Oxytocin, but not vasopressin, decreases willingness to harm others by promoting moral emotions of guilt and shame.

Prosocial and moral behaviors have overlapping neural systems and can both be affected in a number of psychiatric disorders, although whether they involve similar neurochemical systems is unclear. In the current registered randomized placebo-controlled trial on 180 adult male and female subjects, we investigated the effects of intranasal administration of oxytocin and vasopressin, which play key roles in influencing social behavior, on moral emotion ratings for situations involving harming others and on judgments of moral dilemmas where others are harmed for a greater good. Oxytocin, but not vasopressin, enhanced feelings of guilt and shame for intentional but not accidental harm and reduced endorsement of intentionally harming others to achieve a greater good. Neither peptide influenced arousal ratings for the scenarios. Effects of oxytocin on guilt and shame were strongest in individuals scoring lower on the personal distress subscale of trait empathy. Overall, findings demonstrate for the first time that oxytocin, but not vasopressin, promotes enhanced feelings of guilt and shame and unwillingness to harm others irrespective of the consequences. This may reflect associations between oxytocin and empathy and vasopressin with aggression and suggests that oxytocin may have greater therapeutic potential for disorders with atypical social and moral behavior.

Perseveration and Shifting in Obsessive-Compulsive Disorder as a Function of Uncertainty, Punishment, and Serotonergic Medication.

Background: The nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD. Methods: We recruited 49 patients with OCD, 21 of whom were unmedicated, and 43 healthy control participants matched for age, IQ, and gender. Participants were tested on 2 tasks: a novel visuomotor deterministic reversal learning task with 3 reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a 2-choice visual probabilistic reversal learning task with uncertain feedback and a single reversal measuring win-stay and lose-shift. Bayesian computational modeling provided measures of learning rate, reinforcement sensitivity, and stimulus stickiness. Results: Unmedicated patients with OCD were impaired on the deterministic reversal task under punishment only at the first and third reversals compared with both control participants and medicated patients with OCD, who had no deficit. Perseverative errors were correlated with OCD severity. On the probabilistic reversal task, unmedicated patients were only impaired at reversal, whereas medicated patients were impaired at both the learning and reversal stages. Computational modeling showed that the overall change was reduced feedback sensitivity in both OCD groups. Conclusions: Both perseveration and increased shifting can be observed in OCD, depending on test conditions including the predictability of reinforcement. Perseveration was related to clinical severity and remediated by serotonergic medication.

Functional brain responses to emotional faces after three to five weeks of intake of escitalopram in healthy individuals: a double-blind, placebo-controlled randomised study.

Short-term intake of selective serotonin reuptake inhibitors (SSRIs) modulates threat-related amygdala responses in healthy individuals. However, how SSRI intake over a clinically relevant time period modulates threat-related amygdala responses is less clear. In a semi-randomised, double-blind, placebo-controlled study of 64 healthy individuals (SSRI n = 32, placebo n = 32), we examined the effect of 3-5 weeks of SSRI escitalopram (20 mg daily) on brain response to angry, fearful and neutral faces using BOLD fMRI. Data was analysed using a whole-brain region-wise approach extracting standardised effects (i.e., Cohen's D). The study was conducted at the Copenhagen University Hospital. A priori, we hypothesised that SSRI would attenuate amygdala responses to angry and fearful faces but not to neutral ones. Whether SSRI modulates correlations between amygdala responses to emotional faces and negative mood states was also explored. Compared to placebo, 3-5 weeks of SSRI intake did not significantly affect the amygdala response to angry, fearful, or neutral faces (|Cohen's D|< 0.2, PFWER = 1). Whole-brain, region-wise analyses revealed significant differences in frontal (|Cohen's D|< 0.6, PFWER < .01) and occipital regions (|Cohen's D|< 0.5, PFWER < .01). SSRI did not modulate correlations between amygdala responses to emotional faces and negative mood states. Our findings indicate that a 3-5 week SSRI intake impacts cortical responses to emotional stimuli, an effect possibly involved in SSRI's therapeutic efficacy.Trial registration Clinical Trials NCT04239339.

