexibly respond to complex stimuli and is impaired in schizophrenia. METHODS: This study investigated the impact of increasing complexity of CC processing in 140 subjects with psychosis and 39 healthy adults, with assessments of behavioral performance, neural regions of interest and symptom severity. RESULTS: The lowest level of CC (Stroop task) was impaired in all patients; the intermediate level of CC (Faces task) with explicit emotional information was most impaired in patients with first episode psychosis. Patients showed activation of distinct neural CC and reward networks, but iterative learning based on the higher-order of CC during the trust game, was most impaired in chronic schizophrenia. Subjects with first episode psychosis, and patients with lower symptom load, demonstrate flexibility of the CC network to facilitate learning, which appeared compromised in the more chronic stages of schizophrenia. CONCLUSION: These data suggest optimal windows for opportunities to introduce therapeutic interventions to improve CC.

Self-reported childhood family adversity is linked to an attenuated gain of trust during adolescence.

A longstanding proposal in developmental research is that childhood family experiences provide a template that shapes a capacity for trust-based social relationships. We leveraged longitudinal data from a cohort of healthy adolescents (n = 570, aged 14-25), which included decision-making and psychometric data, to characterise normative developmental trajectories of trust behaviour and inter-individual differences therein. Extending on previous cross-sectional findings from the same cohort, we show that a task-based measure of trust increases longitudinally from adolescence into young adulthood. Computational modelling suggests this is due to a decrease in social risk aversion. Self-reported family adversity attenuates this developmental gain in trust behaviour, and within our computational model, this relates to a higher 'irritability' parameter in those reporting greater adversity. Unconditional trust at measurement time point T1 predicts the longitudinal trajectory of self-reported peer relation quality, particularly so for those with higher family adversity, consistent with trust acting as a resilience factor.

Neuroimaging glutamatergic mechanisms differentiating antipsychotic treatment-response.

Glutamatergic dysfunction is associated with failure to respond to antipsychotic medication in individuals with schizophrenia. Our objective was to combine neurochemical and functional brain imaging methods to investigate glutamatergic dysfunction and reward processing in such individuals compared with those with treatment responsive schizophrenia, and healthy controls. 60 participants played a trust task, while undergoing functional magnetic resonance imaging: 21 classified as having treatment-resistant schizophrenia, 21 patients with treatment-responsive schizophrenia, and 18 healthy controls. Proton magnetic resonance spectroscopy was also acquired to measure glutamate in the anterior cingulate cortex. Compared to controls, treatment responsive and treatment-resistant participants showed reduced investments during the trust task. For treatment-resistant individuals, glutamate levels in the anterior cingulate cortex were associated with signal decreases in the right dorsolateral prefrontal cortex when compared to those treatment-responsive, and with bilateral dorsolateral prefrontal cortex and left parietal association cortex when compared to controls. Treatment-responsive participants showed significant signal decreases in the anterior caudate compared to the other two groups. Our results provide evidence that glutamatergic differences differentiate treatment resistant and responsive schizophrenia. The differentiation of cortical and sub-cortical reward learning substrates has potential diagnostic value. Future novel interventions might therapeutically target neurotransmitters affecting the cortical substrates of the reward network.

Exploring cognitive, behavioral and autistic trait network topology in very preterm and term-born children.

