Brigitte Dahmen

A real-time fMRI-based spelling device immediately enabling robust motor-independent communication.

Human communication entirely depends on the functional integrity of the neuromuscular system. This is devastatingly illustrated in clinical conditions such as the so-called locked-in syndrome (LIS), in which severely motor-disabled patients become incapable to communicate naturally--while being fully conscious and awake. For the last 20 years, research on motor-independent communication has focused on developing brain-computer interfaces (BCIs) implementing neuroelectric signals for communication (e.g., [2-7]), and BCIs based on electroencephalography (EEG) have already been applied successfully to concerned patients. However, not all patients achieve proficiency in EEG-based BCI control. Thus, more recently, hemodynamic brain signals have also been explored for BCI purposes. Here, we introduce the first spelling device based on fMRI. By exploiting spatiotemporal characteristics of hemodynamic responses, evoked by performing differently timed mental imagery tasks, our novel letter encoding technique allows translating any freely chosen answer (letter-by-letter) into reliable and differentiable single-trial fMRI signals. Most importantly, automated letter decoding in real time enables back-and-forth communication within a single scanning session. Because the suggested spelling device requires only little effort and pretraining, it is immediately operational and possesses high potential for clinical applications, both in terms of diagnostics and establishing short-term communication with nonresponsive and severely motor-impaired patients.

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.

Neural Response to Social Rejection in Children With Early Separation Experiences

OBJECTIVE Nonhuman and human studies have documented the adverse effects of early life stress (ELS) on emotion regulation and underlying neural circuitry. Less is known about how these experiences shape social processes and neural circuitry. In this study, we thus investigated how ELS affects childrens perception of, and neural response to, negative social experiences in a social exclusion paradigm (Cyberball). METHOD Twenty-five foster or adopted children with ELS (age 10.6 ± 1.8 years, 13 male and 12 female) and 26 matched nonseparated controls (age 10.38 ± 1.7 years, 12 male and 14 female) took part in a Cyberball paradigm during functional magnetic resonance imaging (fMRI). RESULTS During peer rejection, children with ELS reported significantly more feelings of exclusion and frustration than nonseparated controls. On the neural level, children with ELS showed reduced activation in the dorsal anterior cingulate cortex (dACC) and dorsolateral prefrontal cortex (dlPFC), and reduced connectivity between dlPFC-dACC, areas previously implicated in affect regulation. Conversely, children with ELS showed increased neural activation in brain regions involved in memory, arousal, and threat-related processing (middle temporal gyrus, thalamus, ventral tegmental area) relative to controls during social exclusion. The number of separation experiences before entering the permanent family predicted reductions in fronto-cingulate recruitment. The relationship between early separations and self-reported exclusion was mediated by dlPFC activity. CONCLUSION The findings suggest that ELS leads to alterations in neural circuitry implicated in the regulation of socioemotional processes. This neural signature may underlie foster childrens differential reactivity to rejection in everyday life and could increase risk for developing affective disorders.

No effect of acute tryptophan depletion on verbal declarative memory in young persons with ADHD

Animal experiments and studies in adults have shown that the neurotransmitter serotonin (5‐HT) plays an important role in learning and memory processes. However, data on this relationship in young persons are scarce, and neurodietary research in this age group is limited compared with the extensive literature on adults. Here, we aimed to explore the effects of a diminished central nervous 5‐HT synthesis, which is achieved by acute tryptophan depletion (ATD) Moja‐De , on memory function in young males with attention deficit hyperactivity disorder (ADHD).

Early pathogenic care and the development of ADHD-like symptoms

Early pathogenic care that is characterised by disregard for the child’s basic emotional needs can lead to severe global psychosocial and cognitive dysfunction and deviant developmental trajectories of brain maturation. Reactive attachment disorder (RAD) is a developmental disorder associated with early pathogenic care that is characterised by markedly disturbed ways of relating socially in most contexts. In addition to other severe emotional dysfunctions, children suffering from RAD often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms such as inattention, impulsivity and hyperactivity. It is not yet clear whether ADHD-like symptoms in children exposed to pathogenic care represent a true comorbidity of ADHD or similarities in behavioural dysfunction with a different neurodevelopmental pathway in terms of a phenocopy. In this review, we summarise the findings on the neurobiological consequences of early pathogenic care. Pathogenic care is considered a form of care by a primary caretaker involving a lack or a loss of expectable care, e.g., by early separation, frequent change in caregivers, institutionalisation or neglect. The reviewed studies suggest that a primary dysfunction of limbic brain circuits after early pathogenic care might lead to an interference by motivational or emotional cues impinging on prefrontal executive functions resulting in behavioural similarities with ADHD. Thus, the complex phenotype observed after early pathogenic care might be best described by a dimensional approach with behavioural and neurobiological similarities to ADHD coinciding to a certain degree as a function of early experience. Based on this evidence, suggestions for the treatment of ADHD-like symptoms in children after adverse early life experiences are provided.