Methylphenidate Ameliorates Behavioural and Neurobiological Deficits in Executive Function for Patients with Chronic Traumatic Brain Injury.

(1) Background: Traumatic brain injury (TBI) often results in cognitive impairments, including in visuospatial planning and executive function. Methylphenidate (MPh) demonstrates potential improvements in several cognitive domains in patients with TBI. The Tower of London (TOL) is a visuospatial planning task used to assess executive function. (2) Methods: Volunteers with a history of TBI (n = 16) participated in a randomised, double-blinded, placebo-controlled, fMRI study to investigate the neurobiological correlates of visuospatial planning and executive function, on and off MPh. (3) Results: Healthy controls (HCs) (n = 18) and patients on placebo (TBI-placebo) differed significantly in reaction time (p < 0.0005) and accuracy (p < 0.0001) when considering all task loads, but especially for high cognitive loads for reaction time (p < 0.001) and accuracy (p < 0.005). Across all task loads, TBI-MPh were more accurate than TBI-placebo (p < 0.05) but remained less accurate than HCs (p < 0.005). TBI-placebo substantially improved in accuracy with MPh administration (TBI-MPh) to a level statistically comparable to HCs at low (p = 0.443) and high (p = 0.175) cognitive loads. Further, individual patients that performed slower on placebo at low cognitive loads were faster with MPh (p < 0.05), while individual patients that performed less accurately on placebo were more accurate with MPh at both high and low cognitive loads (p < 0.005). TBI-placebo showed reduced activity in the bilateral inferior frontal gyri (IFG) and insulae versus HCs. MPh normalised these regional differences. MPh enhanced within-network connectivity (between parietal, striatal, insula, and cerebellar regions) and enhanced beyond-network connectivity (between parietal, thalamic, and cerebellar regions). Finally, individual changes in cerebellar-thalamic (p < 0.005) and cerebellar-parietal (p < 0.05) connectivity with MPh related to individual changes in accuracy with MPh. (4) Conclusions: This work highlights behavioural and neurofunctional differences between HCs and patients with chronic TBI, and that adverse differences may benefit from MPh treatment.

Irritable Bowel Syndrome Is Associated With Brain Health by Neuroimaging, Behavioral, Biochemical, and Genetic Analyses.

BACKGROUND: Irritable bowel syndrome (IBS) interacts with psychopathology in a complex way; however, little is known about the underlying brain, biochemical, and genetic mechanisms. METHODS: To clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of IBS, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and 2-sample Mendelian randomization analysis. RESULTS: The phenome-wide association analysis showed that IBS was linked to brain health problems, including anxiety and depression, and poor cognitive performance. Significantly lower brain volumes associated with more severe IBS were found in key areas related to emotional regulation and higher-order cognition, including the medial orbitofrontal cortex/ventromedial prefrontal cortex, anterior insula, anterior and mid-cingulate cortices, dorsolateral prefrontal cortex, and hippocampus. Higher triglycerides, lower high-intensity lipoprotein, and lower platelets were also related (p < 1 × 10-10) to more severe IBS. Finally, Mendelian randomization analyses demonstrated potential causal relationships between IBS and brain health and indicated possible mediating effects of dyslipidemia and inflammation. CONCLUSIONS: For the first time, this study provides a comprehensive understanding of the relationship between IBS and brain health phenotypes, integrating perspectives from neuroimaging, behavioral performance, biochemical factors, and genetics, which is of great significance for clinical applications to potentially address brain health impairments in patients with IBS.

The Modulatory Effects of Atomoxetine on Aberrant Connectivity During Attentional Processing in Cocaine Use Disorder.

