[Beyond NICE: Updated Systematic Review on the Current Evidence of Using Puberty Blocking Pharmacological Agents and Cross-Sex-Hormones in Minors with Gender Dysphoria]. / Beyond NICE: Aktualisierte systematische Übersicht zur Evidenzlage der Pubertätsblockade und Hormongabe bei Minderjährigen mit Geschlechtsdysphorie.

Beyond NICE: Updated Systematic Review on the Current Evidence of Using Puberty Blocking Pharmacological Agents and Cross-Sex-Hormones in Minors with Gender Dysphoria Abstract: Objective: The suppression of physiological puberty using puberty-blocking pharmacological agents (PB) and prescribing cross-sex hormones (CSH) to minors with gender dysphoria (GD) is a current matter of discussion, and in some cases, PB and CSH are used in clinical practice for this particular population. Two systematic reviews (one on PB, one on CSH treatment) by the British National Institute for Clinical Excellence (NICE) from 2020 indicated no clear clinical benefit of such treatments regarding critical outcome variables. In particular, these two systematic NICE reviews on the use of PB and CSH in minors with GD detected no clear improvements of GD symptoms. Moreover, the overall scientific quality of the available evidence, as discussed within the above-mentioned two NICE reviews, was classified as "very low certainty" regarding modified GRADE criteria. Method: The present systematic review presents an updated literature search on this particular topic (use of PB and CSH in minors with GD) following NICE principles and PICO criteria for all relevant new original research studies published since the release of the two above-mentioned NICE reviews (updated literature search period was July 2020-August 2023). Results: The newly conducted literature search revealed no newly published original studies targeting NICE-defined critical and important outcomes and the related use of PB in minors with GD following PICO criteria. For CSH treatment, we found two new studies that met PICO criteria, but these particular two studies had low participant numbers, yielded no significant additional clear evidence for specific and clearly beneficial effects of CSH in minors with GD, and could be classified as "low certainty" tfollowing modified GRADE criteria. Conclusions: The currently available studies on the use of PB and CSH in minors with GD have significant conceptual and methodological flaws. The available evidence on the use of PB and CSH in minors with GD is very limited and based on only a few studies with small numbers, and these studies have problematic methodology and quality. There also is a lack of adequate and meaningful long-term studies. Current evidence doesn't suggest that GD symptoms and mental health significantly improve when PB or CSH are used in minors with GD. Psychotherapeutic interventions to address and reduce the experienced burden can become relevant in children and adolescents with GD. If the decision to use PB and/or CSH is made on an individual case-by-case basis and after a complete and thorough mental health assessment, potential treatment of possibly co-occurring mental health problems as well as after a thoroughly conducted and carefully executed individual risk-benefit evaluation, doing so as part of clinical studies or research projects, as currently done in England, can be of value in terms of generation of new research data. The electronic supplement (ESM) 1 is an adapted and abreviated English version of this work.

Effects of dietary omega-3 intake on vigilant attention and resting-state functional connectivity in neurotypical children and adolescents.

BACKGROUND: Vigilant Attention (VA) is a critical cognitive function allowing to maintain our attention, particularly in redundant or intellectually unchallenging situations. Evidence has shown that, as the brain develops, VA abilities rapidly improve throughout childhood and adolescence. Dietary omega-3 polyunsaturated fats (PUFA), playing a critical role for proper brain development and maturation of cortical regions, may contribute to variations in VA abilities. OBJECTIVE: The present study investigated the effect of dietary omega-3 PUFA intake (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) on resting-state functional connectivity (rsFC) of a meta-analytically defined VA network in 24 neurotypical children and adolescents (7.3-17.2 years) from the Healthy Brain Network databank. METHODS: Functional MRI and phenotypical information were collected from the Healthy Brain Network databank. Intake of omega-3 DHA and EPA was assessed using a food frequency questionnaire and was adjusted for total calorie intake. Out of scanner VA-related performance was assessed using the VA condition of the Adaptive Cognitive Evaluation tool. RESULTS: Overall, reported intake of omega-3 PUFA was not significantly associated with VA-related performance. Furthermore, energy-adjusted omega-3 intake was not significantly correlated with rsFC within the VA network. A complementary whole-brain analysis revealed that energy-adjusted omega-3 intake was correlated with decreased rsFC between parieto-occipital brain regions. CONCLUSION: The present study was not able to detect a relationship between dietary omega-3 and rsFC or VA performance.