Introduction: Compared to full-term (FT) born peers, children who were born very preterm (VPT; <32 weeks' gestation) are likely to display more cognitive and behavioral difficulties, including inattention, anxiety and socio-communication problems. In the published literature, such difficulties tend to be studied independently, thus failing to account for how different aspects of child development interact. The current study aimed to investigate children's cognitive and behavioral outcomes as interconnected, dynamically related facets of development that influence one another. Methods: Participants were 93 VPT and 55 FT children (median age 8.79 years). IQ was evaluated with the Wechsler Intelligence Scale for Children-4th edition (WISC-IV), autism spectrum condition (ASC) traits with the social responsiveness scale-2nd edition (SRS-2), behavioral and emotional problems with the strengths and difficulties questionnaire (SDQ), temperament with the temperament in middle childhood questionnaire (TMCQ) and executive function with the behavior rating inventory of executive functioning (BRIEF-2). Outcome measures were studied in VPT and FT children using Network Analysis, a method that graphically represents partial correlations between variables and yields information on each variable's propensity to form a bridge between other variables. Results: VPT and FT children exhibited marked topological differences. Bridges (i.e., the variables most connected to others) in the VPT group network were: conduct problems and difficulties with organizing and ordering their environment. In the FT group network, the most important bridges were: difficulties with initiating a task or activity and prosocial behaviors, and greater emotional problems, such as lower mood. Discussion: These findings highlight the importance of targeting different aspects of development to support VPT and FT children in person-based interventions.

Longitudinal neonatal brain development and socio-demographic correlates of infant outcomes following preterm birth.

Preterm birth results in premature exposure of the brain to the extrauterine environment during a critical period of neurodevelopment. Consequently, infants born preterm are at a heightened risk of adverse behavioural outcomes in later life. We characterise longitudinal development of neonatal regional brain volume and functional connectivity in the first weeks following preterm birth, sociodemographic factors, and their respective relationships to psychomotor outcomes and psychopathology in toddlerhood. We study 121 infants born preterm who underwent magnetic resonance imaging shortly after birth, at term-equivalent age, or both. Longitudinal regional brain volume and functional connectivity were modelled as a function of psychopathology and psychomotor outcomes at 18 months. Better psychomotor functioning in toddlerhood was associated with greater relative right cerebellar volume and a more rapid decrease over time of sensorimotor degree centrality in the neonatal period. In contrast, increased 18-month psychopathology was associated with a more rapid decrease in relative regional subcortical volume. Furthermore, while socio-economic deprivation was related to both psychopathology and psychomotor outcomes, cognitively stimulating parenting predicted psychopathology only. Our study highlights the importance of longitudinal imaging to better predict toddler outcomes following preterm birth, as well as disparate environmental influences on separable facets of behavioural development in this population.

Parsing brain-behavior heterogeneity in very preterm born children using integrated similarity networks.

Very preterm birth (VPT; ≤32 weeks' gestation) is associated with altered brain development and cognitive and behavioral difficulties across the lifespan. However, heterogeneity in outcomes among individuals born VPT makes it challenging to identify those most vulnerable to neurodevelopmental sequelae. Here, we aimed to stratify VPT children into distinct behavioral subgroups and explore between-subgroup differences in neonatal brain structure and function. 198 VPT children (98 females) previously enrolled in the Evaluation of Preterm Imaging Study (EudraCT 2009-011602-42) underwent Magnetic Resonance Imaging at term-equivalent age and neuropsychological assessments at 4-7 years. Using an integrative clustering approach, we combined neonatal socio-demographic, clinical factors and childhood socio-emotional and executive function outcomes, to identify distinct subgroups of children based on their similarity profiles in a multidimensional space. We characterized resultant subgroups using domain-specific outcomes (temperament, psychopathology, IQ and cognitively stimulating home environment) and explored between-subgroup differences in neonatal brain volumes (voxel-wise Tensor-Based-Morphometry), functional connectivity (voxel-wise degree centrality) and structural connectivity (Tract-Based-Spatial-Statistics). Results showed two- and three-cluster data-driven solutions. The two-cluster solution comprised a 'resilient' subgroup (lower psychopathology and higher IQ, executive function and socio-emotional scores) and an 'at-risk' subgroup (poorer behavioral and cognitive outcomes). No neuroimaging differences between the resilient and at-risk subgroups were found. The three-cluster solution showed an additional third 'intermediate' subgroup, displaying behavioral and cognitive outcomes intermediate between the resilient and at-risk subgroups. The resilient subgroup had the most cognitively stimulating home environment and the at-risk subgroup showed the highest neonatal clinical risk, while the intermediate subgroup showed the lowest clinical, but the highest socio-demographic risk. Compared to the intermediate subgroup, the resilient subgroup displayed larger neonatal insular and orbitofrontal volumes and stronger orbitofrontal functional connectivity, while the at-risk group showed widespread white matter microstructural alterations. These findings suggest that risk stratification following VPT birth is feasible and could be used translationally to guide personalized interventions aimed at promoting children's resilience.