BACKGROUND: Cocaine use disorder is associated with cognitive deficits that reflect dysfunctional processing across neural systems. Because there are currently no approved medications, treatment centers provide behavioral interventions that have only short-term efficacy. This suggests that behavioral interventions are not sufficient by themselves to lead to the maintenance of abstinence in patients with cocaine use disorder. Self-control, which includes the regulation of attention, is critical for dealing with many daily challenges that would benefit from medication interventions that can ameliorate cognitive neural disturbances. METHODS: To address this important clinical gap, we conducted a randomized, double-blind, placebo-controlled, crossover design study in patients with cocaine use disorder (n = 23) and healthy control participants (n = 28). We assessed the modulatory effects of acute atomoxetine (40 mg) on attention and conflict monitoring and their associated neural activation and connectivity correlates during performance on the Eriksen flanker task. The Eriksen flanker task examines basic attentional processing using congruent stimuli and the effects of conflict monitoring and response inhibition using incongruent stimuli, the latter of which necessitates the executive control of attention. RESULTS: We found that atomoxetine improved task accuracy only in the cocaine group but modulated connectivity within distinct brain networks in both groups during congruent trials. During incongruent trials, the cocaine group showed increased task-related activation in the right inferior frontal and anterior cingulate gyri, as well as greater network connectivity than the control group across treatments. CONCLUSIONS: The findings of the current study support a modulatory effect of acute atomoxetine on attention and associated connectivity in cocaine use disorder.

Early-initiated childhood reading for pleasure: associations with better cognitive performance, mental well-being and brain structure in young adolescence.

BACKGROUND: Childhood is a crucial neurodevelopmental period. We investigated whether childhood reading for pleasure (RfP) was related to young adolescent assessments of cognition, mental health, and brain structure. METHODS: We conducted a cross-sectional and longitudinal study in a large-scale US national cohort (10 000 + young adolescents), using the well-established linear mixed model and structural equation methods for twin study, longitudinal and mediation analyses. A 2-sample Mendelian randomization (MR) analysis for potential causal inference was also performed. Important factors including socio-economic status were controlled. RESULTS: Early-initiated long-standing childhood RfP (early RfP) was highly positively correlated with performance on cognitive tests and significantly negatively correlated with mental health problem scores of young adolescents. These participants with higher early RfP scores exhibited moderately larger total brain cortical areas and volumes, with increased regions including the temporal, frontal, insula, supramarginal; left angular, para-hippocampal; right middle-occipital, anterior-cingulate, orbital areas; and subcortical ventral-diencephalon and thalamus. These brain structures were significantly related to their cognitive and mental health scores, and displayed significant mediation effects. Early RfP was longitudinally associated with higher crystallized cognition and lower attention symptoms at follow-up. Approximately 12 h/week of youth regular RfP was cognitively optimal. We further observed a moderately significant heritability of early RfP, with considerable contribution from environments. MR analysis revealed beneficial causal associations of early RfP with adult cognitive performance and left superior temporal structure. CONCLUSIONS: These findings, for the first time, revealed the important relationships of early RfP with subsequent brain and cognitive development and mental well-being.

Protective factors for children with autism spectrum disorder during COVID-19-related strict lockdowns: a Shanghai autism early developmental cohort study.

BACKGROUND: COVID-19 lockdowns increased the risk of mental health problems, especially for children with autism spectrum disorder (ASD). However, despite its importance, little is known about the protective factors for ASD children during the lockdowns. METHODS: Based on the Shanghai Autism Early Developmental Cohort, 188 ASD children with two visits before and after the strict Omicron lockdown were included; 85 children were lockdown-free, while 52 and 51 children were under the longer and the shorter durations of strict lockdown, respectively. We tested the association of the lockdown group with the clinical improvement and also the modulation effects of parent/family-related factors on this association by linear regression/mixed-effect models. Within the social brain structures, we examined the voxel-wise interaction between the grey matter volume and the identified modulation effects. RESULTS: Compared with the lockdown-free group, the ASD children experienced the longer duration of strict lockdown had less clinical improvement (ß = 0.49, 95% confidence interval (CI) [0.19-0.79], p = 0.001) and this difference was greatest for social cognition (2.62 [0.94-4.30], p = 0.002). We found that this association was modulated by parental agreeableness in a protective way (-0.11 [-0.17 to -0.05], p = 0.002). This protective effect was enhanced in the ASD children with larger grey matter volumes in the brain's mentalizing network, including the temporal pole, the medial superior frontal gyrus, and the superior temporal gyrus. CONCLUSIONS: This longitudinal neuroimaging cohort study identified that the parental agreeableness interacting with the ASD children's social brain development reduced the negative impact on clinical symptoms during the strict lockdown.