Age-related resting-state functional connectivity of the Vigilant Attention network in children and adolescents.

The development of Vigilant Attention (VA), the ability to focus and maintain our attention to repetitive and cognitively unchallenging tasks over time, has been investigated for more than a decade. The development of this critical executive function across the lifespan has been characterised by a rapid improvement in VA performance throughout childhood and adolescence, a steady improvement in adulthood and a slow decline in older adulthood. However, the development of the neural correlates of VA in children and adolescents remains poorly understood. Using a cross-sectional design, the present study used a meta-analytically defined VA network in children and adolescents to explore the developmental trend of the resting-state functional connectivity (rsFC) within the VA network across two independent cohorts. The results showed a linear and non-linear decrease of rsFC between the left and right VA brain regions across age. However, the results could not be reproduced in the replication cohort, potentially due to a smaller sample size. Based on previous findings from behavioural studies, the present findings suggest that changes in rsFC may underlie a developmental shift in cognitive strategies in neurotypical children and adolescents.

Functional consequences of acute tryptophan depletion on raphe nuclei connectivity and network organization in healthy women.

Previous research on central nervous serotonin (5-HT) function provided evidence for a substantial involvement of 5-HT in the regulation of brain circuitries associated with cognitive and affective processing. The underlying neural networks comprise core subcortical/cortical regions such as amygdala and medial prefrontal cortex, which are assumed to be modulated amongst others by 5-HT. Beside the use of antidepressants, acute tryptophan depletion (ATD) is a widely accepted technique to manipulate of 5-HT synthesis and its respective metabolites in humans by means of a dietary and non-pharmacological tool. We used a double-blind, randomized, cross-over design with two experimental challenge conditions, i.e. ATD and tryptophan (TRP) supplementation (TRYP+) serving as a control. The aim was to perturb 5-HT synthesis and to detect its impact on brain functional connectivity (FC) of the upper serotonergic raphe nuclei, the amygdala and the ventromedial prefrontal cortex as well as on network organization using resting state fMRI. 30 healthy adult female participants (age: M â€‹= â€‹24.5 â€‹± â€‹4.4 â€‹yrs) were included in the final analysis. ATD resulted in a 90% decrease of TRP in the serum relative to baseline. Compared to TRYP â€‹+ â€‹for the ATD condition a significantly lower FC of the raphe nucleus to the frontopolar cortex was detected, as well as greater functional coupling between the right amygdala and the ventromedial prefrontal cortex. FC of the raphe nucleus correlated significantly with the magnitude of TRP changes for both challenge conditions (ATD & TRYP+). Network-based statistical analysis using time series from 260 independent anatomical ROIs revealed significantly greater FC after ATD compared to TRYP+ in several brain regions being part of the default-mode (DMN) and the executive-control networks (ECN), but also of salience or visual networks. Finally, we observed an impact of ATD on the rich-club organization in terms of decreased rich-club coefficients compared to TRYP+. In summary we could confirm previous findings that the putative decrease in brain 5-HT synthesis via ATD significantly alters FC of the raphe nuclei as well as of specific subcortical/cortical regions involved in affective, but also in cognitive processes. Moreover, an ATD-effect on the so-called rich-club organization of some nodes with the high degree was demonstrated. This may indicate effects of brain 5-HT on the integration of information flow from several brain networks.

Functional connectivity of the vigilant-attention network in children and adolescents with attention-deficit/hyperactivity disorder.