Distinct Neurodevelopmental Trajectories in Groups of Very Preterm Children Screening Positively for Autism Spectrum Conditions.

Very preterm (VPT; < 33 weeks' gestation) toddlers screening positively for autism spectrum conditions (ASC) may display heterogenous neurodevelopmental trajectories. Here we studied neonatal brain volumes and childhood ASC traits evaluated with the Social Responsiveness Scale (SRS-2) in VPT-born toddlers (N = 371; median age 20.17 months) sub-divided into three groups based on their Modified-Checklist for Autism in Toddlers scores. These were: those screening positively failing at least 2 critical items (critical-positive); failing any 3 items, but less than 2 critical items (non-critical-positive); and screening negatively. Critical-positive scorers had smaller neonatal cerebellar volumes compared to non-critical-positive and negative scorers. However, both positive screening groups exhibited higher childhood ASC traits compared to the negative screening group, suggesting distinct aetiological trajectories associated with ASC outcomes.

Neuroimaging oxytocin modulation of social reward learning in schizophrenia.

BACKGROUND: Conventional pharmacological approaches have limited effectiveness for schizophrenia. There is interest in the application of oxytocin, which is involved in social cognition. Clinical trials have yielded mixed results, with a gap in understanding neural mechanisms. AIMS: To evaluate the behavioural impact of oxytocin administration on a social learning task in individuals with schizophrenia, and elucidate any differential neural activity produced. METHOD: We recruited 20 clinically stable right-handed men diagnosed with schizophrenia or schizoaffective disorder. In a double-blind cross-over randomised controlled study, 40 IU of oxytocin or placebo were administered before functional magnetic resonance imaging of participants playing a multi-round economic exchange game of trust. Participants had the role of investors (investment trials) receiving repayment on their investments (repayment trials), playing one session against a computer and a second against a player believed to be human. RESULTS: During investment trials, oxytocin increased neural signalling in the right lateral parietal cortex for both human and computer player trials, and attenuated signalling in the right insula for human player trials. For repayment trials, oxytocin elicited signal increases in left insula and left ventral caudate, and a signal decrease in right amygdala during the human player trials; conversely it resulted in right dorsal caudate activation during the computer player trials. We did not find a significant change in behavioural performance associated with oxytocin administration, or any associations with symptoms. CONCLUSIONS: During a social learning task oxytocin modulates cortical and limbic substrates of the reward-processing network. These perturbations can be putatively linked to the pathoaetiology of schizophrenia.

White matter disruptions related to inattention and autism spectrum symptoms in tuberous sclerosis complex.

Tuberous sclerosis complex is a rare genetic multisystem condition that is associated with a high prevalence of neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder. The underlying neural mechanisms of the emergence of these symptom domains in tuberous sclerosis complex remain unclear. Here, we use fixel-based analysis of diffusion-weighted imaging, which allows for the differentiation between multiple fibre populations within a voxel, to compare white matter properties in 16 participants with tuberous sclerosis complex (aged 11-19) and 12 age and sex matched control participants. We further tested associations between white matter alterations and autism and inattention symptoms as well as cognitive ability in participants with tuberous sclerosis complex. Compared to controls, participants with tuberous sclerosis complex showed reduced fibre density cross-section (FDC) in the dorsal branch of right superior longitudinal fasciculus and bilateral inferior longitudinal fasciculus, reduced fibre density (FD) in bilateral tapetum, and reduced fibre cross-section (FC) in the ventral branch of right superior longitudinal fasciculus. In participants with tuberous sclerosis complex, the extent of FDC reductions in right superior longitudinal fasciculus was significantly associated with autism traits (social communication difficulties and restricted, repetitive behaviours), whereas FDC reductions in right inferior longitudinal fasciculus were associated with inattention. The observed white matter alterations were unrelated to cognitive ability. Our findings shed light on the fibre-specific biophysical properties of white matter alterations in tuberous sclerosis complex and suggest that these regional changes are selectively associated with the severity of neurodevelopmental symptoms.