Comparable roles for serotonin in rats and humans for computations underlying flexible decision-making.

Serotonin is critical for adapting behavior flexibly to meet changing environmental demands. Cognitive flexibility is important for successful attainment of goals, as well as for social interactions, and is frequently impaired in neuropsychiatric disorders, including obsessive-compulsive disorder. However, a unifying mechanistic framework accounting for the role of serotonin in behavioral flexibility has remained elusive. Here, we demonstrate common effects of manipulating serotonin function across two species (rats and humans) on latent processes supporting choice behavior during probabilistic reversal learning, using computational modelling. The findings support a role of serotonin in behavioral flexibility and plasticity, indicated, respectively, by increases or decreases in choice repetition ('stickiness') or reinforcement learning rates following manipulations intended to increase or decrease serotonin function. More specifically, the rate at which expected value increased following reward and decreased following punishment (reward and punishment 'learning rates') was greatest after sub-chronic administration of the selective serotonin reuptake inhibitor (SSRI) citalopram (5 mg/kg for 7 days followed by 10 mg/kg twice a day for 5 days) in rats. Conversely, humans given a single dose of an SSRI (20 mg escitalopram), which can decrease post-synaptic serotonin signalling, and rats that received the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which destroys forebrain serotonergic neurons, exhibited decreased reward learning rates. A basic perseverative tendency ('stickiness'), or choice repetition irrespective of the outcome produced, was likewise increased in rats after the 12-day SSRI regimen and decreased after single dose SSRI in humans and 5,7-DHT in rats. These common effects of serotonergic manipulations on rats and humans-identified via computational modelling-suggest an evolutionarily conserved role for serotonin in plasticity and behavioral flexibility and have clinical relevance transdiagnostically for neuropsychiatric disorders.

Structural neurodevelopment at the individual level - a life-course investigation using ABCD, IMAGEN and UK Biobank data.

Adolescents exhibit remarkable heterogeneity in the structural architecture of brain development. However, due to the lack of large-scale longitudinal neuroimaging studies, existing research has largely focused on population averages and the neurobiological basis underlying individual heterogeneity remains poorly understood. Using structural magnetic resonance imaging from the IMAGEN cohort (n=1,543), we show that adolescents can be clustered into three groups defined by distinct developmental patterns of whole-brain gray matter volume (GMV). Genetic and epigenetic determinants of group clustering and long-term impacts of neurodevelopment in mid-to-late adulthood were investigated using data from the ABCD, IMAGEN and UK Biobank cohorts. Group 1, characterized by continuously decreasing GMV, showed generally the best neurocognitive performances during adolescence. Compared to Group 1, Group 2 exhibited a slower rate of GMV decrease and worsened neurocognitive development, which was associated with epigenetic changes and greater environmental burden. Further, Group 3 showed increasing GMV and delayed neurocognitive development during adolescence due to a genetic variation, while these disadvantages were attenuated in mid-to-late adulthood. In summary, our study revealed novel clusters of adolescent structural neurodevelopment and suggested that genetically-predicted delayed neurodevelopment has limited long-term effects on mental well-being and socio-economic outcomes later in life. Our results could inform future research on policy interventions aimed at reducing the financial and emotional burden of mental illness.

