T.J. Gaber

Effects of tryptophan depletion on reactive aggression and aggressive decision‐making in young people with ADHD

Kötting WF, Bubenzer S, Helmbold K, Eisert A, Gaber TJ, Zepf FD. Effects of tryptophan depletion on reactive aggression and aggressive decision‐making in young people with ADHD.

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.

Cognitive and neural strategies during control of the anterior cingulate cortex by fMRI neurofeedback in patients with schizophrenia

Cognitive functioning is impaired in patients with schizophrenia, leading to significant disabilities in everyday functioning. Its improvement is an important treatment target. Neurofeedback (NF) seems a promising method to address the neural dysfunctions underlying those cognitive impairments. The anterior cingulate cortex (ACC), a central hub for cognitive processing, is one of the brain regions known to be dysfunctional in schizophrenia. Here we conducted NF training based on real-time functional magnetic resonance imaging (fMRI) in patients with schizophrenia to enable them to control their ACC activity. Training was performed over 3 days in a group of 11 patients with schizophrenia and 11 healthy controls. Social feedback was provided in accordance with the evoked activity in the selected region of interest (ROI). Neural and cognitive strategies were examined off-line. Both groups learned to control the activity of their ACC but used different neural strategies: patients activated the dorsal and healthy controls the rostral subdivision. Patients mainly used imagination of music to elicit activity and the control group imagination of sports. In a stepwise regression analysis, the difference in neural control did not result from the differences in cognitive strategies but from diagnosis alone. Based on social reinforcers, patients with schizophrenia can learn to regulate localized brain activity. However, cognitive strategies and neural network location differ from healthy controls. These data emphasize that for therapeutic interventions in patients with schizophrenia compensatory strategies may emerge. Specific cognitive skills or specific dysfunctional networks should be addressed to train impaired skills. Social NF based on fMRI may be one method to accomplish precise learning targets.

Effects of serotonin depletion on punishment processing in the orbitofrontal and anterior cingulate cortices of healthy women

Diminished synthesis of the neurotransmitter serotonin (5-HT) has been linked to disrupted impulse control in aversive contexts. However, the neural correlates underlying a serotonergic modulation of female impulsivity remain unclear. The present study investigated punishment-induced inhibition in healthy young women. Eighteen healthy female subjects (aged 20-31) participated in a double-blinded, counterbalanced, placebo-controlled, within subjects, repeated measures study. They were assessed on two randomly assigned occasions that were controlled for menstrual cycle phase. In a randomized order, one day, acute tryptophan depletion (ATD) was used to reduce 5-HT synthesis in the brain. On the other day, participants received a tryptophan-balanced amino acid load (BAL) as a control condition. Three hours after administration of ATD/BAL, neural activity was recorded during a modified Go/No-Go task implementing reward or punishment processes using functional magnetic resonance imaging (fMRI). Neural activation during No-Go trials in punishment conditions after BAL versus ATD administration correlated positively with the magnitude of central 5-HT depletion in the ventral and subgenual anterior cingulate cortices (ACC). Furthermore, neural activation in the medial orbitofrontal cortex (mOFC) and the dorsal ACC correlated positively with trait impulsivity. The results indicate reduced neural sensitivity to punishment after short-term depletion of 5-HT in brain areas related to emotion regulation (subgenual ACC) increasing with depletion magnitude and in brain areas related to appraisal and expression of emotions (mOFC and dorsal ACC), increasing with trait impulsivity. This suggests a serotonergic modulation of neural circuits related to emotion regulation, impulsive behavior, and punishment processing in females.

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 reward improves the voluntary control over localized brain activity in fMRI-based neurofeedback training.

Neurofeedback (NF) based on real-time functional magnetic resonance imaging (rt-fMRI) allows voluntary regulation of the activity in a selected brain region. For the training of this regulation, a well-designed feedback system is required. Social reward may serve as an effective incentive in NF paradigms, but its efficiency has not yet been tested. Therefore, we developed a social reward NF paradigm and assessed it in comparison with a typical visual NF paradigm (moving bar). We trained twenty-four healthy participants, on three consecutive days, to control activation in dorsal anterior cingulate cortex (ACC) with fMRI-based NF. In the social feedback group, an avatar gradually smiled when ACC activity increased, whereas in the standard feedback group, a moving bar indicated the activation level. In order to assess a transfer of the NF training both groups were asked to up-regulate their brain activity without receiving feedback immediately before and after the NF training (pre- and post-test). Finally, the effect of the acquired NF training on ACC function was evaluated in a cognitive interference task (Simon task) during the pre- and post-test. Social reward led to stronger activity in the ACC and reward-related areas during the NF training when compared to standard feedback. After the training, both groups were able to regulate ACC without receiving feedback, with a trend for stronger responses in the social feedback group. Moreover, despite a lack of behavioral differences, significant higher ACC activations emerged in the cognitive interference task, reflecting a stronger generalization of the NF training on cognitive interference processing after social feedback. Social reward can increase self-regulation in fMRI-based NF and strengthen its effects on neural processing in related tasks, such as cognitive interference. A particular advantage of social feedback is that a direct external reward is provided as in natural social interactions, opening perspectives for implicit learning paradigms.