The ability to maintain attention to simple tasks (i.e., vigilant attention, VA) is often impaired in attention-deficit/hyperactivity disorder (ADHD), but the underlying pathophysiological mechanisms at the brain network level are not clear yet. We therefore investigated ADHD-related differences in resting-state functional connectivity within a meta-analytically defined brain network of 14 distinct regions subserving VA (comprising 91 connections in total), as well as the association of connectivity with markers of behavioural dysfunction in 17 children (age range: 9-14 years) with a diagnosis of ADHD and 21 age-matched neurotypical controls. Our analyses revealed selective, rather than global, differences in the intrinsic coupling between nodes of the VA-related brain network in children with ADHD, relative to controls. In particular, ADHD patients showed substantially diminished intrinsic coupling for 7 connections and increased coupling for 4 connections, with many differences involving connectivity with the anterior insula. Moreover, connectivity strength of several aberrant connections was found to be associated with core aspects of ADHD symptomatology, such as poor attention, difficulties with social functioning, and impaired cognitive control, attesting to the behavioural relevance of specific connectivity differences observed in the resting state.

Dietary manipulation of serotonergic and dopaminergic function in C57BL/6J mice with amino acid depletion mixtures.

Amino acid (AA) depletion techniques have been used to decrease serotonin (5-HT) and/or dopamine (DA) synthesis after administration of a tryptophan (acute tryptophan depletion, ATD) or phenylalanine/tyrosine-free (phenylalanine-tyrosine depletion, PTD) AA formula and are useful as neurochemical challenge procedures to study the impact of DA and 5-HT in patients with neuropsychiatric disorders. We recently demonstrated that the refined Moja-De ATD paradigm decreases brain 5-HT synthesis in humans and mice and lowers brain 5-HT turnover. In the present study we validated the neurochemical effects of three developed AA formulas on brain 5-HT and DA function in mice. To distinguish the direct and indirect effects of such mixtures on 5-HT and DA and to determine whether additive depletion of both could be obtained simultaneously, we compared the effects of ATD for 5-HT, PTD for DA, and a combined monoamine depletion mixture (CMD) compared to a control condition consisting of a balanced amino acid mixture. Food-deprived male C57BL/6J mice were gavaged with AA mixtures. Serum and brain samples were collected and analyzed for determination of tryptophan (Trp), tyrosine (Tyr), 5-HT, 5-HIAA, DA, DOPAC and HVA levels. ATD was the most effective at decreasing Trp, 5-HT and 5-HIAA. In contrast, PTD reduced Tyr globally but HVA only in certain brain regions. Although CMD affected both 5-HT and DA synthesis, it was less effective when compared with ATD or PTD alone. The present results demonstrate that two newly developed PTD and CMD formulas differentially impact brain 5-HT and DA synthesis relative to 5-HT-specific ATD Moja-De. Different effects on 5-HT and DA function by these mixtures suggest that the exact composition may be a critical determinant for effectiveness with respect to the administered challenge procedure.

Atypical Antipsychotic Prescribing in Australian Children and Adolescents: A Survey of Medical Practitioners.

OBJECTIVE: Prescriptions for atypical antipsychotics in children and adolescents are increasing globally. However, a precise understanding of the clinical variables and evidence that prescribers consider before using these agents is lacking. While empirical literature on the long-term safety and efficacy of these medications is available, the literature concerning their use in these younger age groups is relatively sparse. In this study, we examined the current prescribing patterns of medical professionals employed by a public health service in Australia. METHODS: A survey examining their current practice when prescribing atypical antipsychotics to children and adolescents was completed by 103 physicians. Questions were asked about commonly prescribed atypical antipsychotics, indications, dose ranges, target symptoms, duration of treatment, and the evidence base(s) used when making treatment decisions. RESULTS: Physicians prescribed atypical antipsychotics for a wide range of indications in this age group, with the most common agents being risperidone, quetiapine, and olanzapine. Adverse effects were reported as the main reason for treatment discontinuation. More than half of the respondents indicated that the most common source of guidance/evidence they referred to when initiating prescriptions were peers or expert opinion. CONCLUSIONS: Children and adolescents were prescribed a number of atypical antipsychotics for a variety of indications, with variable perceived confidence and a relatively heavy reliance on "own or peer experience" as opposed to good quality evidence. Challenges exist for both prescribers and policymakers, and further "head-to-head" studies are needed in this age group to ensure that a balance is maintained between therapeutic benefit and safety.