Effects of escitalopram on synaptic density in the healthy human brain: a randomized controlled trial.

Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is not clear. The hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants with no history of psychiatric or cognitive disorders were randomized to receive daily oral dosing of either 20 mg escitalopram (n = 17) or a placebo (n = 15). After an intervention period of 3-5 weeks, participants underwent a [11C]UCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24-38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between [11C]UCB-J binding and duration of escitalopram intervention. Our findings suggest that brain synaptic plasticity evolves over 3-5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs.

Decoding anxiety-impulsivity subtypes in preadolescent internalising disorders: findings from the Adolescent Brain Cognitive Development study.

BACKGROUND: Internalising disorders are highly prevalent emotional dysregulations during preadolescence but clinical decision-making is hampered by high heterogeneity. During this period impulsivity represents a major risk factor for psychopathological trajectories and may act on this heterogeneity given the controversial anxiety-impulsivity relationships. However, how impulsivity contributes to the heterogeneous symptomatology, neurobiology, neurocognition and clinical trajectories in preadolescent internalising disorders remains unclear. AIMS: The aim was to determine impulsivity-dependent subtypes in preadolescent internalising disorders that demonstrate distinct anxiety-impulsivity relationships, neurobiological, genetic, cognitive and clinical trajectory signatures. METHOD: We applied a data-driven strategy to determine impulsivity-related subtypes in 2430 preadolescents with internalising disorders from the Adolescent Brain Cognitive Development study. Cross-sectional and longitudinal analyses were employed to examine subtype-specific signatures of the anxiety-impulsivity relationship, brain morphology, cognition and clinical trajectory from age 10 to 12 years. RESULTS: We identified two distinct subtypes of patients who internalise with comparably high anxiety yet distinguishable levels of impulsivity, i.e. enhanced (subtype 1) or decreased (subtype 2) compared with control participants. The two subtypes exhibited opposing anxiety-impulsivity relationships: higher anxiety at baseline was associated with higher lack of perseverance in subtype 1 but lower sensation seeking in subtype 2 at baseline/follow-up. Subtype 1 demonstrated thicker prefrontal and temporal cortices, and genes enriched in immune-related diseases and glutamatergic and GABAergic neurons. Subtype 1 exhibited cognitive deficits and a detrimental trajectory characterised by increasing emotional/behavioural dysregulations and suicide risks during follow-up. CONCLUSIONS: Our results indicate impulsivity-dependent subtypes in preadolescent internalising disorders and unify past controversies about the anxiety-impulsivity interaction. Clinically, individuals with a high-impulsivity subtype exhibit a detrimental trajectory, thus early interventions are warranted.

Common and disorder-specific cortical thickness alterations in internalizing, externalizing and thought disorders during early adolescence: an Adolescent Brain and Cognitive Development study.

BACKGROUND: A growing body of neuroimaging studies has reported common neural abnormalities among mental disorders in adults. However, it is unclear whether the distinct disorder-specific mechanisms operate during adolescence despite the overlap among disorders. METHODS: We studied a large cohort of more than 11 000 preadolescent (age 9-10 yr) children from the Adolescent Brain and Cognitive Development cohort. We adopted a regrouping approach to compare cortical thickness (CT) alterations and longitudinal changes between healthy controls (n = 4041) and externalizing (n = 1182), internalizing (n = 1959) and thought disorder (n = 347) groups. Genome-wide association study (GWAS) was performed on regional CT across 4468 unrelated European youth. RESULTS: Youth with externalizing or internalizing disorders exhibited increased regional CT compared with controls. Externalizing (p = 8 × 10-4, Cohen d = 0.10) and internalizing disorders (p = 2 × 10-3, Cohen d = 0.08) shared thicker CT in the left pars opercularis. The somatosensory and the primary auditory cortex were uniquely affected in externalizing disorders, whereas the primary motor cortex and higher-order visual association areas were uniquely affected in internalizing disorders. Only youth with externalizing disorders showed decelerated cortical thinning from age 10-12 years. The GWAS found 59 genome-wide significant associated genetic variants across these regions. Cortical thickness in common regions was associated with glutamatergic neurons, while internalizing-specific regional CT was associated with astrocytes, oligodendrocyte progenitor cells and GABAergic neurons. LIMITATIONS: The sample size of the GWAS was relatively small. CONCLUSION: Our study provides strong evidence for the presence of specificity in CT, developmental trajectories and underlying genetic underpinnings among externalizing and internalizing disorders during early adolescence. Our results support the neurobiological validity of the regrouping approach that could supplement the use of a dimensional approach in future clinical practice.