The role of cognitive control in the positive symptoms of psychosis.

BACKGROUND: Positive symptoms of psychosis (e.g., hallucinations) often limit everyday functioning and can persist despite adequate antipsychotic treatment. We investigated whether poor cognitive control is a mechanism underlying these symptoms. METHODS: 97 patients with early psychosis (30 with high positive symptoms (HS) and 67 with low positive symptoms (LS)) and 40 healthy controls (HC) underwent fMRI whilst performing a reward learning task with two conditions; low cognitive demand (choosing between neutral faces) and high cognitive demand (choosing between angry and happy faces - shown to induce an emotional bias). Decision and feedback phases were examined. RESULTS: Both patient groups showed suboptimal learning behaviour compared to HC and altered activity within a core reward network including occipital/lingual gyrus (decision), rostral Anterior Cingulate Cortex, left pre-central gyrus and Supplementary Motor Cortex (feedback). In the low cognitive demand condition, HS group showed significantly reduced activity in Supplementary Motor Area (SMA)/pre-SMA during the decision phase whilst activity was increased in LS group compared to HC. Recruitment of this region suggests a top-down compensatory mechanism important for control of positive symptoms. With additional cognitive demand (emotional vs. neutral contrast), HS patients showed further alterations within a subcortical network (increased left amygdala activity during decisions and reduced left pallidum and thalamus activity during feedback) compared to LS patients. CONCLUSIONS: The findings suggest a core reward system deficit may be present in both patient groups, but persistent positive symptoms are associated with a specific dysfunction within a network needed to integrate social-emotional information with reward feedback.

Early Childhood Temperamental Trajectories following Very Preterm Birth and Their Association with Parenting Style.

Childhood temperament is an early characteristic shaping later life adjustment. However, little is currently known about the stability of early temperament and its susceptibility to the environment in children born very preterm (VPT; <33 weeks' gestation). Here, we investigated infant-to-childhood temperamental trajectories, and their interaction with parental practices, in VPT children. Maternal reports of infant temperament were collected in 190 infants (mean age: 11.27 months; range 9−18 months) enrolled in the longitudinal Evaluation of Preterm Imaging (ePrime; Eudra: CT 2009-011602-42) study, using the ePrime questionnaire on infant temperament. At 4−7 years of age, further assessments of child temperament (Children's Behavior Questionnaire­Very Short Form) and parenting style (Arnold's Parenting Scale) were conducted. Results showed that more difficult temperament in infancy was associated with increased Negative Affectivity in childhood, regardless of parenting practices. This lends support to the stability of early temperamental traits reflecting negative emotionality. In contrast, a lax parenting style moderated the relationship between easy infant temperament and Negative Affectivity at 4−7 years, such that an easier infant temperament was increasingly associated with higher childhood Negative Affectivity scores as parental laxness increased. These results highlight a potential vulnerability of VPT infants considered by their mothers to be easy to handle, as they may be more susceptible to the effects of suboptimal parenting in childhood.

Neonatal amygdala resting-state functional connectivity and socio-emotional development in very preterm children.