Severe affective and behavioral dysregulation in youths is associated with a proinflammatory state.

OBJECTIVE: A heritable behavioral phenotype, the so-called Dysregulation Profile (DP), characterized by extreme scores on the syndrome scales Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AGG), has been identified on the Child Behavior Checklist (CBCL). It characterizes children with severe affective and behavioral dysregulation. The present study examined possible alterations of the inflammatory system in CBCL-DP using a clinical sample of n = 133 children and adolescents. METHOD: Participants with the CBCL-DP scoring ≥ 2.5 SDs above average constituted the CBCL-DP subgroup (n = 51). Those with CBCL-DP scores of 1 SD or less above average were regarded as controls (n = 82). Groups were compared in terms of serum levels of C-reactive protein (CRP) and albumin. RESULTS: Participants showing the CBCL-DP exhibited increased CRP and decreased albumin levels compared to controls. CRP was correlated with AGG, AP, and the CBCL-DP total score. A negative correlation was observed between albumin and AGG, AP, the CBCL-DP score, and A/D. These associations could not be attributed to differences in age, sex, weight, socioeconomic status, global functioning, or duration of illness. CONCLUSIONS: This is the first study to demonstrate associations between the CBCL-DP and a proinflammatory state. Limitations include the lack of a healthy control group, the use of a single measurement of inflammatory markers, and the lack of follow-up data. Future research should address whether inflammatory diathesis in these children confers increased susceptibility to later development of cardiovascular disease and other medical morbidities.

Who wants to become a child psychiatrist? Lessons for future recruitment strategies from a student survey at seven German medical schools.

OBJECTIVE: The objective of this survey was to investigate undergraduate German medical students' attitudes toward child and adolescent psychiatry (CAP) and to describe the characteristics of students considering CAP as a possible career choice. METHODS: The authors conducted a cross-sectional, multicenter survey of medical students (at the time of their first CAP lecture) at seven German medical schools. The students completed an anonymous self-report questionnaire, asking about their attitude toward CAP and their view of CAP as a possible career choice. RESULTS: Of the 574 students, 42.9% had "high" or "very high" interest in CAP, and 59.4% rated CAP basic knowledge as "highly" or "very highly" relevant for their prospective work as physicians. CAP was a possible career choice for 25.4%. The most frequently mentioned reasons for choosing CAP were interesting clinical cases (65.8%), helping ill children (52.1%), and close patient-physician contact (50.7%). The most frequently mentioned reasons against this decision were a definite decision for another subspecialty (54.8%), expected difficulties in working with parents and family members (35.3%), and an expected high emotional burden (29.6%). In addition to the highly significant correlation with general interest in CAP, students with previous experience in general psychiatry and CAP clinical courses, as well as female students and students with relatives or acquaintances with CAP-related disorders, showed the highest interest in CAP as a possible career choice. CONCLUSION: The majority of the students surveyed showed a positive attitude toward CAP and considered CAP basic knowledge to be relevant for their future work. When designing recruitment strategies, it may be helpful to consider that CAP exposure early in the curriculum might be decisive and that students with previous clinical courses in this field, as well as female students, showed the highest interest in CAP as a possible career choice.

[What do medical students expect of lectures in child and adolescent psychiatry?]. / Was erwarten medizinstudierende von vorlesungen in der kinder- und jugendpsychiatrie?

OBJECTIVE: In child and adolescent psychiatry (CAP) lectures are the most common teaching format for medical students. Besides conveying basic knowledge and skills related to the medical management of children and adolescents with mental health problems, lectures also play a decisive role in the recruitment of future residents for this discipline. Thus, knowledge of the expectations of medical students of lectures is a crucial factor. METHOD: 1,029 medical students at ten German medical schools were surveyed with a questionnaire in a cross-sectional design. RESULTS: Items perceived as most important were knowledge of disorders (73 %), medical skills in handling children and adolescents (61 %), and differential diagnosis of normal and abnormal child behaviour in children and adolescents (59 %). 71 % set a high value on patient presentation, while 41 % expressed ethical concerns about presenting mentally ill minors in lectures. CONCLUSIONS: The expectations of medical students toward CAP lectures are mainly related to the transfer of specialty-related knowledge and generic skills. The important area of teaching attitudes could best be covered via patient presentations, which are desired by most students. However, ethical concerns over patient presentation also need to be discussed with students.