Neurodevelopmental risk and adaptation as a model for comorbidity among internalizing and externalizing disorders: genomics and cell-specific expression enriched morphometric study.

BACKGROUND: Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing disorders on anatomical differences represent a simple aggregate of the effects on each disorder and if these comorbidity-associated cortical surface differences relate to a distinct genetic underpinning. METHODS: We studied the cortical surface area (SA) and thickness (CT) of 11,878 preadolescents (9-10 years) from the Adolescent Brain and Cognitive Development Study. Linear mixed models were implemented in comparative and association analyses among internalizing (dysthymia, major depressive disorder, disruptive mood dysregulation disorder, agoraphobia, panic disorder, specific phobia, separation anxiety disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder), externalizing (attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder) diagnostic groups, a group with comorbidity of the two and a healthy control group. Genome-wide association analysis (GWAS) and cell type specificity analysis were performed on 4468 unrelated European participants from this cohort. RESULTS: Smaller cortical surface area but higher thickness was noted across patient groups when compared to controls. Children with comorbid internalizing and externalizing disorders had more pronounced areal reduction than those without comorbidity, indicating an additive burden. In contrast, cortical thickness had a non-linear effect with comorbidity: the comorbid group had no significant CT differences, while those patient groups without comorbidity had significantly higher thickness compare to healthy controls. Distinct biological pathways were implicated in regional SA and CT differences. Specifically, CT differences were associated with immune-related processes implicating astrocytes and oligodendrocytes, while SA-related differences related mainly to inhibitory neurons. CONCLUSION: The emergence of comorbidity across distinct clusters of psychopathology is unlikely to be due to a simple additive neurobiological effect alone. Distinct developmental risk moderated by immune-related adaptation processes, with unique genetic and cell-specific factors, may contribute to underlying SA and CT differences. Children with the highest risk but lowest resilience, both captured in their developmental morphometry, may develop a comorbid illness pattern.

Association between vmPFC gray matter volume and smoking initiation in adolescents.

Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic experience) highlights a potential reward-based mechanism for sustaining addictive behaviour. Taken together, our findings reveal vmPFC GMV as a possible biomarker for the early stages of nicotine addiction, with implications for its prevention and treatment.

Potential cognitive and neural benefits of a computerised cognitive training programme based on Structure Learning in healthy adults: study protocol for a randomised controlled trial.