Very preterm children are more likely to exhibit difficulties in socio-emotional processing than their term-born peers. Emerging socio-emotional problems may be partly due to alterations in limbic system development associated with infants' early transition to extrauterine life. The amygdala is a key structure in this system and plays a critical role in various aspects of socio-emotional development, including emotion regulation. The current study tested the hypothesis that amygdala resting-state functional connectivity at term-equivalent age would be associated with socio-emotional outcomes in childhood. Participants were 129 very preterm infants (<33 weeks' gestation) who underwent resting-state functional MRI at term and received a neurodevelopmental assessment at 4-7 years (median = 4.64). Using the left and right amygdalae as seed regions, we investigated associations between whole-brain seed-based functional connectivity and three socio-emotional outcome factors which were derived using exploratory factor analysis (Emotion Moderation, Social Function and Empathy), controlling for sex, neonatal sickness, post-menstrual age at scan and social risk. Childhood Emotion Moderation scores were significantly associated with neonatal resting-state functional connectivity of the right amygdala with right parahippocampal gyrus and right middle occipital gyrus, as well as with functional connectivity of the left amygdala with the right thalamus. No significant associations were found between amygdalar resting-state functional connectivity and either Social Function or Empathy scores. The current findings show that amygdalar functional connectivity assessed at term is associated with later socio-emotional outcomes in very preterm children.

Adult outcome of preterm birth: Implications for neurodevelopmental theories of psychosis.

Preterm birth is associated with an elevated risk of developmental and adult psychiatric disorders, including psychosis. In this review, we evaluate the implications of neurodevelopmental, cognitive, motor, and social sequelae of preterm birth for developing psychosis, with an emphasis on outcomes observed in adulthood. Abnormal brain development precipitated by early exposure to the extra-uterine environment, and exacerbated by neuroinflammation, neonatal brain injury, and genetic vulnerability, can result in alterations of brain structure and function persisting into adulthood. These alterations, including abnormal regional brain volumes and white matter macro- and micro-structure, can critically impair functional (e.g. frontoparietal and thalamocortical) network connectivity in a manner characteristic of psychotic illness. The resulting executive, social, and motor dysfunctions may constitute the basis for behavioural vulnerability ultimately giving rise to psychotic symptomatology. There are many pathways to psychosis, but elucidating more precisely the mechanisms whereby preterm birth increases risk may shed light on that route consequent upon early neurodevelopmental insult.

Associations Between Neonatal Brain Structure, the Home Environment, and Childhood Outcomes Following Very Preterm Birth.

BACKGROUND: Very preterm birth is associated with an increased risk of childhood psychopathology and cognitive deficits. However, the extent to which these developmental problems associated with preterm birth are amenable to environmental factors or determined by neurobiology at birth remains unclear. METHODS: We derived neonatal brain structural covariance networks using non-negative matrix factorization in 384 very preterm infants (median gestational age [range], 30.29 [23.57-32.86] weeks) who underwent magnetic resonance imaging at term-equivalent age (median postmenstrual age, 42.57 [37.86-44.86] weeks). Principal component analysis was performed on 32 behavioral and cognitive measures assessed at preschool age (n = 206; median age, 4.65 [4.19-7.17] years) to identify components of childhood psychopathology and cognition. The Cognitively Stimulating Parenting Scale assessed the level of cognitively stimulating experiences available to the child at home. RESULTS: Cognitively stimulating parenting was associated with reduced expression of a component reflecting developmental psychopathology and executive dysfunction consistent with the preterm phenotype (inattention-hyperactivity, autism spectrum behaviors, and lower executive function scores). In contrast, a component reflecting better general cognitive abilities was associated with larger neonatal gray matter volume in regions centered on key nodes of the salience network, but not with cognitively stimulating parenting. CONCLUSIONS: Our results suggest that while neonatal brain structure likely influences cognitive abilities in very preterm children, the severity of behavioral symptoms that are typically observed in these children is sensitive to a cognitively stimulating home environment. Very preterm children may derive meaningful mental health benefits from access to cognitively stimulating experiences during childhood.

Neonatal White Matter Microstructure and Emotional Development during the Preschool Years in Children Who Were Born Very Preterm.