You are only coming through in waves: wakefulness variability and assessment in patients with impaired consciousness

The vegetative state (VS) is defined as a condition of wakefulness without awareness. Being awake and being asleep are two behavioral and physiological manifestations of the daily cycles of vigilance and metabolism. International guidelines for the diagnosis of VS propose that a patient fulfills criteria for wakefulness if he/she exhibits cycles of eye closure and eye opening giving the impression of a preserved sleep-wake cycle. We argue that these criteria are insufficient and we suggest guidelines to address wakefulness in a more comprehensive manner in this complex and heterogeneous group of patients. Four factors underlying wakefulness, as well as their interactions, are considered: arousal/responsiveness, circadian rhythms, sleep cycle, and homeostasis. The first refers to the arousability and capacity to, consciously or not, respond to external stimuli. The second deals with the circadian clock as a synchronizer of physiological functions to environmental cyclic changes. The third evaluates general sleep patterns, while homeostasis refers to the capacity of the body to regulate its internal state and maintain a stable condition. We present examples of reflex responses, activity rhythms, and electroencephalographic (EEG) measurements from patients with disorders of consciousness (DOC) to illustrate these factors of wakefulness. If properly assessed, they would help in the evaluation of consciousness by informing when and in which context the patient is likely to exhibit maximal responsiveness. This evaluation has the potential to improve diagnosis and treatment and may also add prognostic value to the multimodal assessment in DOC.

Altered brain network integrity after childhood maltreatment: a structural connectomic DTI-study

Childhood maltreatment is associated with alterations in neural architecture that potentially put these children at increased risk for psychopathology. Alterations in white matter (WM) tracts have been reported, however no study to date has investigated WM connectivity in brain networks in maltreated children to quantify global and local abnormalities through graph theoretical analyses of DTI data. We aimed for a multilevel investigation examining the DTI‐based structural connectome and its associations with basal cortisol levels of 25 children with documented maltreatment experiences before age 3, and 24 matched controls (age: 10.6 ± 1.75 years). On the global and lobar level, maltreated children showed significant reductions in global connectivity strength, local connectivity and increased path length, suggesting deviations from the small‐world network architecture previously associated with psychopathology. Reductions in global connectivity were associated with placement instability, attenuated cortisol secretion and higher levels of internalizing and externalizing behaviours. Regional measures revealed lower connectivity strength especially in regions within the ventromedial prefrontal cortex (vMPFC) in maltreated children. These findings show that childhood maltreatment is associated with systemic global neurodevelopmental alterations in WM networks next to regional alterations in areas involved in the regulation of affect. These alterations in WM organization could underlie global functional deficits and multi‐symptom patterns frequently observed in children with maltreatment experiences. Hum Brain Mapp 38:855–868, 2017.

Studying the effects of dietary body weight-adjusted acute tryptophan depletion on punishment-related behavioral inhibition

Background Alterations in serotonergic (5-HT) neurotransmission are thought to play a decisive role in affective disorders and impulse control. Objective This study aims to reproduce and extend previous findings on the effects of acute tryptophan depletion (ATD) and subsequently diminished central 5-HT synthesis in a reinforced categorization task using a refined body weight–adjusted depletion protocol. Design Twenty-four young healthy adults (12 females, mean age [SD]=25.3 [2.1] years) were subjected to a double-blind within-subject crossover design. Each subject was administered both an ATD challenge and a balanced amino acid load (BAL) in two separate sessions in randomized order. Punishment-related behavioral inhibition was assessed using a forced choice go/no-go task that incorporated a variable payoff schedule. Results Administration of ATD resulted in significant reductions in TRP measured in peripheral blood samples, indicating reductions of TRP influx across the blood–brain barrier and related brain 5-HT synthesis. Overall accuracy and response time performance were improved after ATD administration. The ability to adjust behavioral responses to aversive outcome magnitudes and behavioral adjustments following error contingent punishment remained intact after decreased brain 5-HT synthesis. A previously observed dissociation effect of ATD on punishment-induced inhibition was not observed. Conclusions Our results suggest that neurodietary challenges with ATD Moja–De have no detrimental effects on task performance and punishment-related inhibition in healthy adults.

Acute tryptophan depletion – converging evidence for decreasing central nervous serotonin synthesis in rodents and humans