Implication of saturated fats in the aetiology of childhood attention deficit/hyperactivity disorder - A narrative review.

Attention Deficit/Hyperactivity Disorder (ADHD) is the most common mental health disorder in the paediatric population. ADHD is highly comorbid with obesity, and has also been associated with poor dietary patterns such as increased consumption of refined carbohydrates and saturated fats. Although ADHD in children was associated with high consumption of saturated fats, so far there has been no evidence-based attempt to integrate dietary strategies controlling for intake of saturated fats into the etiological framework of the disorder. Evidence from human studies and animal models has shown that diets high in saturated fats are detrimental for the development of dopaminergic neurocircuitries, synthesis of neurofactors (e.g. brain derived neurotrophic factor) and may promote brain inflammatory processes. Notably, animal models provide evidence that early life consumption of a high saturated fats diet may impair the development of central dopamine pathways. In the present paper, we review the impact of high saturated fats diets on neurobiological processes in human studies and animal models, and how these associations may be relevant to the neuropathophysiology of ADHD in children. The validation of this relationship and its underlying mechanisms through future investigative studies could have implications for the prevention or exacerbation of ADHD symptoms, improve the understanding of the pathogenesis of the disorder, and help design future dietary studies in patients with ADHD.

The Perth Gender Picture (PGP): Young people's feedback about acceptability and usefulness of a new pictorial and narrative approach to gender identity assessment and exploration.

BACKGROUND: A number of psychological assessment tools have been developed to describe various dimensions of gender. Some of these tools are restricted to a binary gender concept and are inflexible in reflecting how a young person's gender may change and develop over time. Most are text questionnaires which require a good level of literacy. AIMS: This study aimed to evaluate a newly developed pictorial tool that facilitates a conversation about gender between a child or adolescent (aged 11-18) and their clinician, enabling a diverse understanding and expression of gender identity. METHODS: The Perth Gender Picture (PGP) was co-created between clinicians and young clients between 2016 and 2018. In 2018, the measure was evaluated through a pilot study at the Gender Diversity Service at Perth Children's Hospital in Western Australia. After use of the PGP during a clinical consultation, clients were invited to fill in a feedback questionnaire about their experience of its use. Clinicians participated in unstructured interviews to give their feedback. RESULTS: Most participants rated the PGP as easy to understand, acceptable and useful, and many stated that they found gender easier to describe with the picture rather than words. The results show positive uptake from clients, demonstrating feasible implementation with gender diverse young people. DISCUSSION: This evaluation positions the PGP as a useful tool to facilitate conversations about gender identity between gender diverse children and adolescents and their clinicians, in a nonjudgmental and playful manner. It is well-suited to young people who may have limited literacy or difficulty with complex language. The PGP has potential for use in other age groups and non-clinical contexts.

Serotonergic neurotransmission and lapses of attention in children and adolescents with attention deficit hyperactivity disorder: availability of tryptophan influences attentional performance.

Deficiencies in serotonergic (5-HT) neurotransmission have frequently been linked to altered attention and memory processes. With attention deficit hyperactivity disorder (ADHD) being associated with impaired attention and working memory, this study investigated the effects of a diminished 5-HT turnover achieved by rapid tryptophan depletion (RTD) on attentional performance in children and adolescents with ADHD. Twenty-two male patients with ADHD (aged 9-15 yr) received the RTD procedure Moja-De and a tryptophan (Trp)-balanced placebo (Pla) in a randomized, double-blind, within-subject crossover design on two separate study days. Lapses of attention (LA) and phasic alertness (PA) were assessed within the test battery for attentional performance under depleted and sham-depleted conditions 120 (T1), 220 (T2) and 300 (T3) min after intake of RTD/Pla. At T1 there was a significant main effect for RTD, indicating more LA under intake of a Trp-balanced Pla compared to diminished 5-HT neurotransmission. For T2/T3 there were no such effects. PA was not affected by the factors RTD/Pla and time. Interactions of 5-HT with other neurotransmitters as possible underlying neurochemical processes could be subject to further investigations involving healthy controls as regards altered attentional performance in children and adolescents.