BACKGROUND: Cognitive flexibility refers to the capacity to shift between conceptual representations particularly in response to changes in instruction and feedback. It enables individuals to swiftly adapt to changes in their environment and has significant implications for learning. The present study focuses on investigating changes in cognitive flexibility following an intervention programme-Structure Learning training. METHODS: Participants are pseudo-randomised to either the Training or Control group, while matched on age, sex, intelligence and cognitive flexibility performance. In the Training group, participants undergo around 2 weeks of training (at least 13 sessions) on Structure Learning. In the Control group, participants do not have to undergo any training and are never exposed to the Structure Learning task. The effects of Structure Learning training are investigated at both the behavioural and neural level. We measured covariates that can influence an individual's training performance before the training phase and outcome measures that can potentially show training benefits after the training phase. At the behavioural level, we investigated outcomes in both cognitive and social aspects with a primary focus on executive functions. At the neural level, we employed a multimodality approach and investigated potential changes to functional connectivity patterns, neurometabolite concentration in the frontal brain regions, and brain microstructure and myelination. DISCUSSION: We reported the development of a novel training programme based on Structure Learning that aims to hone a general learning ability to potentially achieve extensive transfer benefits across various cognitive constructs. Potential transfer benefits can be exhibited through better performance in outcome measures between Training and Control participants, and positive associations between training performance and outcomes after the training in Training participants. Moreover, we attempt to substantiate behavioural findings with evidence of neural changes across different imaging modalities by the Structure Learning training. TRIAL REGISTRATION: National Institutes of Health U.S. National Library of Medicine ClinicalTrials.gov NCT05611788. Registered on 7 November 2022. PROTOCOL VERSION: 11 May 2023.

Brain and molecular mechanisms underlying the nonlinear association between close friendships, mental health, and cognition in children.

Close friendships are important for mental health and cognition in late childhood. However, whether the more close friends the better, and the underlying neurobiological mechanisms are unknown. Using the Adolescent Brain Cognitive Developmental study, we identified nonlinear associations between the number of close friends, mental health, cognition, and brain structure. Although few close friends were associated with poor mental health, low cognitive functions, and small areas of the social brain (e.g., the orbitofrontal cortex, the anterior cingulate cortex, the anterior insula, and the temporoparietal junction), increasing the number of close friends beyond a level (around 5) was no longer associated with better mental health and larger cortical areas, and was even related to lower cognition. In children having no more than five close friends, the cortical areas related to the number of close friends revealed correlations with the density of µ-opioid receptors and the expression of OPRM1 and OPRK1 genes, and could partly mediate the association between the number of close friends, attention-deficit/hyperactivity disorder (ADHD) symptoms, and crystalized intelligence. Longitudinal analyses showed that both too few and too many close friends at baseline were associated with more ADHD symptoms and lower crystalized intelligence 2 y later. Additionally, we found that friendship network size was nonlinearly associated with well-being and academic performance in an independent social network dataset of middle-school students. These findings challenge the traditional idea of 'the more, the better,' and provide insights into potential brain and molecular mechanisms.

Close friendships are crucial during the transition from late childhood to adolescence as children become more independent from their parents and influenced by their peers. The brain undergoes a tremendous amount of development during this period, and it is also a time when mental health disorders often begin to emerge. Scientists are still learning about how friendships shape brain development and mental health during this transition. Maintaining friendships takes time and mental resources so there may be limits on how many friends are beneficial. Here, Shen, Rolls et al. show that the having more friends is not always directly related to better mental health and cognitive abilities. In the study, Shen, Rolls et al. analyzed data from nearly 7,500 young people between around 10 to 12 years old: this included, their number of close friends, their mental health and cognitive abilities such as working memory, attention and processing speed, and images of their brains. Data from a second set of about 16,000 young people were then analyzed to confirm the results. Shen, Rolls et al. found having a higher number of close friends was associated with improved mental health and cognitive ability. However, this association stopped once around five friends had been reached, after which having more friends was no longer linked to better mental health and was even correlated with lower cognition. Additionally, individuals with too few or too many friends had more symptoms of Attention-deficit/hyperactivity disorder (ADHD) and were less able to learn from their experiences. This non-linear relationship between number of friends and mental health and cognitive abilities can be partly explained by the structure of the brain. Shen, Rolls et al. found that brain regions associated with friendship were larger in individuals with more close friends, but did not increase any further once the number of friends a person had exceeded five individuals with around five close friends also had more of a receptor that is part of the opioid system, which may make them more responsive to laughter, friendly touch, or other positive social interactions. These findings challenge the idea that having more friends is always better. It also provides insights into how friendships affect brain health during the transition from late childhood to adolescence. Insights from this study may aid the development of interventions to support healthy brain development during youth.