We read the comment provided by Simon N. Young (1) on the articles (2–5) in the special issue of Acta Psychiatrica Scandinavica (6) dealing with the acute tryptophan depletion (ATD) methodology with great interest. ATD is a pharmacological method designed to lower central nervous system (CNS) synthesis of the neurotransmitter serotonin (5-HT) for a brief period that can also be used in both adults and young people (7). As 5-HT plays an important role in behavioral inhibition (8– 10) and other important processes in the brain (11–14), ATD is a translational method to study the effects of changes in CNS 5-HT function that has particular value, as discussed at a recent symposium dedicated to the role of 5-HT in psychopathology (7–11, 15). The author of this particular comment expressed concerns that ATD might not always decrease CNS 5-HT synthesis and that the lack of the amino acid histidine (HIS) in the depletion mixtures used might influence the results due to the potential role of 5-HT–histamine interactions in any observed outcome. We appreciate the comments made and would like to address the issues raised, point by point. Young argues that ‘there is no evidence that ATD does always decrease serotonin release (in humans)’. This is contradictory by decades of work in rodents and in humans demonstrating that ATD can decrease 5-HT synthesis and release in rodents and lower 5-HIAA in human CSF (16–19). In one of our laboratories, the acute tryptophan depletion (ATD) protocol termed ‘Moja-De’ has been shown to decrease 5-HT release in rodents (20, 21) and to lower tryptophan (TRP) comparably in humans (22), suggesting that this mixture successfully decreases 5-HT synthesis as postulated. While some experiments (23) fail to detect changes in central 5-HT function after ATD, this is the exception rather than the rule in published studies. The author of this comment was also concerned that there would be regional variations in the inhibition of serotonin function. This is logical and consistent with published data on the effects of Moja-De ATD in mice. Mouse studies indicated that depletion of TRP was comparable across different brain areas but that the extent of decrease in 5-HIAA varied by region (20, 21). Regional release of 5-HT is controlled by a combination of cell firing including regionally selective input, the concentration of 5-HT1b receptors on terminals, the amount of tryptophan hydroxylase, and many other factors (24). However, there is no evidence that 5-HT release happens only in selective regions, but we agree the magnitude of ATD effects on release is likely to vary between regions despite comparable depletion of TRP. As regards potential interactions between 5-HT and histamine, we agree that measurement of histidine after depletion of TRP or any other formula lacking HIS is of interest. Young has questioned the results of ATD experiments in which HIS was not included, stating that ‘histidine is an essential amino acid’. However, the essentiality of this amino acid is not clearly established (25). It has been reported that HIS was not necessary for the maintenance of nitrogen balances in short-term (26, 27). Kriengsunyos et al. (28) observed after a long-term histidine depletion administered to healthy adults that there were no effects on the protein metabolism (urinary nitrogen excretion and nitrogen balance). They suggested that the essentiality of this amino acid in healthy adults is still unclear as there are some components that may serve as sources of HIS, although the data they reported indicate that this amount may not be enough for maintain the HIS pool. The other concern expressed by Young was that effects of ATD could reflect disruption of a histamine–serotonin interaction, as ATD would cause a dramatic decrease in histamine synthesis. This is possible, as it is well established that the neurotransmitter histamine is formed from HIS (29), and histamine turnover seems to occur faster than other biogenic amines, such as norepinephrine or 5-HT (30). Therefore, in the absence of HIS, competition from the amino acid mixtures could indeed lower histamine production. However, neither the control nor the ATD mixture in most studies contains histidine, and so histamine would not be differentially affected by the ATD mixture, but should be comparably depleted in both control and ATD mixtures. Nevertheless, it is possible that some interaction between histamine depletion and 5-HT depletion could have behavioral effects. Unfortunately, no behavioral effects of histamine depletion have been clearly established in the literature. A study by Young and his collaborators of HIS depletion effects on sensory and motor behavior in healthy adults (31) showed that HIS in plasma decreased 20% and the ratio HIS/ΣLNAA decreased 59%, but there were no behavioral effects of this depletion. Finally, we disagree with the statement that ‘the relevance of such animal studies to the far more complex human brain is uncertain’. It is well known that validation of translational methods has allowed modeling many aspects of the neuropsychopathology with the use of appropriate animal models, the majority of them throughout the use of rodents (32, 33). Translation of behavioral findings is challenging, due to limits in extrapolating simple behavioral tasks in rodents to sophisticated behaviors in humans. However, biochemical studies of ATD effects in humans and rodents have shown considerable concordance. For example, our studies in humans (5, 22) have been validated in mice (20, 21), consistent with the field as described above (16–19). As Dr. Young points out, detailed anatomic studies of 5-HT synthesis in the human brain are technologically demanding and rarely conducted. However, the concordance between the dependent measures that can be collected in humans (CSF 5-HIAA for example) and comparable measures in rodents (tissue 5-HIAA content, 5-HT and 5-HIAA content in microdialysate) supports the concordance of findings after ATD in humans. In summary, there is convincing and converging evidence that ATD decreases 5-HT synthesis in the brain in both rodents and humans. Interactions between 5-HT and

[Adolescent parenting – developmental risks for the mother-child dyad].

Adolescent mothers and their children are exposed to multiple psychosocial risk factors and represent a high-risk group for adverse developmental outcomes. It is not the mothers young age alone which contributes to the developmental risk of the mother-child dyad. Rather, both the combination of risks, such as poverty, domestic violence, dysfunctional family relationships, or a psychiatric disorder, all of which predispose to adolescent pregnancy, as well as the strains of parenthood during the mothers own developmental stage add to the psychosocial risks of children of teenage mothers. Early motherhood can lead to lower levels of education and a lower socioeconomic status. In addition, there is a higher risk for psychopathology in both the teenage mother and her child. This article provides an overview of the current research findings regarding adolescent parenting and its associated risks. Risk factors leading to early motherhood are reviewed and associated with differences in parenting behaviors and the developmental outcomes of their children. This article will conclude with a short overview on intervention programs for adolescent mothers and their children. Further research is needed to develop age-appropriate support programs for adolescent mothers and their children to cope with the complexity of risks and improve their developmental trajectories.