Social reinforcement can regulate localized brain activity.

Social learning is essential for adaptive behavior in humans. Neurofeedback based on functional magnetic resonance imaging (fMRI) trains control over localized brain activity. It can disentangle learning processes at the neural level and thus investigate the mechanisms of operant conditioning with explicit social reinforcers. In a pilot study, a computer-generated face provided a positive feedback (smiling) when activity in the anterior cingulate cortex (ACC) increased and gradually returned to a neutral expression when the activity dropped. One female volunteer without previous experience in fMRI underwent training based on a social reinforcer. Directly before and after the neurofeedback runs, neural responses to a cognitive interference task (Simon task) were recorded. We observed a significant increase in activity within ACC during the neurofeedback blocks, correspondent with the a-priori defined anatomical region of interest. In the course of the neurofeedback training, the subject learned to regulate ACC activity and could maintain the control even without direct feedback. Moreover, ACC was activated significantly stronger during Simon task after the neurofeedback training when compared to before. Localized brain activity can be controlled by social reward. The increased ACC activity transferred to a cognitive task with the potential to reduce cognitive interference. Systematic studies are required to explore long-term effects on social behavior and clinical applications.

Meta-analysis of the neural correlates of vigilant attention in children and adolescents.

Vigilant Attention (VA), defined as the ability to maintain attention to cognitively unchallenging activities over a prolonged period of time, is critical to support higher cognitive functions and many behaviours in our everyday life. Evidence has shown that VA rapidly improves throughout childhood and adolescence until young adulthood and tends to decline in older adulthood. Although neuroimaging studies have extensively investigated this cognitive function in adults, the neural correlates of VA in neurotypical children and adolescents remain unclear. The current meta-analysis reviewed and examined functional neuroimaging studies in paediatric populations that used behavioural tasks involving VA. The selected studies (N = 25) were analyzed using the activation likelihood estimation method. Findings showed convergence of activation in mainly right-lateralized brain areas, including dorsomedial frontal cortex and parieto-temporal areas, and are consistent with previous literature on the neural correlates of VA. Results are discussed in terms of their functional and developmental implications for VA in children and adolescents.

Attention deficit-hyperactivity disorder and early-onset bipolar disorder: two facets of one entity?

Early-onset bipolar disorder (BD) and attention-deficit-hyperactivity disorder (ADHD) have recently been the subject of highly controversial debate, due to theories regarding underlying pathophysiological processes and a clinical overlap of symptoms. Epidemiological data, clinical aspects neuroimaging, neurochemical, and genetic studies suggest that there may be a possible relationship between biological factors and clinical characteristics in the development of symptoms. However, longitudinal data supporting the hypothesis of a diagnostic shift from BD to ADHD symptoms and vice versa are currently not available. These would be essential to enable further investigations into whether these two disorders possibly represent two different aspects of an underlying common psychopathophysiological entity.

[Withdrawal syndrome after abuse of GHB (Gamma-Hydroxybutyrate) and its physiological precursors - its relevance for child and adolescent psychiatrists]. / Entzugsdelir nach Missbrauch von GHB-(Gamma-Hydroxybutyrat) und seiner Vorstufen: Grundlagen und Bedeutung für die Kinder- und Jugendpsychiatrie.