Amino acid challenge and depletion techniques in human functional neuroimaging studies: an overview

Imbalances of neurotransmitter systems, particularly serotonin (5-HT) and dopamine (DA), are known to play an essential role in many neuropsychiatric disorders. The transient manipulation of such systems through the alteration of their amino acid precursors is a well-known research tool. Among these methods are alterations of tryptophan, the essential amino acid (AA) precursor of 5-HT, as well as manipulations of tyrosine and phenylalanine, the AA precursors of DA, which can be metabolized into norepinephrine and subsequently into epinephrine. These systems can be loaded by applying a large dose of these AAs or depleted by applying an amino acid mixture lacking the respective AAs serving as precursors. Functional neuroimaging has given insights into differential brain activation patterns and functions depending on the tasks performed, pharmacological treatments or specific disorders. Such research has shed light on the function of many brain areas as well as their interactions. The combination of AA challenge approaches with neuroimaging techniques has been subject of numerous studies. Overall, the studies conducted in this particular field of research have shown that AA challenge techniques are valid and effective research tools that allow the investigation of serotonergic and dopaminergic systems without causing serious side effects or long-term damage to the subjects. In this review, we will present an overview of the results obtained so far and discuss the implications of these findings as well as open questions that remain to be answered.

Migration background and juvenile mental health:a descriptive retrospective analysis of diagnostic rates of psychiatric disorders in young people

Introduction This article presents diagnostic rates for specific mental disorders in a German pediatric inpatient population over a period of 20 years with respect to migration background and socioeconomic status (SES). Methods Diagnostic data were obtained over a period of 20 years from 8,904 patients who visited a child and adolescent psychiatry mental health service in Germany. Data from 5,985 diagnosed patients (ICD-9 and ICD-10 criteria) were included with respect to gender, migration background, and SES. Results Migration- and gender-specific effects were found for both periods of assessment. The group of boys with a migration background showed significantly higher rates of reactions to severe stress, adjustment disorders, and posttraumatic stress disorder compared to their male, non-migrant counterparts. Conversely, boys without a migration background showed a significantly higher percentage rate of hyperkinetic disorders than male migrants. Similar results were found for female migrants in the latter assessment period (ICD-10). In addition, female migrants showed lower rates of emotional disorders whose onset occurs in childhood compared to their non-migrant counterparts. Conclusions Data from this investigation provide preliminary evidence that the prevalence of various psychiatric disorders in children and adolescents is influenced by migration background and SES.Introduction This article presents diagnostic rates for specific mental disorders in a German pediatric inpatient population over a period of 20 years with respect to migration background and socioeconomic status (SES). Methods Diagnostic data were obtained over a period of 20 years from 8,904 patients who visited a child and adolescent psychiatry mental health service in Germany. Data from 5,985 diagnosed patients (ICD-9 and ICD-10 criteria) were included with respect to gender, migration background, and SES. Results Migration- and gender-specific effects were found for both periods of assessment. The group of boys with a migration background showed significantly higher rates of reactions to severe stress, adjustment disorders, and posttraumatic stress disorder compared to their male, non-migrant counterparts. Conversely, boys without a migration background showed a significantly higher percentage rate of hyperkinetic disorders than male migrants. Similar results were found for female migrants in the latter assessment period (ICD-10). In addition, female migrants showed lower rates of emotional disorders whose onset occurs in childhood compared to their non-migrant counterparts. Conclusions Data from this investigation provide preliminary evidence that the prevalence of various psychiatric disorders in children and adolescents is influenced by migration background and SES.

Neural correlates of reactive aggression in children with attention-deficit/hyperactivity disorder and comorbid disruptive behaviour disorders

Attention deficit hyperactivity disorder (ADHD) is often linked with impulsive and aggressive behaviour, indexed by high comorbidity rates between ADHD and disruptive behaviour disorders (DBD). The present study aimed to investigate underlying neural activity of reactive aggression in children with ADHD and comorbid DBD using functional neuroimaging techniques (fMRI).

Effects of dietary tryptophan and phenylalanine-tyrosine depletion on phasic alertness in healthy adults - A pilot study

Background The synthesis of the neurotransmitters serotonin (5-HT) and dopamine (DA) in the brain can be directly altered by dietary manipulation of their relevant precursor amino acids (AA). There is evidence that altered serotonergic and dopaminergic neurotransmission are both associated with impaired attentional control. Specifically, phasic alertness is one specific aspect of attention that has been linked to changes in 5-HT and DA availability in different neurocircuitries related to attentional processes. The present study investigated the impact of short-term reductions in central nervous system 5-HT and DA synthesis, which was achieved by dietary depletion of the relevant precursor AA, on phasic alertness in healthy adult volunteers; body weight–adapted dietary tryptophan and phenylalanine–tyrosine depletion (PTD) techniques were used. Methods The study employed a double-blind between-subject design. Fifty healthy male and female subjects were allocated to three groups in a randomized and counterbalanced manner and received three different dietary challenge conditions: acute tryptophan depletion (ATD, for the depletion of 5-HT; N=16), PTD (for the depletion of DA; N=17), and a balanced AA load (BAL; N=17), which served as a control condition. Three hours after challenge intake (ATD/PTD/BAL), phasic alertness was assessed using a standardized test battery for attentional performance (TAP). Blood samples for AA level analyses were obtained at baseline and 360 min after the challenge intake. Results Overall, there were no significant differences in phasic alertness for the different challenge conditions. Regarding PTD administration, a positive correlation between the reaction times and the DA-related depletion magnitude was detected via the lower plasma tyrosine levels and the slow reaction times of the first run of the task. In contrast, higher tryptophan concentrations were associated with slower reaction times in the fourth run of the task in the same challenge group. Conclusion The present study is the first to demonstrate preliminary data that support an association between decreased central nervous system DA synthesis, which was achieved by dietary depletion strategies, and slower reaction times in specific runs of a task designed to assess phasic alertness in healthy adult volunteers; these findings are consistent with previous evidence that links phasic alertness with dopaminergic neurotransmission. A lack of significant differences between the three groups could be due to compensatory mechanisms and the limited sample size, as well as the dietary challenge procedures administered to healthy participants and the strict exclusion criteria used. The potential underlying neurochemical processes related to phasic alertness should be the subject of further investigations.