Children born very preterm (<33 weeks of gestation) are at a higher risk of developing socio-emotional difficulties compared with those born at term. In this longitudinal study, we tested the hypothesis that diffusion characteristics of white matter (WM) tracts implicated in socio-emotional processing assessed in the neonatal period are associated with socio-emotional development in 151 very preterm children previously enrolled into the Evaluation of Preterm Imaging study (EudraCT 2009-011602-42). All children underwent diffusion tensor imaging at term-equivalent age and fractional anisotropy (FA) was quantified in the uncinate fasciculus (UF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), and superior longitudinal fasciculus (SLF). Children's socio-emotional development was evaluated at preschool age (median = 4.63 years). Exploratory factor analysis conducted on the outcome variables revealed a three-factor structure, with latent constructs summarized as: "emotion moderation," "social function," and "empathy." Results of linear regression analyses, adjusting for full-scale IQ and clinical and socio-demographic variables, showed an association between lower FA in the right UF and higher "emotion moderation" scores (ß = -0.280; p < 0.001), which was mainly driven by negative affectivity scores (ß = -0.281; p = 0.001). Results further showed an association between higher full-scale IQ and better social functioning (ß = -0.334, p < 0.001). Girls had higher empathy scores than boys (ß = -0.341, p = 0.006). These findings suggest that early alterations of diffusion characteristics of the UF could represent a biological substrate underlying the link between very preterm birth and emotional dysregulation in childhood and beyond.

Harmonized Segmentation of Neonatal Brain MRI.

Deep learning based medical image segmentation has shown great potential in becoming a key part of the clinical analysis pipeline. However, many of these models rely on the assumption that the train and test data come from the same distribution. This means that such methods cannot guarantee high quality predictions when the source and target domains are dissimilar due to different acquisition protocols, or biases in patient cohorts. Recently, unsupervised domain adaptation techniques have shown great potential in alleviating this problem by minimizing the shift between the source and target distributions, without requiring the use of labeled data in the target domain. In this work, we aim to predict tissue segmentation maps on T 2-weighted magnetic resonance imaging data of an unseen preterm-born neonatal population, which has both different acquisition parameters and population bias when compared to our training data. We achieve this by investigating two unsupervised domain adaptation techniques with the objective of finding the best solution for our problem. We compare the two methods with a baseline fully-supervised segmentation network and report our results in terms of Dice scores obtained on our source test dataset. Moreover, we analyse tissue volumes and cortical thickness measures of the harmonized data on a subset of the population matched for gestational age at birth and postmenstrual age at scan. Finally, we demonstrate the applicability of the harmonized cortical gray matter maps with an analysis comparing term and preterm-born neonates and a proof-of-principle investigation of the association between cortical thickness and a language outcome measure.

Preference uncertainty accounts for developmental effects on susceptibility to peer influence in adolescence.

Adolescents are prone to social influence from peers, with implications for development, both adaptive and maladaptive. Here, using a computer-based paradigm, we replicate a cross-sectional effect of more susceptibility to peer influence in a large dataset of adolescents 14 to 24 years old. Crucially, we extend this finding by adopting a longitudinal perspective, showing that a within-person susceptibility to social influence decreases over a 1.5 year follow-up time period. Exploiting this longitudinal design, we show that susceptibility to social influences at baseline predicts an improvement in peer relations over the follow-up period. Using a Bayesian computational model, we demonstrate that in younger adolescents a greater tendency to adopt others' preferences arises out of a higher uncertainty about their own preferences in the paradigmatic case of delay discounting (a phenomenon called 'preference uncertainty'). This preference uncertainty decreases over time and, in turn, leads to a reduced susceptibility of one's own behaviour to an influence from others. Neuro-developmentally, we show that a measure of myelination within medial prefrontal cortex, estimated at baseline, predicts a developmental decrease in preference uncertainty at follow-up. Thus, using computational and neural evidence, we reveal adaptive mechanisms underpinning susceptibility to social influence during adolescence.