BACKGROUND: The chronic abuse of Gamma-Hydroxybutyrate (GHB) as a designer drug as well as it's physiological precursors Gamma-Butyrolactone (GBL) and 1,4-Butandiole (1,4-BD) confronts child and adolescent psychiatrists with new challenges. The acute withdrawal of GHB with its cardiovascular and delirant symptoms is of particular importance for child and adolescent psychiatrists. METHODS: In the present paper theoretical and biological aspects of acute GHB-/GBL-/1,4-BD-withdrawal syndrome are presented, and selected cases are discussed as regards potential treatment. RESULTS: High dose treatment with benzodiazepines was successful in some cases of acute GHB-/GBL-/1,4-BD-withdrawal syndrome. Complications were severe dystonia under neuroleptic treatment, and also side-effects of treatment with benzodiazepines. Further problems were vegetative symptoms, electrocardiographic changes, rhabdomyolysis, acute renal failure, and death. CONCLUSION: Acute GHB-withdrawal syndrome is a life-threatening condition which requires immediate intensive care treatment along with continuous monitoring of vital parameters. As acute GHB-withdrawal syndrome can present with symptoms close to psychotic episodes or acute alcohol withdrawal this condition is relevant for child and adolescent psychiatrists.

Correction to: Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks.

The article "Central serotonin modulates neural responses to virtual violent actions in emotion regulation networks", written by Dhana Wolf, Martin Klasen, Patrick Eisner, Florian D. Zepf, Mikhail Zvyagintsev, Nicola Palomero­Gallagher, René Weber, Albrecht Eisert, Klaus Mathiak was originally published electronically on the publisher's internet portal (currently SpringerLink) on June, 08, 2018 without open access.

Serotonergic Contributions to Human Brain Aggression Networks.

Aggressive behavior is associated with dysfunctional frontolimbic emotion regulation circuits. Recent findings suggest serotonin as a primary transmitter for prefrontal amygdala control. However, the association between serotonin levels, amygdala regulation, and aggression is still a matter of debate. Neurobehavioral models furthermore suggest a possible mediating influence of the monoamine oxidase A gene (MAOA) on this brain-behavior relationship, with carriers of low expressing allele varieties being a risk group for aggression. In the present study, we investigated the influence of brain serotonin modulation and MAOA genotype on functional amygdala connectivity during aggressive behavior. Modulation of serotonergic neurotransmission with acute tryptophan depletion (ATD) and placebo were administered in a double-blind, cross-over design in 38 healthy male participants. Aggressive behavior was modeled in a violent video game during simultaneous assessment of brain activation with functional magnetic resonance imaging (fMRI). Trait aggression was measured with the Buss-Perry Aggression Questionnaire (BP-AQ), and MAOA genotypes were assessed from blood samples. Voxel-wise functional connectivity with anatomically defined amygdala was calculated from the functional data. Tryptophan depletion with ATD reduced aggression-specific amygdala connectivity with bilateral supramarginal gyrus. Moreover, ATD impact was associated with trait aggression and MAOA genotype in prefrontal cortex regions. In summary, serotonergic corticolimbic projections contribute to aggressive behavior. Genotype-specific vulnerability of frontolimbic projections may underlie the elevated risk in low expressing allele carriers.

Acute Tryptophan Depletion Moja-De: A Method to Study Central Nervous Serotonin Function in Children and Adolescents.

Serotonin (5-HT) is widely implicated as a key neurotransmitter relevant to a range of psychiatric disorders and psychological processes. The role of central nervous 5-HT function underlying these processes can be examined through serotonergic challenge methodologies. Acute tryptophan depletion (ATD) is a key challenge method whereby a diminished dietary intake of tryptophan-the amino acid precursor to brain 5-HT synthesis-results in temporary diminished central nervous 5-HT synthesis. While this particular methodology has been used in adult populations, it was only recently that modifications were made to enable the use of ATD in child and adolescent populations. Additionally, the Moja-De modification of the ATD challenge methodology has demonstrated benefits over other ATD techniques used previously. The aim of this protocol paper is to describe the ATD Moja-De methodology in detail, its benefits, as well as studies that have been conducted to validate the procedure in child and adolescent samples. The ATD Moja-De protocol provides a potential methodology for investigating the role of central nervous 5-HT via manipulation of brain tryptophan availability in human psychopathology from a developmental viewpoint.